A very long and detailed clinical evaluation of the use of Chinese herbs to mitigate toxic effects of infections.
My question is, "Do Lyme or Babesia or the other tickborne coinfections produce endotoxins?" Is that really what causes a herx?
Hubby did have one expensive test done once that showed elevated levels of endotoxins. At the time he also had elevated antibodies to Klebsiella and some other pathogenic G.I. bacteria which were believed to be the cause of his elevated blood ammonia and symptoms of hepatic encephalopathy.
Hubby did not use the Lactulose (prescription med for elevated ammonia) but I sure wish we had had the "Medicine to Subdue Toxic Heat" -- said to be 263 times more effective!!!
This was a couple of months after his IV Rocephin -- now I am curious as to what really produced those endotoxins -- he was on no antibiotics at the time of the test and had not been for a month or two.
Summary:
Bile supplements (listed here as Bear gall) look to be beneficial -- have always seemed to help hubby with fat digestion anyway. Haven't tried any of the other herbs mentioned yet. Looks like Ginseng is a good herb choice as it helps mitigate toxins by its effect on the immune system (RES). Also looks like Rhubarb (herb) is useful as well -- did help when hubby was treating for parasites.
Research Progress in the Prevention and the Treatment for Endotoxic Diseases with Traditional Chinese Medicine (TCM)
by Deng Wenlong Sichuan Provincial Institute of Chinese Materia Medica
(Proceedings of TCM Conference at West China University of Medical Science 1995)
The term "pathogenic toxin" refers to a special pathogenic factor in the theory of etiology of TCM, which is either included in the six exogenous causes of disease - wind, cold, summer heat, dampness, and fire, or dissociates itself from them. The concept of "toxin" may trace back to text Jinguiyaolue (Synopsis of Prescriptions from the Golden Chamber), which stated "diseases caused by Yang- toxin have the symptoms of flushed face with brocaded veins, sore throat, vomiting, blood, and pus."
The term "pathogenic toxin" was widely used after the time of the Jin and Yuan dynasties. Up till now, this term has had very broad connotations, but it mainly refers to the pathogenic factors which cause acute contagious and infectious diseases and their complications.
In this article we will attempt to show that the characteristics of the pathogenicity of endotoxin--chemicals released into the host from the breakdown of the cell walls of gram-negative organisms--accords closely with that of the "pathogenic toxins" in TCM, and that TCM treatments can improve the clinical course of febrile disease by reducing endotoxin in infected hosts.
The TCM differentiation of endotoxic diseases are usually placed in the category of febrile diseases caused by toxins. Endotoxic diseases not in the category of febrile disease have the signs of toxic heat directly invading Ying and Xue level (stages in the progression of infectious disease according to TCM).
For instance, septicemia is caused by toxic heat; acute pneumonic failure is caused by retention of toxic heat, dampness, and blood stasis in the lung; acute hepatic failure is caused by the movement of toxic heat and the accumulation of damp heat in the liver; acute disseminated intravascular coagulation is caused by excessive toxic heat invading Ying and Xue level,etc.
Abundant clinical tests show that the tendency and prognosis of the above diseases is closely related to the content of endotoxin in the blood, so much so that the content of endotoxin in the blood by itself can serve as a single index for the prognosis of diseases.
We have studied the significance of endotoxins in clinical and experimental febrile diseases systematically by using the Limulus test to determine the content of endotoxin in the blood of many kinds of febrile diseases (such as high fever caused by respiratory tract infection, pulmonary infection, biliary tract infection, septicemia, acute hepatic diseases, shock, etc.). The results show that the content of endotoxin in blood in most of thesediseases is high.
For instance, more than half of the patients suffering from infection with gram-negative bacteria have positive test results for the presence of endotoxin in their blood. One third of patients suffering from infections from gram-positive bacteria and virus have endotoxin measures in their blood of more than 50pg/ml.
Dynamic observation shows that the patients' clinical condition is closely related to the content of endotoxin in their blood. This indicates that endotoxin it not only the main pathogenic factor of infection from gram-negative bacteria, but also a factor which causes deterioration in the state of those infected by virus and gram-positive bacteria. In terms of infection by virus and gram-positive bacteria, the endotoxin in the blood comes from the "endotoxin pool" in the intestines.
W have studied the action of endotoxin in experimentally induced febrile diseases. By applying different dosages of endotoxin to rabbits through intravenous injection, we could duplicate the experimental febrile diseases which have the characters of the full course of Wei, Qi, Ying, Xue phases. Their appearances and objective tests of the animals are in full accord with the patients suffering from febrile diseases.
Effective therapeutic methods utilizing herbs and formulas for the treatment of febrile disease in practice have obvious curative effect, and the same methods show similar therapeutic effect for the treatment of experimentally induced febrile disease.
For instance, using the methods of "clearing heat and detoxification" can markedly control the syndrome of excessive heat in Qi level manifested as high fever; using the method of "clearing heat and detoxification," or "cooling blood and removing blood stasis" can remarkably improve the syndrome excessive heat at the Ying and Xue level with severe weakness and fever.
The TCM Treatment for Endotoxic Diseases
A) Clearing heat and detoxifying, B) tonifying Qi and detoxifying, C) and cleansing the viscera and purging toxins
are the three main therapeutic methods employed by TCM to prevent and treat endotoxic diseases.
A) Clearing Heat and Detoxifying
Research has found that many herbs that clear heat have anti- endotoxin activity. These herbs can either inactivate endotoxin directly or antagonize the actions of endotoxin, such as fever, inflammation etc. These herbs include
Coptis root (Huang lian) Dandelion herb (Pugongying), Pulsatilla root(Bai tou weng), Green chiretta (Chuan xin lian), Chinese Gentian ( Long dancao), Forsythia fruit (Lian qiao) , Honeysuckle flower (Ji yin hua), Moutan bark (Mudan pi), Ox gallstone (Niu huang), Scutellaria root (Huang qin), Scrophularia (Xuanshen ), Patrinia herb ( Baijiangcao ), Isatis root(Banlangen) , lsatis leaf (Da qing ye), etc.
Applicable formulas include
White Tiger Decoction (Bai hu Tang), Antipyretic and Antitoxic Decoction(Qing wen Bai du Yin), Pill of Six Ingredients with Magical Effects (Liu shenWan), Decoction of Gentian for Purging the Liver (Long dan Xie gan Tang), Decoction for Detoxifying and Removing Blood Stasis (Jie du Hua yu Tang), Decoction of Pulsatilla Root combination (Bai tou wen Tang), etc.
According to the heterogeneity of endotoxin and its unparalleled character of biological activities, and according to the characteristics of traditional Chinese herbs, we've designed a research system to act directly against the action of endotoxin.
For example, after culture in vitro, we use the Limulus test or the rabbit pyrogenic test to determine the change of the toxicity of endotoxin, and use the lowest effective concentration of drugs as the pharmacodynamic index.
The change of the active groups of endotoxin molecules as determined by chemical methods is taken as evidence of anti - endotoxic function. The disappearance of the antigenicity of endotoxin under the influence of traditional Chinese herbs serves as the counterevidence of anti-endotoxic action. In this way the anti-endotoxic action of herbs is determined.
Then the herb's action on the signs of fever, shock, death of rabbit or mouse caused by the attack of endotoxin after using drugs through injection or oral administration is used as evidence of the drug's practical use in the clinic. The test of the herb's sensitive spectrum against endotoxin from various bacteria is taken as a determinant of possible value in clinical practice.
Based on the above systematic mode, the direct anti-endotoxic function of more than 100 traditional Chinese herbs, formulae and their chemical components were examined. The result shows that traditional anti-endotoxin herbs, such as
Akebia (Zi cao) , Moutan bark (Mu dan pi) Honeysuckle flower(Jin yin hua), Sophora root (Ku shen), Forsythia fruit (Lian qiao), Toad venom ( Can su), Bear gall ( Xiong dan), Scutellaria root (Huang qin), Formula to Clear Toxic Heat ( Redu qing), Formula to Detoxify the Viscera(Jie du tong fi Fang)etc.
are all of value.
We've gotten a monomer from the most effective formula by analyzing its ingredients and chemical components. Under the influence of this monomer, the ultrastructure of endotoxin underwent expansion, breaking and disintegration. The toxicity and antigenicity of endotoxin then became weak and then disappeared.
The minimal concentration of the monomer to detoxify the endotoxin from 5 kinds of bacteria sources is 0.012 - imp/ml. It has obvious protective action when it is applied through intravenous injection or oral administration to high fever of rabbit or death of mouse caused by endotoxin.
The above researches provide not only the experimental basis for the method of clearing heat and detoxifying which can act directly against the toxicity of endotoxin and inactivate the endotoxin, but also gives direct evidence of the material basis for this therapeutic method of action against endotoxin.
In clinical practice, the therapeutic methods of clearing heat and detoxifying to treat acute infectious endotoxic diseases are quite good. For instance, using a Formula to Clear Toxic Heat (Redu qing) to treat 282 patients with acute infection, the effective rate is 85.8%
The Formula to Detoxify and Remove Stasis (Jie du hua yu Fang) can obviously decrease the concentration of endotoxin in blood of patients and improve the symptoms of febrile diseases significantly.
The Formula to Clear Heat from Ying Level(Liang ying tou re Fang) can lower the temperature of the patients with high fever caused by febrile diseases of the Ying level, and make the presence of endotoxin in blood become negative.
Injection of Forsythia fruit can obviously decrease the temperature and concentration of endotoxin in blood of the patients with high fever caused by trauma together with serious infection and presence of endotoxin in blood.
We've developed a new kind of patent medicine called 'Redu ping" (medicine to Subdue Toxic Heat) mainly used on the method of clearing heat and detoxifying. Its anti-endotoxic function in vitro is 263 times that of lactulose, it is similar to polymyxin B.
Through oral administration it can significantly protect against the death of mice caused by endotoxin or aminogalactose or sensitization of actinomycin O. It can also act obviously against the fever caused by endotoxin and tumor necrotic factor (TNF).
In clinical practice, it has been used to treat 51 patients with high fever caused by the presence of endotoxin in blood . The therapeutic effectiveness is quite good because it can promptly decrease the concentration of endotoxin in blood, and let the body temperature become normal within 36.1 hours.
B) Tonifying Qi and Detoxifying
This method refers to increasing the ability of the body to eliminate pathogenic toxins by using herbs and formulas that tonify Qi and strengthen the body resistance. It originates from Niejing, which records that "The organism is not disturbed by harmful environmental agents when vital energy is sufficiently strong". This aphorism sets the stage for our research on the Qi tonifying and detoxifying herbs and formulas which can increase the body' s homeostasis function, especially the function of immune system in the aspects of modern pharmacology of TCM.
It seems likely that increasing the phagocytic activity of reticuloendothelial system (RES) may increase the ability of the body to eliminate endotoxin, because the endotoxin in blood is mainly eliminated by the phagocytic function of mononuclear macrophages(which are the first barrier of immune system) and EJECTED THROUGH THE BILIARY TRACT.
Thus, we designed the following experimental procedures to research the function of herbs in these respects;
1) Using the ability of the herb or herbal compound to increase the phagocytic activity of RES as the chief condition;
2) Using a measure of the protective effects against such toxic actions as shock or death of experimental animals caused by endotoxin as the pharmacodynamic index;
3)Taking the non-specific function of anti -command anti-infection as counterevidence.
Practical methods included:
1) Observing the influence on the phagocytic function of RES in swallowing three kinds of foreign bodies (inert carbon, 32P marked staphylococcus and number 32P chicken erythrocytic) by applying drugs to various kinds of animals such as mice hamsters, guinea pigs and rabbits.
2) Observing the influence on the shock and death of mice and hamsters caused by the attack of endotoxin, the fever of guinea pigs and rabbits or the drop of temperature of hamsters caused by endotoxin, and peripheral changes in white blood cells and diarrhea of mice caused by endotoxin.
3) Observing the protective action against superior mesenteric artery occlusion shock and venous infection of gram-positive and gram -negative bacteria of mice.
We carried out systematic research on more than 200 formulas, herbs, herbal chemical components and their derivatives based on the above research protocols . The result shows that formulas and herbs that tonify Qi and strengthen body resistance can significantly reinforce the phagocytic function of RES.
For instance, such herbs and formulas as
Ginseng (Ren shen), Pilose asiabell root (Dang shen), Astragalus root (Huang qi), polysaccharidum versicolor (Yun zhi) , White Jelly Fungus (Yi ner), Wulingshen and Pulse-activating Injection(Ginseng, Ophiopogon root,Schizandra fruit), injection of Ginseng and Ophiopogon, injection of Ginseng and prepared Aconite Root, Protecting Vital Qi Decoction (Bao yuan tang),etc.
all have the ability to increase the phagocytic index of RES 2-5 times, thus accelerating the clearance of endotoxin from the blood stream. The experimental animals to which the above medicines have been administered showed obvious resistance against fever, change of white blood cells, diarrhea, shock and death caused by the attack of endotoxin.
In addition, RES has strong phagocytic action against the pathogenic microorganisms (which are the source of endotoxin) as well as the pathologic biochemical by-products such as the by-products of coagulation and fibrinolytics, alexinic fragments, and immunocomplexes triggered by endotoxin inside the body.
Therefore, it is clear that the herbs and herbal formulas should have the action against non-specific infection and shock by virtue of their reinforcement of the function of RES.
This has been shown by our experiments that demonstrate that the three medicines
Pulse- activating injection, Ginseng, and Polysaccharidum versicolor
all have obvious protective action against the death of mice caused by infection of gram-negative and gram positive bacteria, and can prevent the rise of the content of endotoxin in blood and can lower the death rate in the disease of superior mesenteric artery occlusion shock of hamsters.
Moreover, the state and tendency of illness of endotoxic diseases with deficient vital Qi is closely related to the function of the mononuclear macrophage. For example, the recovery from various acute infections and septicemia depends on the RES's elimination of both the pathogenic microorganism and its toxic by-products in the blood stream.
The occurrence and development of DIC has a close relation to the Reuse's incomplete elimination of the by-products of coagulation and fibrinolytics in the blood stream, and RES failure is the cause of death in acute DIC. The occurrence of intractable shock also is related to the failure of RES.
Therefore, resuscitating the RES is the key for intractable shock to transform into reversible shock. Death from severe hepatitis and multiple system organ failure( MSOF) is likewise caused by RES failure. It is thus clear that using the formulas and herbs which tonify Qi and strengthen body resistance to reinforce the RES activity is another main therapeutic method to treat endotoxic diseases.
In clinic practice, Pulse Activating injection has a good therapeutic track record in the treatment of toxic shock, such as severe pneumonic shock, biliary shock, epidemic hemorrhagic fever and hemorrhagic shock caused by infection.
The injection can alleviate toxemia, raise the blood pressure and improve the general condition of the patients. Using Western medicine alone to treat shock, the death rate is 12.2 % while using the combination of Western medicine and Pulse-activating injection, the death rate is 4.2% .
In the treatment of infectious toxic shock (52 cases) by using the injection of Ginseng and Ophiopogon, the restoration of optimal blood pressure and the correction rate of shock are much better than in the control group treated by Western medicine.
The injections of Ginseng and Prepared Aconite Root, Shenfuqing, etc. all have the ingredient Ginseng, which can strongly increase the ability of the RES to eliminate the endotoxin inside the body. Therefore, it has obvious therapeutic effect in the treatment of various kinds of acute, chronic hepatic injury. It is thus evident that tonifying the Qi and Detoxifying is an effective method of TCM for treating endotoxic diseases.
C) Cleansing the Viscera and Purging Toxins
There exist a large amount of gram-negative bacteria in the intestines. When the body faces stress conditions such as high fever, blood loss, burns, or severe trauma, it will result in serious abnormal fermentation in the intestines, thus producing a large amount of endotoxin.
The change in the permeability of the walls of the intestine caused by lack of oxygen and blood supply will lead to the absorption of large amounts of endotoxin into the blood. This is not only the main reason that gram-negative infections cause high content of endotoxin in blood, but also the most important reason for sudden endotoxic shock in various kinds of acute abdominal and intestinal operations.
In clinical practice, the content of endotoxin increased obviously in the blood of patients with "Syndrome of Yang Ming Bowel Organs." Therefore, purgative herbs are used to get rid of the intestinal endotoxin pool, improve blood circulation, restore the barrier action of the enteric membrane, and reduce the absorption of enterogenous endotoxin.
Experiments showed that the
herb Rhubarb
and the formula Drastic Purgative Decoction (Rhubarb, Glauber's salt, Magnolia bark, and Immature Bitter Orange)
have the above function, because of their strong purgative and anti -bacterial action. Rhubarb and its formulas can treat experimental fever effectively and quickly.
In clinical practice, the method of purging off the toxins of the intestines is applied to treat acute hemorrhagic necrotic pancreatitis, intestinal obstruction, enterogenous shock, severe hepatitis, epidemic hemorrhagic fever, acute renal failure and acute respiratory disease (ARD).
For instance, Decoction to Purge the Heat (Rhubarb, Glauber's salt, Scrophularia, Licorice), when it is used to treat adult pneumonia, can achieve full antipyretic function within 24-72 hours, and lower the content of endotoxin in blood.
Research shows that Rhubarb doesn't have direct anti -endotoxic function, but it has a good therapeutic and preventive action against enterogenous endotoxin in blood. The therapeutic mechanism is that Rhubarb can prevent enterogenous endotoxin from entering the bloodstream.
Serving as antagonists against endotoxin, Rhubarb is completely different from lactulose. The method of purging off toxins in the intestines to treat enterogenous endotoxic disease therefore has a much broader meaning than the simple laxative function as understood by modern medicine.
From planetherbs.com
[ 16. November 2006, 04:22 PM: Message edited by: seibertneurolyme ]
Posted by clairenotes (Member # 10392) on :
Bea,
This is a really useful article/resource! I still need to go back and read it again because there is a lot of information to absorb.
I have been trying to understand the role of endotoxins in this illness, especially lately, and I don't think it is talked about enough or that it's importance is recognized. If we had a better understanding, we might know how to better deal with some of the herxing that endotoxins might contribute to, and/or speed the healing process, especially after 'die-offs.'
I think it is interesting that there was a connection between your husband's parasite issue and the endotoxins.
One time I took some ozonated water and suddenly I was stricken with inflammation and dehydration. After much research, I am starting to conclude that it had to do with a sudden and strong parasitic 'die off' and consequent endotoxins. It took months to clear. Just didn't understand, at all, what was going on! Endotoxins came up consistently during this period in bioresonant testing, but didn't know what to do about them. This occurred on a smaller scale with ozonated oil.
Since I am continuing to go after any and all unfriendly microbes (gram negative) etc., maybe it is important to have some of the chinese herbs mentioned, on hand.
Thanks so much for posting this.
Claire Posted by seibertneurolyme (Member # 6416) on :
Claire,
Glad you found the post of interest. I went back and cleaned it up a little and did some highlighting.
Hubby has had primarily G.I. and neuro symptoms and is currently off all antibiotics (continues with some herbs and other alternative treatments). Have been trying to heal gastritis and superficial gastric ulcers for over 4 months now.
I plan to order a few of the specific Chinese herbs mentioned as so far it has been a very much up and down struggle to heal his G.I. Will post back later as to how things work out.
Bea Seibert
Posted by seibertneurolyme (Member # 6416) on :
up
Posted by Marnie (Member # 773) on :
Bb does not have an endotoxin.
You'd know it right away if a pathogen has an endotoxin!
These kill fast.
Bb's outer wall is so much like our own cell walls...which IS a huge problem.
I think it is Hg (bound to choline) and Mn released when Bb is destroyed (via calprotectin in our neutrophils that binds Zn) that is triggering the "herxes".
Hg and high levels of Mn are toxic.
These metals maybe triggering TNF alpha ...causing it to "spike" = OUCH!
To remove Hg...additional choline might work.
To (dissolve, not displace) Mn...research CoQ10.
Find Parkinson's doses.
Be careful "purging the intestines". You will go downhill FAST. We MUST have beneficial bacteria in our gut to absorb and make nutrients for us...without those nutrients, no hormones, no enzymes, no antibodies, no neurotransmitters. Aren't abx. destroying the beneficial bacteria and thus releasing their "endotoxins" as their cell walls are destroyed?
Posted by clairenotes (Member # 10392) on :
Marnie,
I am not sure exactly what is happening with Bea's husband and the endotoxin issue, nor do I really understand my own case, but I do know this for sure...
Last December, I was doing really well until I drank several glasses of ozonated water and suddenly there was an extreme reaction of some sort. A bio-resonance test picked up endotoxins, which had not existed previously (I test frequently). This continued for months before I could get them to clear.
Perhaps the endotoxins were not from Bb but from other gram negative pathogen/s or parasites? The lymephotos people say that Bb has two components, i.e., the borrelia bacteria and a nematode, a parasite (this does not include co-infections). Have been working on the parasite side of the equation more lately.
I think an endotoxin is a fragment of a cell-wall that has combined with a lipoprotein (?).
Anyway... I would sure like to know what is happening in these die-off reactions, and what exactly the toxins are that are being released. It seems that something is being released. I have known, even prior to learning about LD, that there was some sort of dance going on in my new bid to get well, of die-off and clean-up.
I don't know what Hg or Mn are. I don't know what TNF alpha is. Could you please explain what these stand for? Don't have a chemistry background.
By the way, even though I don't understand some of what you say... I really appreciate the info you provide. The science will sink in eventually, hopefully.
Also... wasn't there something about cell wall fragments and heart health that you responded to? Seems related. Maybe I should pull that topic up. But it too, was difficult to follow.
Claire Posted by treepatrol (Member # 4117) on :
Hey Bea I stuck this in Newbie Links.
Posted by nellypointis (Member # 1719) on :
Marnie,
I don't always read everything you write but I have read enough of your writings to understand that
a) you think abx are not the way to go, that they are dangerous b) that, basically, magnesium cures everything, as per a Rumanian study
Your mails are always fairly cryptic, like: "the answers are here, in my posts, but you're gonna have to work hard to get to the essence of my message".
Marnie, could I ask you to put us out of our miseries and state clearly once and for all what regimen you think would work for chronic Lyme and other tick-borne infections? (besides magnesium of course, which btw, I can't take because it invariably gives me diarrhea, all forms of magnesium, in even fairly small amounts)
Thanks
Nelly
Posted by Marnie (Member # 773) on :
Endotoxin definition:
A bacterial toxin composed of protein, lipid, and polysaccharides.
a lipopolysaccharide component of the membrane of gram-negative bacteria that is heat stable and toxic; a secreted toxin produced by bacteria is termed an "exotoxin"
TNF alpha is a proinflammatory cytokine. Hg is mercury. Mn is manganese.
Bea,
Continuous infusion of a nonlethal dose of Escherichia coli lipopolysaccharide (LPS) (0.5 mg/kg) induced early (3 h) accumulation of polymorphonuclear leukocytes (PMNL) in rat liver followed by later (30 h) greater extravasation of mononuclear phagocytes (MNP) (E. B. Rodriguez de Turco and J. A. Spitzer, J. Leukocyte Biol. 48:488-494, 1990).
E. coli is a normal bacteria in our intestines that abx. destroy.
Nelly...I HAVE stated exactly what I would do if I had lyme and I got BLASTED because I said I would NOT take antibiotics.
I respect YOUR RIGHT to take these and understand that they do indeed reduce inflammation and lessen the "ouch".
Which is why I support the "march".
I respect your RIGHT to be given the drugs that reduce inflammation and knock out co-infections.
I may not agree it is the best way to go, but I sure as heck hate to see another "free choice" taken away...esp. since nonstop abx. ARE used for other diseases.
Posted by TerryK (Member # 8552) on :
Very interesting discussion. Apparently neither syphillis or Bb release endotoxins but they may release an endotoxin-like material.
Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions M. W. Pound*� PharmD BCPS and D. B. May*� PharmD BCPS � Summary
Objective:�To review the aetiologies and preventative methods associated with Jarisch-Herxheimer reactions (JHR).
Data sources:�Ovid Medline� (1966-June Week 1 2004) was utilized to assess biomedical literature; a review of the bibliographies of articles was also performed.
Data synthesis:�JHR often occurs with the treatment of spirochete infections. However, the mechanism by which the reaction takes place is not clearly defined.
Conclusion:�Studies suggest with conflicting evidence that the JHR is caused by release of endotoxin-like material from the spirochete as well as cytokine elevation in the body. It appears the type of drug and the rate of spirochete clearance from the body have little effect on the incidence of the reaction. Many pretreatment options have been explored with limited efficacy with the exception of anti-tumour necrosis factor antibodies.
Since I started abx, I've needed many anti-inflammatory supplements/enzymes etc. via muscle testing so I figured inflammation was a big factor and this was confirmed at my recent LLMD appointment.
I asked why I have had swelling and soreness in my left knee and lots of cracking in my bones as well as sudden cramping in muscles since starting abx. I was told that when the bugs die, they cause inflammation. In some of the studies I've looked at, inflammation seems to be a big factor.
I was also told that metals and viruses are released when the bugs die. All things that are mentioned on this board repeatedly.
I've also been told that toxins are being released which is why I've been put on the actos/Questran therapy so it appears that some of the experts feel that toxins are being released.
Since most of us are burdened with many infections due to a suppressed immune system, it makes sense that abx may kill many other bugs besides Bb, including but not limited to tick co-infections. Perhaps some of those release endotoxins?
Then we have the release of viruses, and as is well known, most of us have many dormant viruses. This probably means that one or more could become active, making us feel bad. So even though our last testing for viruses may have shown that they were dormant, it could be that they are now active and playing a role in our reaction to abx.
Also, since our immune systems are weak, we may be prone to getting any bug that comes along, especially since our systems are so burdened when on treatment.
AND lets not forget the release of metals. Something else that can cause us to feel very ill.
AND then there is the fact that abx or other bug killing agents can cause or exacerbate a systemic yeast infection. Another horrible infection that causes tons of overlapping symptoms and is hard to get rid of.
AND there is always the possibility that we have a reaction to the abx/herb (or whatever we are using to kill bugs) itself which can cause symptoms that are hard to sort out.
There are likely other things that are part of the picture that are as yet to be discovered or that I don't know about or forgot to list.
Is it any wonder that we feel horrible when killing these bugs? Terry
[ 17. November 2006, 04:23 PM: Message edited by: TerryK ]
Posted by Marnie (Member # 773) on :
The immune system is not suppressed, it looks to be in HYPERdrive.
Slanted to the Th1 pathway. T-cells. Come from the thymus.
Th2 pathway kicks in if exposed to a virus. B cells. Come from the bone marrow.
We are supposed to be able to alternate between these pathways. Apparently both do not work simultaneously.
The body has to decide the biggest threat at the moment.
In 1986 we knew Bb had an endotoxin-LIKE reaction.
The toxins look to be Hg (bound to choline) and too much Mn released. Zinc too?
Zinc dissolves copper. (I'm in the process of transferring old files and am surprised to reread what I found about 4-5 years ago and now that I understand things better...not completely, but better, this all fits.)
We know, in lyme zinc is up and copper down. Apparently too much zinc. Must be in Bb's outer wall as calprotectin in neutrophils (most abundant WBC) binds to this.
Mg in high doses will DISPLACE, not dissolve, zinc.
CoQ10 (enzyme) in very high doses does dissolve Mn. Find Parkinson's dosages.
Hg binds to choline...
Soooooooo if you are going to try a far infrared sauna, it might be wise to have some choline and CoQ10 on hand prior. Perhaps?
What to do about excessive zinc?
Posted by TerryK (Member # 8552) on :
quote:The immune system is not suppressed, it looks to be in HYPERdrive.
I think the fact that CD-57 is typically low in chronic lyme is why Dr. B and others say that the immune system is suppressed. See page 8 under CD57. Dr. B specifically states that the immune system is suppressed. http://www.ilads.org/files/burrascano_0905.pdf
The immune system is certainly dysregulated. I've had periods of time when I caught everything that came along and other times when my immune system is overly responsive. I have a lot to learn about lyme and the immune system but I do think that the consensus is that the immune system is suppressed.
As far as zinc. I don't know technically what's going on with zinc and borrelia but via muscle tesitng I've needed both zinc and copper. I do believe that they need to be in balance with each other. Terry
Posted by Marnie (Member # 773) on :
CD 57 is a protein marker...an indication that your NK cell levels are low. NK are natural killer cells. They "squirt" precancerous cells with a free radical (neg. charge) to destroy them...at a rate of about 4 per day.
They ONLY FUNCTION IN AN ALKALINE ENVIRONMENT.
Acids downregulate other acids.
Lyme patients are in metabolic ACIDOSIS.
Normally acids, negative charges, destroy pathogens as well as cancerous cells.
Ideally we directly target them BECAUSE...acids, negative charges, also damage healthy cells and then cancer is triggered.
Cancer only happens in an ongoing acidic environment.
The Th1 pathway is upregulated.
Too much TNF alpha is present for many reasons which I have listed here numerous times. It becomes obvious when you see how "protective" this pro-inflammatory cytokine is.
But...too much is not good. It is a protein, an acid.
Humira (et al) blocks TNF alpha to a certain extent.
This, as well as abx. (to reduce inflammation)DOWNREGULATE the Th1 pathway.
If you look strictly at the antibodies...way too many are damaged and don't work. This is BECAUSE it takes enough Mg and Ca to make HEALTHY antibodies. Without enough of these minerals (Ca isn't a problem...we have a ton to spare and our diets are very high in this)the "fab" portion of the antibody to Bb is damaged. Restoring Mg and Ca levels restores the "health" of our OWN antibodies that we make specifically to eliminate Bb. That has been documented on pubmed.
The word antibiotic came from our knowledge of antibodies. We MAKE our own highly targeted "antibiotics" IF we have the nutrients to do so.
This PART of the immune system is kapoot...so another takes over.
Taking this another step...you take abx. and knock out a few of Bb's buddies as well as your own beneficial bacteria which release endotoxins.
Now, with the beneficial bacteria down, up goes yeast which bind zinc (Bb uses zinc) and lower cholesterol. Now you take something to rid the yeast and RELEASE zinc into the system. Bb is happy once again. Up goes the need for more WBCs neutrophils to bind that zinc.
Do you see this can become a vicious circle?
Posted by nellypointis (Member # 1719) on :
[QUOTE]Originally posted by Marnie: [QB] Nelly...I HAVE stated exactly what I would do if I had lyme and I got BLASTED because I said I would NOT take antibiotics.
Marnie,
I must've missed it, I keep reading your posts which are like biochem lectures (I am not saying they are not interesting, they are) but unlike you, I have Lyme and I can't read through loads and loads of stuff and even less follow things up by researching stuff in a more thorough fashion.
That's why I would greatly appreciate it if you stated clearly what you would do and what you would not do/not take if you had persisting Lyme of very long duration (plus other bacterial and/or other infections).
You say you wouldn't take abx, I certainly wouldn't BLAST you for saying this, I would be interested in what you would do INSTEAD.
May I say that you take it as an accepted fact that abx act because of some antiinflammatory effect. That has never been proven, just hypothesised and only for some macrolides. I also saw something on cyclines but it was totally unconvincing.
>I respect YOUR RIGHT to take these and >understand that they do indeed reduce >inflammation and lessen the "ouch".
Marnie, abx certainly don't reduce the "ouch" and in fact "ouch" is not my main problem (although I have some of that as well) I suffer INCREASED inflammation, increased "ouch" on the abx that seem to work.
I actually feel terrible whilst I am on them, especially initially, and then I gradually feel better, some symptoms improve (some not) but the BEST I feel is AFTER I stop abx (a week to 2-3 weeks after I have STOPPED taking them and before the infection has made a come back. So much for the abx as painkillers.
As for mag as a cure-all, a) I can't take it, it goes right through me, b)you only ever quoted those Rumanian studies where they cured one or two cases of Lyme of not very long standing.
I would really like to see in one place your suggestions (dos and don'ts) for people with chronic PERSISTING Lyme.
I, for one, can assure you I am genuinely interested in your opinion, just frustrated that your posts seem to leave out the final part of your reasoning, kind of "now you go home and work it out for yourselves".
Please, Marnie, give us the answer, and please take into account the fact that in most cases abx are not working because of some hypothesised antiinflammatory effect.
for eg: take magnesium (prefered form)as it will help your immune functioning
do not take zinc as it will ....
etc.
We are adults and we know you are only trying to think the whole mess through, and we now this is only your opinion not the word of God, so we can decide for ourselves what we should or shouldn't do, but it would be nice to have the benefit of all the thinking you have put into all this.
I appreciate that you are taking a keen interest in this whole Lyme business but I usually end up not reading your posts, too frustrating.
Nelly
Posted by Areneli (Member # 6740) on :
Bb HAS AN ENDOTOXIN.
No strong direct evidence for so far but several indirect are sufficient.
In support of endotoxin are: 1. Presence of Herxheimer’s reaction 2. Symptomatic help with factors that remove and bind bile (such as Cholestyramine) 3. Work of Dr Donta (he has found that part of Bb genome encodes something that is very close to botulinum neurotoxin)
Posted by bigmamma (Member # 7181) on :
I believe inhibitors of TNF include Boswellia, Quercetin, Cat's Claw, Turmeric, NAC (N-acetyl-cysteine).
check out salmon oil as and lyprinol as well.
Posted by clairenotes (Member # 10392) on :
So much to comment on...
First... this has been really helpful. I think I now understand what is being released in Bb die-offs, i.e., hg and mn, which causes or contributes to the inflammatory response. Other endotoxins from other bacterial die-offs, etc., may also be occuring, even from friendly bacteria. This may have occurred when I drank the ozone and why Bea's husband needs to be careful with intestinal issues.
But... if you believe what the lymephoto people say... (and I know that not everyone is familiar with their ideas, or in agreement with them), that there are two issues operating in Bb, the actual Bb bacterial and a nematode (a microfilarial worm), then there would also be some 'releases,' whether exotoxins or endotoxins, from this situation. I know that parasites are carriers of viruses and I have heard from this board, also carriers of metals.
From my own experience, I used a lot of anti-bacterial and anti-viral homeopathics during the initial stages (before I knew about LD), and now a moderate amount. Per bio-resonant testing my bacterial and viral loads were way down. When I introduced an anti-parasitic remedy, inflammation started to go up as did viral issues. I experienced a very different set of herx reactions when dealing with this... a new set of symptoms, especially strong headaches. Increased anti-virals and things normalized.
What we need to clean-up after the die-off always relates to what is being killed, so it is important to know what is being killed with our remedies/abx, to clear them.
Regarding immunity... I believe my immune system is suppressed, per bio-resonant testing, whereas my daughter's is hyper-active. She does not have classis LD symptoms, only some strong allergies, and some brain chemistry issues, i.e. hyper-reactive. Watching closely. But these observations are based on bio-resonant tests... not medical tests.
Anyway... all we need to take to clear Hg is choline? Thought it was a little more complicated.
Does far infrared sauna help when toxins are in brain?
Also... the mg/ca issue makes a lot of sense to me, and increasing it, even more important for people on abx. Still not sure about zinc. Do we try to lower it as much as possible to keep Bb weakened?
Other ideas about reducing inflammatory responses? Maybe the chinese herbs hold promise.
Claire
Posted by clairenotes (Member # 10392) on :
**** Just read Areneli's and Big Momma's posts. Had not seen them prior to my last post. I am now pondering their information.
Posted by Marnie (Member # 773) on :
Genetic research has shown us exactly what Bb is "made of".
Areneli, You state loud and clear: Bb HAS AN ENDOTOXIN.
Please LINK that information because my information/resources does NOT indicate that. It wouldn't be unusual for research to conflict. It does all the time.
Your reference to Dr. D...this will hit a nerve for many on this board.
The botulism anti-toxin is trivalent. It is very expensive.
There is a big difference between endotoxin and endotoxin-like.
Now...about Questran:
Pulling an old file,so some of the links may no longer work, but it was all a "cut and paste":
If the drug is taken for a long period of time, deficiencies of vitamins A, D, E, and K can result, and vitamin supplements may be necessary.
Interactions Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, phenobarbital, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, cephalexin, and metronidazole; thiazide diuretics; valproic acid; troglitazone; coadministration with pravastatin increases effects
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Documented hypersensitivity; caution in constipation and phenylketonuria; chronic use may lead to insufficiency of fat-soluble vitamins and contribute to bleeding.
Modern drugs used to lower cholesterol, all (or at least most) seem to have some risk of an adverse effect on muscles.
In its most extreme form this can result in enough muscle breakdown to cause a pronounced elevation of the CK level (muscle enzyme measured in the blood), weakness, and pain.
I have never seen anyone have a severe reaction, but I have seen patients who have had aches and felt a bit weak. The usual solution is to stop the drug and try to use more effective dietary measures.
Even drugs like Questran and niacin, which are not "statins," seem to have some risk of similar side effects.
Drugs that interfere with folic acid actually raise homocysteine levels including methotrexate, an immunosuppressive drug used to treat cancer, rheumatoid arthritis and psoriasis; the anticonvulsant drugs, phenytoin (Dilantin) and carbamazepine (Tegritol, Epitol); and the cholesterol lowering drugs, cholestipol (Colestid) and
cholestyramine (Questran).
Homocysteine can be easily and inexpensively lowered by supplementing with vitamins B-6, B-12, and folic acid.4
Other effects of cholestyramine were an ***increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine.
Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone.
A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.
PMID: 3987479
The production of CoQ10 in the body is a complex process. At least 15 different reactions are necessary (each catalyzed by an enzyme), as well as a number of cofactor substances including vitamins B3, B5, B6, B12, C, and folate.(4)
In spite of its complex manufacture, most CoQ10 is made within the body. There is good evidence, however, that dietary CoQ contributes significantly to the endogenous body-pool of CoQ10. This has been shown in patients receiving total parenteral nutrition (TPN) that contains no CoQ. In these patients, who are dependent totally on endogenous CoQ10 synthesis, CoQ10 levels dropped by almost 50% within 1 week on a diet free of CoQ.(5)
These levels remained depressed for the 12 weeks of the study. This represents good evidence that dietary sources are indeed a significant contributor to the body pool of CoQ10.
CoQ10 is the enzyme that carries hydrogen INTO the cells.
IMO, if you continue to deplete the available nutrients which are needed to make the neurotransmitters, all the proteins, hormones, enzymes, antibodies...you will be in a bigger mess.
nellypointis,
Actually Re: the anti-inflammatory effects of antibiotics ... under a heading titled: The fight for antibiotics that I posted a few days ago, I linked the PROOF...that is if you believe microbiologists in Europe who did the research.
...evidence of the augmentation of immune responses by tetracyclines...
This is the first study to show an effect of antibiotic therapy on cytokine levels in vivo. PMID: 8331300
Nelly, are you from France? Have you also explored the European Lyme boards? The strains of Bb in Europe are significantly different...at least they were. In Europe, lyme caused primarily neuro symptoms, while here it caused arthritic symptoms...not so long ago. But, I know...times have changed...and so has Bb. 53 strains now.
Claire, you are pretty on target with your views. Keep in mind, kids have much higher "stores" of Mg than we adults do...and many other factors come into play...her estrogen level to keep Ca in the bones, growth hormone, etc.
Children stand a better chance at recovery. Sorta "survival of the species". Lots of "built in" protective mechanisms at play. That's why they bounce back from colds, flu, etc. much faster than those of us with a few grey hairs.
I wrapped most links.
Posted by clairenotes (Member # 10392) on :
hmmmm...
I don't know anything about Dr. D, but I don't think we should discount anything. Botulism (sp) is not good.
Perhaps some experimentation with a homeopathic nosode for botulism introduced after Bb die-off? Not sure... just thinking out loud.
Posted by Areneli (Member # 6740) on :
Marnie, You don't because you are fixed on magnesium.
Anyway for you or anybody else who wants to know:
1999 LDF Conference Abstract -- New York City, NY 12th Annual International Conference on Lyme Borreliosis and Other Tick-borne Disorders Chronic Lyme Disease: Basic Science and Clinical Approaches Mark J. Cartwright, Ph.D. Boston University Medical Center Boston VA Medical Center 88 East Newton Street, E-639 Boston, MA 02118
A Novel Toxin (Bb Tox 1) of Borrelia burgdorferi Mark J. Cartwright, Ph.D.*, Suzanne E. Martin, Ph.D. and Sam T. Donta, M.D.
The mechanisms responsible for many of the symptoms of Lyme disease remain to be delineated. Because many of the symptoms involve the nervous system, we postulated that the Lyme spirochetes produce a toxin that interferes with normal neurophysiological function. We have identified and cloned a gene of B. burgdorferi which encodes a protein that is a neurotoxin.
Initially, degenerate primers were designed to highly conserved regions within various toxin groups. These primers were used for amplification of DNA extracted from B. burgdorferi strain 2591 to identify genes that express proteins analogous to existing toxins. Degenerate primers designed to the highly conserved catalytic domains of diphtheria and pertussis toxins yielded an amplification product. The product was cloned, sequenced, and subsequently identified in The Institute of Genomic Research (TIGR) database as BB0755, a 37 kD protein of unknown function. The full length gene for BB0755 was cloned, expressed and purified using epitope tags in the pET30a expression system, and the resultant recombinant protein renamed Bbtox1. Using the synthetic target agmantine, Bbtox1 exhibited ADP-ribosyltransferase activity. No ADP-ribosyltransferase activity was detected using elongation factor 2 as the target. In tissue culture, Bbtox1 affected the morphology (rounding) of Y1 mouse adrenal cells and C6 rat glial cells. Bbtox1 induced cell death in both Y1 and C6 cells. C6 glial cells responded to Bbtox1 in a dose and time dependent manner. Brefeldin A, an inhibitor of the trans-golgi network, accelerated the onset of action of Bbtox1 an Y1 adrenal cells.
The effects of Bbtox1 are consistent with a mechanism of action similar to that of botulinum C2 and other cytoskeletal toxins. Studies are underway to identify the cellular target of Bbtox1 and its role in Lyme Disease. In addition, a homologous gene in Treponema pallidum of undefined function is being analyzed to determine if it codes for a toxin similar to Bbtox1.
Posted by seibertneurolyme (Member # 6416) on :
Haven't had time to digest everything posted here yet as LymeNet has been up and down for me the past few days.
To throw another monkey wrench into the picture -- hubby tested high for both endotoxin and exotoxin on the same test by Immunosciences. This was over 3 years ago and has not been retested.
Exotoxins include toxins from Clostridia (antibodies were either slightly elevated or high normal as far as I remember).
Does Bb or any of the tickborne diseases produce exotoxins?
P.S. Marnie, I have never read that acidophilus and other good bacteria produced endotoxins -- any references for that?
Posted by Marnie (Member # 773) on :
A secreted toxin is called an exotoxin, not endotoxin.
Once more...I present yet another more recent abstract that clearly states Bb does NOT have an endotoxin:
Furthermore, spirochetes like Treponema pallidum, Borrelia recurrentis, and Borrelia burgdorferi sensu lato
have never been shown to contain classical endotoxins (49, 66, 136).
The bacterial compounds involved in JHR remain to be identified.
For the bacteria containing endotoxin, a JHR-like reaction was first described for typhoid fever. Clinical Microbiology Reviews, January 2002, p. 95-110, Vol. 15, No. 1
Now...that is not to say that Bb doesn't have an exotoxin or trigger endotoxin release, but so far
Bb itself does NOT have an ENDOtoxin.
EXOtoxin...well, it looks like Bb does have an EXOtoxin.
Ayurveda teaches that toxicity is acidic.
Thanks for mentioning magnesium which is so critical to us as it is found as Mg-ATP in every cell of our bodies.
P.S. Good catch, Bea...you are really smart!
E. Coli is gram neg. and lactobacillus is gram positive.
"Endotoxin is a molecular complex of lipid and polysaccharide; hence, the alternate name lipopolysaccharide. The complex is secured to the outer membrane by ionic and hydrophobic forces, and its strong negative charge is neutralized by Ca2+ and Mg2+ ions.
Unlike ***endotoxin, which is a structural component of all Gram-negative cells***,
exotoxins are produced by some members of both Gram-positive and Gram-negative genera.
[ 18. November 2006, 05:03 PM: Message edited by: Marnie ]
Posted by Nori (Member # 8983) on :
Bea
My acupuncturist has been out of town on family emergency and I have developed burning in my stomach, sore tongue and pain in my upper teeth.
I called him to ask for help and I am taking a chinese formula for damp heat of coptis and scute called "huang lian jie du tang.
Its a powder and I put 1 gram in a small bit of water and I swish it in my mouth for 5 minutes so it can be absorbed that way and spit it out. I herxed on it - very effective and no more pain in the teeth. It cleared the heat. The reason I do not swallow these herbs is that they are herbs of cold property and taken over time will cause loose stool in MY case due to my constitution. That might not be the case for others out there The coptis and scute combination are anti-bacterial, anti-viral and anti-yeast.
So conditions of heat - damp heat or other types of heat as the Chinese call them in this article do bear out and these herbs do help.
Thanks for posting this article
[ 18. November 2006, 06:28 PM: Message edited by: Nori ]
Posted by clairenotes (Member # 10392) on :
I believe there is a connection between clostridium and botulism (and tetanus)? In the same family?
This is strange coincidence... have been trying to get more information on a remedy that has caught my attention for quite some time. A hapten for serratia marcenscens. It came up for my daughter many times in bio-resonant testing and appears off and on for me. It has some connection to clostridium and botulism but not sure exactly how.
Will talk to the practitioner and post later if any significant information.
Claire
Posted by Marnie (Member # 773) on :
Claire, if you can dig for the information, see if the things suggested are trivalent.
3 charges, not 2.
Buried in my files somewhere is a list of elements that can carry 3 charges. I remember oxygen and Fe can.
Posted by david1097 (Member # 3662) on :
I will add couple of comments here....
Babesia, when it infects a RBC causes the RBC to secrete a protien that casues the RBC to stick to the vascular wall, and to other RBC's. This can gum upsoem of the timy viens that are in the brian and infect in cattel with bovine babesia, thier brains are very read from being so clogged up(seen when they are dead of course).
For babesia (or malaria, which is far better known) I have not read anywhere that there is a specific endotoxin that is released that is detected by the immunue system that causes an inflamatiory response.
Also the endo, exo and cell wall fragements seem to get used interchangably but they are from different processes. Since you asked about herx and endo toxins, I'll stick to the cell wall fragments that result from a kill by antibiotics. I think the consensus is that it the cell wall fragments are what causes the herxhiemer reaction. Similar reactions occur with a number of bacterial infections that are treated with antibiotics. What is odd about Lyme is that it takes a few days to happen and them happens again weeks later. I can only speculate as to why but my guess is that it has to do with the ability of the bacteria to enter a dormant state (like some mycobacterial infections (ie TB)) but somehow while in this state gets forced into the open every few weeks, likely with a changed skin that may or may not be sensed by the body as a foriegn entity and may or may not have some protein structures that look like the bodies own tissue (and thus the apparent autoinflamatory cycles).
On top of all that it seems (at least with me and some others that i know) that when the lyme emerges, it somehow distracts the immune system and allows other things that are normally silent to crop up. Things like warts, deep absesses and cutaneous as well as mucous membrane infections. These then clear up in a few days only to occur again right after the lyme symptoms flare up.
Thats my .02 worth of comments...
Posted by treepatrol (Member # 4117) on :
Endotoxins are potentially toxic, natural compounds found inside pathogens such as bacteria. Classically, an "endotoxin" is a toxin, which unlike an "exotoxin", is not secreted in soluble form by live bacteria, but is a structural component in the bacteria which is released mainly when bacteria are lysed.The prototypical examples of endotoxin are lipopolysaccharide (LPS) or lipo-oligo-saccharide (LOS) found in the outer membrane of various Gram-negative bacteria. The term LPS is often used exchangeably with endotoxin, owing to its historical discovery. In the 1800s it became understood that bacteria could secrete toxins into their environment, which became broadly known as "exotoxin". The term endotoxin came from the discovery that portions of Gram-negative bacteria itself can cause toxicity, hence the name endotoxin. Studies of endotoxin over the next 50 years revealed that the effects of "endotoxin" was in fact due to lipopolysaccharide. There are, however, endotoxins other than LPS. For example, delta endotoxin of Bacillus thuringiensis makes crystal-like inclusion bodies next to the endospore inside the bacteria. It is toxic to larvae of insects feeding on plants, but is harmless to humans (as we do not possess the enzymes and receptors necessary for its processing followed by toxicity). The only gram positive bacteria that produces endotoxin is Listeria monocytogenes.
LPS consist of a polysaccharide (sugar) chain and a lipid moiety, known as lipid A, which is responsible for the toxic effects. The polysaccharide chain is highly variable amongst different bacteria. Endotoxins are approximately 10 kDa in size but can form large aggregates up to 1000 kDa. Humans are able to produce antibodies to endotoxins after exposure but these are generally directed at the polysaccharide chain and do not protect against a wide variety of endotoxins. Injection of a small amount of endotoxin in human volunteers produced fever, a lowering of the blood pressure, and activation of inflammation and coagulation. Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as Neisseria meningitidis, the pathogen that causes fulminant meningitis.
Two major glycolipids from strains B31, N40, and BL303 of B. burgdorferi were isolated, characterized, and designated as BbGL-I and BbGL-II.
These compounds were purified by silica gel chromatography, and analyzed using GLC-MS, MALDITOF, FAB-MS, NMR spectrometry, and metabolic labeling. The structure of BbGL-I is cholester yl 6-O-acyl--Dgalactopyranoside (Fig. 5), and that of BbGL-II is 1,2-di-O-acyl- 3-O--D-galactopyranosyl-sn-glycerol (Fig. 6). BbGL-II conforms to the structure of MGDG previously described (8): we confirmed the configuration of the D-galactose moiety, the sn configuration of the glycerol, and identified the main unsaturated fatty acid as oleate. Hossain et al. (8) suggested that the other glycolipid (BbGL-I) is also a monogalactosyl diacylglycerol, and that the two differed only in their fatty acid composition. The pseudomolecular masses [M Na] observed for BbGL-I by these investigators, 810 and 836, coincidently match the pseudomolecular masses [M Na] of cholesteryl galactoside, substituted with either palmitic or oleic acids, respectively. Therefore, without NMR analysis, the suggested structure of BbGL-I could have been misinterpreted. Free cholesterol or cholesterol esters are components of several bacterial membranes such as Mycoplasma (20), Helicobacter pylori (21), Micrococcus lysodeikticus, Bacillus megaterium, and Proteus mirabilis (22). Cholesteryl glycosides have been identified in Mycoplasmas (20, 23), H. pylori (21), and Borrelia hermsi (24), in all of which, the carbohydrate was glucose. Cholesteryl Galactoside is now identified in bacteria. LPS has been identified in spirochaetales, but we and others (4) could not find evidence for its presence in B. burgdorferi, nor were we able to detect markers of LPS such as KDO, Lipid A or 3-hydroxy fatty acids (data not shown). Detoxy Gel, an affinity sorbent for binding (removal) of LPS, did not reveal LPS, but bound to BbGL-I. The lack of LPS, the abundance of BbGL-I and BbGL-II in the bacterial membrane, their surface exposure (as indicated by fluorescence labeling; data not shown), and their three-domain structure lead us to suggest that these glycolipids may assume LPS function. Surprisingly, despite its small size, BbGL-I elicited antibodies in mice and rabbits, mostly of the IgM isotype. These antibodies were specific to the homologous glycolipid. In contrast, BbGL-II elicited antibodies that reacted with both glycolipids. Antibodies to these glycolipids have been found in sera of Lyme disease patients (6). First described as a tick-borne spirochetosis in 1982 (25), Lyme disease is now recognized as a cause of common and serious systemic disease worldwide. Little information exists about the protective antigen(s) or the host factor(s) that confer immunity to B. burgdorferi. The licensed vaccine, composed of a lipidated derivative of an outer membrane protein, has been withdrawn by the manufacturer. The comprehensive description of two surface antigens of B. burgdorferi provides an approach to study immunity to this pathogen. We thank John B. Robbins, Andrej Gamian, and Ulrich Zahringer for review of the manuscript, and Noel Whittaker and Victor Livengood for FAB-MS.
Although some structural information has been obtained from other spirochetes, the complete elucidation of the LGLB from S. aurantia represents the first complete structure of a large glycolipid from these bacteria. The dodecasaccharide LGLB is anchored by a diacyl glycerol. A glycolipid containing a single sugar, BbGL-II, and also anchored on a glycerol, has been identified in B. burgdorferi [13]. It is surface localized, and antibodies to this molecule were detected in patients with Lyme disease. A diacyl glycerol anchor has also been purposed for the glycolipids of T. denticola, T. maltophilum, and T. brennaborense [6,12]. A glycolipid identified in T. pectinovorum contained glycerol, and the majority of fatty acids were branched, although on the basis of detection of Kdo in this material, the authors designated it LPS. Adiacyl glycerol anchor may substitute for lipid A, an observation supported by the absence of any homologs to genes involved in lipid A biosynthesis in the completed genomes of B. burgdorferi, T. pallidum or T.denticola [9,10,33]. All of the treponemal glycolipids identified have either fully saturated or branched fatty acids, in contrast to the unsaturated acyl group of BbGL-II. Schultz et al. indicated that the presence of fatty acid branching in T. denticola is analogous to adaptations in Gram-positive bacteria to alter membrane fluidity [12]. Gram-negative bacteria are known to modify the degree of saturation in their fatty acids to modulate membrane fluidity [34,35]. LGLB contained both unsaturated and branched fatty acids (i.e. C14:0, iC15:0, C16:1), the only spirochete glycolipid identified, to date, with both of these modifications, suggesting LGLB may form highly fluid membranes. S. aurantia LGLB comprises 15% lipid by mass, corresponding well with the proportion of fatty acids in the glycolipid OML521 (10.7%) from T. denticola, a glycolipid that is also estimated to be similar in size to Ra LPS [12]. Ra LPS is the minimum LPS unit required for efficient and proper folding, and functioning, of porin [36]. T. denticola and S. aurantia possess two of the largest porins yet discovered in Gram-negative bacteria: given the absence of LPS in these bacteria, OML251 and LGLB may function in place of Ra LPS, and contribute to the folding or stabilization of porin [37,38]. While S. aurantia stains Gram-negative and possesses an outer membrane containing porin, phylogenetically it is not closely related to the bacterial phylum (Proteobacteria) that contains the typical Gram-negative cells, such as E. coli. Other nonproteobacterial organisms in which glycolipids replace LPS include Chloroflexus aurantiacus and Fibrobacter succinogenes. The former bacterium is thought to contain outer membrane galactolipids [39], while the latter contains a low molecular mass glycolipid with glycerol anchor and many charged groups in the oligosaccharide part, which makes it, in overall design, similar to S. aurantia LGLB. Interestingly F. succinogenes also has a capsular polysaccharide with a lipid anchor [40]. Even within the Proteobacteria, one finds examples where LPS has been replaced by glycolipids. Sphingomonas paucimobilis and Novosphingobium capsulatum contain glycosphinogolipids (GSLs) [41-43] in lieu of LPS. Although there is no similarity at a structural level to LPS, studies investigating treponemal glycolipids have shown that most are able to gel LAL and stimulate Toll-like receptors [12,20], suggesting that at a functional level they possess some similarity. LGLB was able to gel LAL, but did not stimulate any TLR examined: this is an unusual situation, paralleled in the spirochete literature only by the inability of the Borrelia glycolipids to activate TLR2 or -4 [13]. TNF-a release was measured following the exposure of human mononuclear cells to two different GSLs from S. paucimobilis: the monoglycosylated GSL-1, and the tetraglycosylated GSL-4A. GSL-1 was unable to activate the release of monokines, in contrast to the larger GSL-4A, although induction was still 10 000-fold below that of the LPS standard [44]. While this appears to be similar to the situation with the monoglycosylated BbGL-II, the inability of LGLB to stimulate TNF-a release precludes size as the only explanation for the difference in biological activity observed with GSLs. Another oral spirochete implicated in periodontal disease, T. medium, contains the glycolipid, Tm-Gp, which abrogates TLR activation through interactions with LPS-binding protein (LBP) and CD14, two important components of TLR-mediated innate immunity [45]. The blocking by Tm-Gp was dependent on the lipid portion of the molecule, but whether S. aurantia LGLB would block a TLR response is unknown. Structural studies of Tm-Gp have focused on a tetrasaccharide repeating unit, likened by Asai and colleagues to the repeating unit of the LPS O-antigen [11]. The characteristic laddering pattern on SDS/ PAGE suggests that Tm-Gp is different from LGLB, although they both contain an aspartic acid residue. The structures of the bioactive portion of Tm-Gp, and of the other treponemal glycolipid TLR agonists, need to be elucidated to begin to identify possible motifs involved in modulating TLR activity. This is especially interesting when one realizes that the existing literature does not contain any direct demonstration of a ligand-type interaction between a TLR and any glycoconjugate, LPS or otherwise. LPS has been shown, however, to bind LBP [46]. Interestingly, a decrease in the fluidity of Re LPS, instigated by a Zn2+- induced increase in acyl chain order, elevated the production of TNF-a from human monocytes. The increase in acyl chain order increased the bond strength between Re LPS and LBP, and was thought to increase the transport of the LPS to the target membrane. LBP is an important precursor in the TLR-dependent release of TNF-a and has been shown to interact with both the T. maltophilum and T. brennaborense glycolipids to enhance their ability to stimulate TLRs [6]. It is tempting to speculate that the highly disordered acyl chains of LGLB could abrogate the interaction with LBP and prevent any release of TNF-a in the whole blood assay for TLR activation. Specific structural entities of LPS, producing certain biological effects, have been extensively studied given the central role of this molecule in pathogenesis and vaccine development. Characterization of any biological activity of spirochete glycolipids is important for similar reasons, especially in the case of B. burgdorferi BbGL-II, given the difficulties in developing an effective proteinaceous vaccine targeting this organism [13,47]. From: febsjournal Posted by nellypointis (Member # 1719) on :
quote:Originally posted by david1097: Babesia, when it infects a RBC causes the RBC to secrete a protien that casues the RBC to stick to the vascular wall, and to other RBC's. This can gum upsoem of the timy viens that are in the brian and infect in cattel with bovine babesia, thier brains are very read from being so clogged up(seen when they are dead of course).
David,
have you read this latest Australian study re Babesia?
Malar J. 2006; 5: 69. Published online 2006 August 4. doi: 10.1186/1475-2875-5-69. Copyright � 2006 Clark et al; licensee BioMed Central Ltd.
Absence of erythrocyte sequestration in a case of babesiosis in a splenectomized human patient Ian A Clark,1 Alison C Budd,1 Gunther Hsue,2 Bret R Haymore,2 Alina J Joyce,2 Richard Thorner,3 and Peter J Krause4
1School of Biochemistry and Molecular Biology Australian National University, Canberra, ACT 0200, Australia
Conclusion This first report on the vascular location of B. microti in human tissue suggests that severe multi-organ failure due to babesiosis ***is independent of sequestration of parasitized erythrocytes. (...) **** complications of human B. microti infection could, therefore, prove to be mediated by the ****same inflammatory processes as are accepted for bacterial sepsis and severe influenza [12]..
quote:
On top of all that it seems (at least with me and some others that i know) that when the lyme emerges, it somehow distracts the immune system and allows other things that are normally silent to crop up. Things like warts, deep absesses and cutaneous as well as mucous membrane infections. These then clear up in a few days only to occur again right after the lyme symptoms flare up. [/QUOTE]
Yes, this is exactly consistant with what I am experiencing and vice-versa as well eg I just had the 'flu and some of my long forgotten Lyme/babesia sxs are back (buzzing in head, vertigo just to name two)
Nelly
[ 20. November 2006, 11:56 AM: Message edited by: nellypointis ]
Posted by treepatrol (Member # 4117) on :
The newly recognized spirochete, Borrelia burgdorferi, the causative agent of Lyme Disease, has been examined for endotoxin-like activities as measured by the standard Farmacopea Ufficiale della Republica Italiana rabbit fever test and the Limulus amoebocyte lysate assay. The suspension of heat-killed microorganism caused a febrile response at a dose of 1 X 10(8) bacteria pro kilo. Similar results were obtained in the Limulus assay where the heat-killed spirochetes stimulated formation of solid clot until the concentration of 1 X 10(5) per ml. Both in pyrogen test and in Limulus assay heat-killed Escherichia coli exhibited a higher degree of potency. These results show that LD-Borrelia possess endotoxin-like activities which could help in understanding the pathogenesis of the clinical symptomatology of the disease. From: pubmed&cmd
Endotoxicity associated with the Lyme disease Borrelia: recent findings.Fumarola D, Munno I, Marcuccio C, Miragliotta G. The endotoxicity of Borrelia burgdorferi, the causative agent of Lyme Disease, a tick-borne spirochetosis, was studied using Limulus assay and pyrogen test in rabbit. Some suspensions of Ixodes ricinus and Ixodes dammini associated Borrelia were able to gelify Limulus lysate and demonstrated a febrile response in rabbit. These findings and other recent data demonstrating an endotoxin-like activity of the Lyme Disease agent are discussed in the context of the pathogenic mechanisms of the illness.
1: Zentralbl Bakteriol Mikrobiol Hyg [A]. 1986 Dec;263(1-2):137-41. Links Borrelia burgdorferi lipopolysaccharide and its role in the pathogenesis of Lyme disease.Habicht GS, Beck G, Benach JL, Coleman JL. Lipopolysaccharides (LPS) are a constitutive part of the outer wall of gram negative bacteria. Because many of the symptoms of Lyme disease could be explained by a spirochetal LPS we have subjected Borrelia burgdorferi to standard LPS extraction techniques which yielded a LPS which accounted for 1.5-4% of the dry weight. The LPS was very similar to classical gram negative bacterial LPS both chemically and in its biological activities which included pyrogenicity, mitogenicity for lymphocytes and the induction of Interleukin 1 production by macrophages. In addition, the LPS produced an acute inflammatory reaction when injected intradermally into rabbit skin. It could also prepare a skin site for the production of the local Shwartzman reaction. These results show that the Lyme disease spirochete contains a hitherto unknown LPS that is biologically active in vitro and in vivo. It is likely that this molecule plays an important role in the pathogenesis of Lyme disease.
PMID: 3577475 [PubMed - indexed for MEDLINE]
41: J Infect Dis. 1985 Jul;152(1):108-17.
Chemical and biologic characterization of a lipopolysaccharide extracted from the Lyme disease spirochete (Borrelia burgdorferi).
Beck G, Habicht GS, Benach JL, Coleman JL.
A lipopolysaccharide (LPS) was isolated from the Lyme disease spirochete by a modification of the hot phenol-water method. The material was composed of 45% carbohydrate, 8% protein, 44% lipid A, and 1% 3-deoxy-D-mannooctulosonic acid and accounted for approximately 1.5% of the cellular dry weight. The isolated LPS possessed several biologic activities characteristic of endotoxins. The LPS was pyrogenic for rabbits, mitogenic for human mononuclear cells and murine splenocytes, capable of clotting limulus lysate, and cytotoxic for murine macrophages. LPS extracted from Borrelia burgdorferi by the petroleum-ether:chloroform:liquid-phenol procedure was also characterized. The results show that the Lyme disease spirochete contains a hitherto unknown LPS that is biologically active in vitro, and the expression of such activities in vivo may play an important role in the pathogenesis of Lyme disease. Some of the clinical manifestations of other spirochetal disease may be explained by similar endotoxins in those organisms. To our knowledge this is the first report of an LPS extracted from a spirochete that is known to be a human pathogen.
Endotoxin-like activity associated with Lyme disease Borrelia.
Fumarola D, Munno I, Marcuccio C, Miragliotta G.
The newly recognized spirochete, Borrelia burgdorferi, the causative agent of Lyme Disease, has been examined for endotoxin-like activities as measured by the standard Farmacopea Ufficiale della Republica Italiana rabbit fever test and the Limulus amoebocyte lysate assay. The suspension of heat-killed microorganism caused a febrile response at a dose of 1 X 10(8) bacteria pro kilo. Similar results were obtained in the Limulus assay where the heat-killed spirochetes stimulated formation of solid clot until the concentration of 1 X 10(5) per ml. Both in pyrogen test and in Limulus assay heat-killed Escherichia coli exhibited a higher degree of potency. These results show that LD-Borrelia possess endotoxin-like activities which could help in understanding the pathogenesis of the clinical symptomatology of the disease.
PMID: 3577476 [PubMed - indexed for MEDLINE]
Immunology. 2004 Nov;113(3):401-8.
Characterization of the B-cell inhibitory protein factor in Ixodes ricinus tick saliva: a potential role in enhanced Borrelia burgdoferi transmission.
Hannier S, Liversidge J, Sternberg JM, Bowman AS.
School of Biological Science, Zoology, University of Aberdeen, UK.
We recently described the inhibition of host B lymphocytes by Ixodes ricinus tick saliva. In this study, we characterized the factor responsible for this activity and examined the modulation of lipopolysaccharide (LPS)- and Borrelia burgdorferi outer surface protein (Osp)-induced proliferation of naive murine B lymphocytes by an enriched fraction of this factor. The B-lymphocyte inhibitory activity was destroyed by trypsin treatment, indicating that a proteinaceous factor was responsible for this activity. The removal of glutathione-S-transferase (GST) from tick salivary glands extracts (SGE) showed that this B-cell inhibitory protein (BIP) was not a GST. Gel filtration liquid chromatography indicated that BIP has a native molecular weight of approximately 18,000. An enrichment protocol, using a combination of anion-exchange and reverse-phase liquid chromatography, was established. BIP-enriched fractions did not suppress T-cell proliferation. Delayed addition of BIP-enriched fractions, up to 7 hr after LPS addition, inhibited the proliferation of isolated B cells. BIP-enriched fractions dramatically inhibited both OspA- and OspC-induced proliferation of isolated B cells. These results strongly suggest that BIP may facilitate B. burgdorferi transmission by preventing B-cell activation, and also highlights the potential of BIP as a therapeutic agent in B-cell maladies.
PMID: 15500628 [PubMed - indexed for MEDLINE]
2: Arthritis Rheum. 2004 Jul;50(7):2360-9.
Outer surface lipoproteins of Borrelia burgdorferi vary in their ability to induce experimental joint injury.
To examine the ability of bacterial lipoproteins from the spirochete Borrelia burgdorferi to cause in vivo tissue injury (arthritis). METHODS: Outer surface proteins (OSPs) from B burgdorferi were used in a rat model of antigen-induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology. RESULTS: Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam(3)Cys-Ser-Lys(4)-OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens but vary greatly with respect to their injury-inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic. CONCLUSION: This is the first study to demonstrate that individual lipoproteins from B burgdorferi can induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.
PMID: 15248237 [PubMed - indexed for MEDLINE]
12: J Immunol. 2001 Jan 1;166(1):473-80.
Borrelia burgdorferi and other bacterial products induce expression and release of the urokinase receptor (CD87).
Coleman JL, Gebbia JA, Benach JL.
State of New York Department of Health, State University of New York, Stony Brook, NY 11794-5120, USA. [email protected]
The urokinase-type plasminogen activator receptor (uPAR, CD87) is a highly glycosylated 55- to 60-kDa protein anchored to the cell membrane through a glycosylphosphatidylinositol moiety that promotes the acquisition of plasmin on the surface of cells and subsequent cell movement and migration by binding urokinase-type plasminogen activator. uPAR also occurs in a soluble form in body fluids and tumor extracts, and both membrane and soluble uPAR are overexpressed in patients with tumors. uPAR may be a factor in inflammatory disorders as well. We investigated whether Borrelia burgdorferi could stimulate up-regulation of cell membrane uPAR in vitro. B. burgdorferi, purified native outer surface protein A, and a synthetic outer surface protein A hexalipopeptide stimulated human monocytes to up-regulate membrane uPAR as measured by immunofluorescence/FACS and Western blot. The presence of soluble uPAR in culture supernatants, measured by Ag capture ELISA, was also observed. LPS from Salmonella typhimurium and lipotechoic acid from Streptococcus pyogenes also induced the up-regulation of both membrane and soluble uPAR protein by monocytes. Up-regulation of uPAR was induced by conditioned medium from B. burgdorferi/monocyte cocultures. The up-regulation of uPAR by B. burgdorferi was concomitant with an increase in uPAR mRNA, indicating that synthesis was de novo. The expression and release of uPAR in response to B. burgdorferi and other bacterial components suggests a role in the pathogenesis of Lyme disease as well as in other bacterial infections.
PMID: 11123326 [PubMed - indexed for MEDLINE]
13: Infect Immun. 2000 Dec;68(12):6663-9.
Interleukin-10 modulates proinflammatory cytokines in the human monocytic cell line THP-1 stimulated with Borrelia burgdorferi lipoproteins.
Murthy PK, Dennis VA, Lasater BL, Philipp MT.
Department of Parasitology, Tulane Regional Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana 70433, USA.
We determined previously that lipoproteins of Borrelia burgdorferi stimulate inflammatory and anti-inflammatory cytokines (interleukin-10 [IL-10]) in monocytes. IL-10 could have an effect on innate and acquired immune responses to B. burgdorferi and influence the magnitude of the infectious inoculum and disease outcome. To understand the mechanism(s) of IL-10 action during early infection, when innate immunity expressed chiefly by skin macrophages is key, we investigated the effect of exogenous and endogenous IL-10 on the production of the macrophage-derived cytokines IL-6, IL-1beta, IL-12, and tumor necrosis factor alpha (TNF-alpha). We used the THP-1 human monocytic cell line and recombinant lipidated OspA (L-OspA) as the model target cell and stimulant, respectively. To determine the kinetics of cytokine production by THP-1 cells, we stimulated them with L-OspA and also with heat-killed B. burgdorferi cells (HBb) and lipopolysaccharide (LPS). Exogenous IL-10 dampened production of inflammatory cytokines, as elicited by lipoproteins. The inhibition of endogenous IL-10 function by anti-IL-10 antibody reduced the production of IL-12 and IL-6 but not that of IL-1beta and TNF-alpha. An inspection of the kinetics of cytokine production clarified this finding. TNF-alpha was produced prior to, and IL-beta was produced at the same time as, IL-10, whereas IL-6 and IL-12 were produced later. HBb, LPS, and L-OspA yielded similar kinetics of cytokine production. This result reinforces the notion that lipoproteins are the functional molecules in HBb and perhaps in vivo. It indicates also that signaling pathways utilized by LPS and lipoproteins may be extensively shared. The results are consistent with a major role played by IL-10 in controlling the initial phase of infection with this spirochete.
PMID: 11083779 [PubMed - indexed for MEDLINE]
15: J Immunol. 1999 Sep 1;163(5):2382-6.
Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2.
Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132, USA.
The agent of Lyme disease, Borrelia burgdorferi, produces membrane lipoproteins possessing potent inflammatory properties linked to disease pathology. The recent association of toll-like receptors (TLR) 2 and 4 with LPS responses prompted the examination of TLR involvement in lipoprotein signaling. The ability of human cell lines to respond to lipoproteins was correlated with the expression of TLR2. Transfection of TLR2 into cell lines conferred responsiveness to lipoproteins, lipopeptides, and sonicated B. burgdorferi, as measured by nuclear translocation of NF-kappaB and cytokine production. The physiological importance of this interaction was demonstrated by the 10-fold greater sensitivity of TLR2-transfected cells to lipoproteins than LPS. Futhermore, TLR2-dependent signaling by lipoproteins was facilitated by CD14. These data indicate that TLR2 facilitates the inflammatory events associated with Lyme arthritis. In addition, the widespread expression of lipoproteins by other bacterial species suggests that this interaction may have broad implications in microbial inflammation and pathogenesis.
PMID: 10452971 [PubMed - indexed for MEDLINE]
16: Infect Immun. 1999 Jan;67(1):140-7.
Induction of pro- and anti-inflammatory cytokines by Borrelia burgdorferi lipoproteins in monocytes is mediated by CD14.
Giambartolomei GH, Dennis VA, Lasater BL, Philipp MT.
Department of Parasitology, Tulane Regional Primate Research Center, Tulane University Medical Center, Covington, Louisiana 70433, USA.
We previously showed that heat-killed Borrelia burgdorferi spirochetes and lipidated outer surface protein A (L-OspA) stimulated the in vitro production of interleukin-10 (IL-10) in peripheral blood mononuclear cells (PBMC) from uninfected humans and rhesus monkeys (G. Giambartolomei et al., Infect. Immun. 66:2691-2697, 1998). Here we demonstrate that uninfected human peripheral blood monocytes, but not B or T cells, are the cells that transcribe the IL-10 cytokine gene in response to heat-killed B. burgdorferi. B. burgdorferi similarly induced an upregulation of the IL-1beta and IL-6 cytokine genes in monocytes and the production of IL-10 and IL-6 in culture supernatants of the human monocytic cell line THP-1. Purified L-OspA (but not unlipidated OspA [U-OspA] or U-OspC) also stimulated the production of both cytokines in THP-1 cells in a dose-dependent fashion, suggesting that acylation of the OspA protein molecule is required for the production of both anti- and pro-inflammatory cytokines in naive monocytes. A lipohexapeptide that contained the tripalmitoyl-modified cysteine motif (Pam3Cys-Hex) of B. burgdorferi lipoproteins but with an arbitrary peptide sequence had the same effect. Monoclonal antibodies (MAbs) MY4 and 60bca, both of which bind to CD14 and are known to block lipopolysaccharide (LPS)-mediated cytokine production, were able to block L-OspA-mediated IL-10 and IL-6 cytokine production. In contrast, MAb 26ic, which also binds to CD14 but does not block LPS function, failed to inhibit L-OspA-mediated cytokine production. These data suggest that activation of monocytes and production of both anti- and pro-inflammatory cytokines induced by lipoproteins proceeds via the CD14 receptor. LPS binding protein was not required for OspA-induced cytokine production. Our results demonstrate that pro- and anti-inflammatory cytokines induced by B. burgdorferi lipoproteins in PBMC are produced by monocytes and that lipoprotein and LPS signaling pathways share at least the initial signaling event that involves the CD14 receptor.
PMID: 9864208 [PubMed - indexed for MEDLINE]
6: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7913-8. Epub 2003 Jun 10.
A newly discovered cholesteryl galactoside from Borrelia burgdorferi.
Ben-Menachem G, Kubler-Kielb J, Coxon B, Yergey A, Schneerson R.
Laboratory of Developmental and Molecular Immunity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. [email protected]
Two major glycolipids, which comprise approximately 36% of the total lipid mass from Borrelia burgdorferi, the etiological agent of Lyme disease, were investigated. We determined the fatty acid type, sugar identity, anomeric configuration, and substituent type and position. The structures were identified as cholesteryl 6-O-acyl-beta-d-galactopyranoside (B. burgdorferi glycolipid 1, BbGL-I), and 1,2-di-O-acyl-3-O-alpha-d-galactopyranosyl-sn-glycerol (BbGL-II). The major fatty acids were palmitate and oleate. The structures were corroborated by gas-liquid chromatography MS, matrix-assisted laser desorption/ionization time-of-flight spectroscopy, fast atom bombardment MS, detailed NMR spectrometry, and metabolic labeling. This is a previously undescribed demonstration of a cholesteryl galactoside in bacteria. Lipopolysaccharide was not detected in B. burgdorferi. The two glycolipids have several properties suggesting they may function as lipopolysaccharide: both are main components of the bacterial membrane, surface exposed, and have a three-domain structure. BbGL-I elicited specific antibodies in mice and rabbits, and BbGL-II elicited antibodies that reacted with both glycolipids.
PMID: 12799465 [PubMed - indexed for MEDLINE]
18: J Immunol. 1998 Jun 1;160(11):5485-92.
The role of CD14 in signaling mediated by outer membrane lipoproteins of Borrelia burgdorferi.
Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132, USA.
Borrelia burgdorferi possesses membrane lipoproteins that exhibit stimulatory properties and, consequently, have been implicated in the pathology related to Lyme disease. As CD14 has been shown to mediate signaling by a number of lipid-modified bacterial products, the involvement of CD14 in signaling mediated by two B. burgdorferi lipoproteins, outer surface protein A (OspA) and OspC, was determined. Lipoprotein-mediated induction of nuclear factor-kappaB nuclear translocation and production of IL-8 and IL-6 in HUVEC was enhanced in the presence of serum or soluble rCD14. CD14-specific Abs that block LPS-mediated signaling also inhibited lipoprotein-dependent signaling in HUVEC and neutrophils. The formation of stable complexes between OspA and CD14 was demonstrated by native gel electrophoresis. LPS was found to compete with OspA for binding with CD14, suggesting that LPS and OspA bind similar regions on CD14. The similarity in binding was further supported by the finding that a mutant soluble CD14, lacking the LPS binding site, did not facilitate lipoprotein signaling, nor did it form a complex with OspA. Binding of OspA to CD14 was dependent on the lipid modification, as unlipidated OspA did not form a complex with CD14 or stimulate cells. In contrast, the lipopeptide remaining after proteinase K digestion both formed a complex with CD14 and retained stimulatory properties. These findings indicate that CD14 facilitates bacterial lipoprotein signaling in mammalian cells.
PMID: 9605151 [PubMed - indexed for MEDLINE]
39: Clin Sci. 1972 Sep;43(3):343-54.
Studies of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating Borrelia endotoxin.
Bryceson AD, Cooper KE, Warrell DA, Perine PL, Parry EH.
PMID: 5077513 [PubMed - indexed for MEDLINE]
21: J Immunol. 1997 May 15;158(10):4838-45.
Borrelia burgdorferi outer surface protein A (OspA) activates and primes human neutrophils.
Morrison TB, Weis JH, Weis JJ.
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
Lyme disease is caused by infection with the spirochete Borrelia burgdorferi and is characterized by bacterial persistence and inflammation of many host tissues. B. burgdorferi express outer surface lipoproteins, including OspA, with inflammatory properties that could contribute to the localized tissue inflammation. Neutrophils are the predominant infiltrate into the inflamed arthritic joints, and are crucial for controlling the spirochete infection. They may also contribute to the joint pathology associated with Lyme arthritis. This study examines the effect of OspA on the activities of the neutrophil. Picomolar concentrations of OspA induce surface markers associated with neutrophil activation: increased CD10 and CD11b expression; decreased CD62-L expression; and an increased adherence to extracellular matrix. These events were similar in kinetics and magnitude to those induced by the strong activators LPS and FMLP. Like LPS, OspA could prime neutrophils for FMLP-induced release of lysosomal granules and production of superoxide. Thus, models of Lyme arthritis should include the possible contribution of direct activation of neutrophils to both defense and disease.
PMID: 9144499 [PubMed - indexed for MEDLINE]
23: Infect Immun. 1996 Sep;64(9):3845-52.
Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-kappa B.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
There is increasing evidence that lipoproteins of Treponema pallidum and Borrelia burgdorferi are key inflammatory mediators during syphilis and Lyme disease. A principal objective of the present study was to identify more precisely similarities and divergences among lipopolysaccharide (LPS)- and lipoprotein-lipopeptide-induced immune cell signaling events. Like LPS, purified native B. burgdorferi OspA and synthetic analogs of OspA, OspB, and two T. pallidum lipoproteins (Tpp47 and Tpp17) all induced NF-kappa B translocation in THP-1 human monocytoid cells. Acylation of OspA and the synthetic peptides was requisite for cell activation. Polymyxin B abrogated only the response to LPS. By using 70Z/3-derived pre-B-cell lines either lacking or expressing human CD14 (the LPS receptor), it was observed that expression of human CD14 imparted responsiveness to LPS but not to OspA or spirochetal lipopeptides (assessed by induction of NF-kappa B and expression of surface immunoglobulin M). Finally, the biological relevance of the observation that T. pallidum lipoproteins-lipopeptides induce both NF-kappa B and cytokine production in monocytes was supported by the ability of the synthetic analogs to promote human immunodeficiency virus replication in chronically infected U1 monocytoid cells; these observations also suggest a potential mechanism whereby a syphilitic chancre can serve as a cofactor for human immunodeficiency virus transmission. The combined data lend additional support to the proposal that spirochetal lipoproteins and LPS initiate monocyte activation via different cell surface events but that the signaling pathways ultimately converge to produce qualitatively similar cellular responses.
A 14,000 MW lipoprotein and a glycolipid-like structure of Borrelia burgdorferi induce proliferation and immunoglobulin production in mouse B cells at high frequencies.
Honarvar N, Schaible UE, Galanos C, Wallich R, Simon MM.
Sonicated preparations of Borrelia burgdorferi are able to stimulate unselected resting BALB/c spleen cells to proliferate and to produce immunoglobulin in vitro. FACS analysis of target cells prestained with an integrated cell-surface marker as well as cell-depletion experiments demonstrate that the majority of responding lymphocytes are B cells. Limiting dilution analyses of resting B cells revealed high frequencies of cells producing IgM (F 1/11-1/62) or IgG (F 1/5-1/163) in response to B. burgdorferi sonicate (B.b. sonicate). These numbers were similar to those obtained with lipopolysaccharide (LPS) (IgM: F 1/20-1/84; IgG: F 1/14-1/85) or a synthetic lipopeptide of Braun's Escherichia coli lipoprotein (IgM: F 1/15, 1/19; IgG: F 1/148, 1/34). The mitogenic structure(s) expressed by B. burgdorferi is distinct from LPS, as similar proliferative responses were obtained with B cells from LPS-resistant (C57BL/10ScCr and C3H/HeJ) and LPS-susceptible (C57BL/10ScSn, C3H/HeN) mice.
Furthermore, B-cell mitogenic properties were also found in two distinct fractions of a phenol-chloroform-petroleum ether extract of B. burgdorferi: they consisted of a lipoprotein distinct from the outer surface proteins (Osp) A and B and glycolipid-like structures, respectively. These data suggest that spirochetes express a multitude of distinct structures with mitogenic activity for B cells including various lipoproteins as well as glycolipid(s).
Interleukin-1 (IL-1) receptor blockade reduces endotoxin and Borrelia burgdorferi-stimulated IL-8 synthesis in human mononuclear cells.
Porat R, Poutsiaka DD, Miller LC, Granowitz EV, Dinarello CA.
Department of Medicine, New England Medical Center, Boston, Massachusetts 02111.
Interleukin-1 (IL-1) is a potent stimulator of IL-8 production by fibroblasts and monocytes. In the present study, we asked how much of endotoxin (LPS)-induced IL-8 production by human peripheral blood mononuclear cells was due to IL-1 induced by LPS. Cells were stimulated with either IL-1 beta, LPS, or Borrelia burgdorferi, and total IL-8 was determined by a specific radioimmunoassay. The addition of saturating concentrations of IL-1 receptor antagonist protein (IRAP) reduced the IL-1 beta-, LPS-, and B. burgdorferi-induced IL-8 synthesis by 85, 50, and 40%, respectively. Increasing the concentration of LPS did not affect the reduction in IL-8 synthesis observed in the presence of IRAP. Significant inhibition of the IL-1 beta-induced IL-8 synthesis was observed when IRAP was added 60 or 90 min after IL-1 beta; similarly, IL-8 synthesis after LPS was also reduced by delayed addition of IRAP. These data suggest that the ameliorative effects of IL-1 receptor blockade in models of inflammation and infection may be due, in part, to suppression of IL-1-induced IL-8.
Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens.
de Souza MS, Fikrig E, Smith AL, Flavell RA, Barthold SW.
Section of Comparative Medicine; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510.
Proliferative responses of naive splenocytes to Borrelia burgdorferi antigens from mice susceptible (C3H) and resistant (BALB) to Lyme borreliosis were investigated. B. burgdorferi spirochetes and recombinant outer surface proteins, OspA and OspB, were found to induce nonspecific proliferation of naive splenocytes from both strains of mice. Cell purification studies localized nonspecific proliferation to the B cell-enriched fraction. B. burgdorferi, OspA, and OspB were found to induce IgM and IgG synthesis in vitro. The mitogenic effect of B. burgdorferi was dissimilar to that of lipopolysaccharide (LPS), in that B cells from C3H/HeJ mice (LPS-unresponsive) responded at levels comparable to those from C3H/HeNCrlBr mice. These results emphasize the need for caution in the study of antigen-specific proliferation for B. burgdorferi.
Borrelia burgdorferi lipopolysaccharide and its role in the pathogenesis of Lyme disease.
Habicht GS, Beck G, Benach JL, Coleman JL.
Lipopolysaccharides (LPS) are a constitutive part of the outer wall of gram negative bacteria. Because many of the symptoms of Lyme disease could be explained by a spirochetal LPS we have subjected Borrelia burgdorferi to standard LPS extraction techniques which yielded a LPS which accounted for 1.5-4% of the dry weight. The LPS was very similar to classical gram negative bacterial LPS both chemically and in its biological activities which included pyrogenicity, mitogenicity for lymphocytes and the induction of Interleukin 1 production by macrophages. In addition, the LPS produced an acute inflammatory reaction when injected intradermally into rabbit skin. It could also prepare a skin site for the production of the local Shwartzman reaction. These results show that the Lyme disease spirochete contains a hitherto unknown LPS that is biologically active in vitro and in vivo. It is likely that this molecule plays an important role in the pathogenesis of Lyme disease.
Endotoxicity associated with the Lyme disease Borrelia: recent findings.
Fumarola D, Munno I, Marcuccio C, Miragliotta G.
The endotoxicity of Borrelia burgdorferi, the causative agent of Lyme Disease, a tick-borne spirochetosis, was studied using Limulus assay and pyrogen test in rabbit. Some suspensions of Ixodes ricinus and Ixodes dammini associated Borrelia were able to gelify Limulus lysate and demonstrated a febrile response in rabbit. These findings and other recent data demonstrating an endotoxin-like activity of the Lyme Disease agent are discussed in the context of the pathogenic mechanisms of the illness.
OspA lipoprotein of Borrelia burgdorferi is a mucosal immunogen and adjuvant.
Erdile LF, Guy B.
Pasteur Merieux Connaught, Marcy L'Etoile, France.
The outer surface protein A (OspA) lipoprotein of Borrelia burgdorferi, like cholera toxin and the heat-labile enterotoxin of Escherichia coli, induces pro-inflammatory cytokines. This suggested that, like those toxins, OspA might be a mucosal immunogen and adjuvant. OspA, administered intranasally (i.n.) or intragastrically, induced strong serum IgG and salivary gland IgA responses. The serum IgG isotypes were indicative of a mixed T helper 1 and T helper 2 response, the latter being more pronounced. The N-terminal tripalmitoyl-S-glyceryl-cysteine (Pam3Cys) lipid moiety was absolutely required. OspA strongly enhanced the serum IgG and salivary gland IgA responses to jack bean urease co-administered by the i.n. route. OspA also enhanced the response to tetanus toxoid and induced limited protection against challenge. A synthetic lipopeptide also adjuvanted the response to urease by the i.n. route, but was ca 500-fold less potent on a molar basis than OspA. These results suggest that OspA or other lipoproteins may be useful in mucosal vaccines.
Characterization of the B-cell inhibitory protein factor in Ixodes ricinus tick saliva: a potential role in enhanced Borrelia burgdoferi transmission.
Hannier S, Liversidge J, Sternberg JM, Bowman AS.
School of Biological Science, Zoology, University of Aberdeen, UK.
We recently described the inhibition of host B lymphocytes by Ixodes ricinus tick saliva. In this study, we characterized the factor responsible for this activity and examined the modulation of lipopolysaccharide (LPS)- and Borrelia burgdorferi outer surface protein (Osp)-induced proliferation of naive murine B lymphocytes by an enriched fraction of this factor. The B-lymphocyte inhibitory activity was destroyed by trypsin treatment, indicating that a proteinaceous factor was responsible for this activity. The removal of glutathione-S-transferase (GST) from tick salivary glands extracts (SGE) showed that this B-cell inhibitory protein (BIP) was not a GST. Gel filtration liquid chromatography indicated that BIP has a native molecular weight of approximately 18,000. An enrichment protocol, using a combination of anion-exchange and reverse-phase liquid chromatography, was established. BIP-enriched fractions did not suppress T-cell proliferation. Delayed addition of BIP-enriched fractions, up to 7 hr after LPS addition, inhibited the proliferation of isolated B cells. BIP-enriched fractions dramatically inhibited both OspA- and OspC-induced proliferation of isolated B cells. These results strongly suggest that BIP may facilitate B. burgdorferi transmission by preventing B-cell activation, and also highlights the potential of BIP as a therapeutic agent in B-cell maladies.
Endotoxicity associated with the Lyme disease Borrelia: recent findings.
Fumarola D, Munno I, Marcuccio C, Miragliotta G.
The endotoxicity of Borrelia burgdorferi, the causative agent of Lyme Disease, a tick-borne spirochetosis, was studied using Limulus assay and pyrogen test in rabbit. Some suspensions of Ixodes ricinus and Ixodes dammini associated Borrelia were able to gelify Limulus lysate and demonstrated a febrile response in rabbit. These findings and other recent data demonstrating an endotoxin-like activity of the Lyme Disease agent are discussed in the context of the pathogenic mechanisms of the illness.
OBJECTIVE: To examine the ability of bacterial lipoproteins from the spirochete Borrelia burgdorferi to cause in vivo tissue injury (arthritis). METHODS: Outer surface proteins (OSPs) from B burgdorferi were used in a rat model of antigen-induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology. RESULTS: Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam(3)Cys-Ser-Lys(4)-OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens, but vary greatly with respect to their injury-inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic. CONCLUSION: This is the first study to demonstrate that individual lipoproteins from B burgdorferi can induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.
Borrelia burgdorferi-induced tolerance as a model of persistence via immunosuppression.
Diterich I, Rauter C, Kirschning CJ, Hartung T.
Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Konstanz, Germany.
If left untreated, infection with Borrelia burgdorferi sensu lato may lead to chronic Lyme borreliosis. It is still unknown how this pathogen manages to persist in the host in the presence of competent immune cells. It was recently reported that Borrelia suppresses the host's immune response, thus perhaps preventing the elimination of the pathogen (I. Diterich, L. Harter, D. Hassler, A. Wendel, and T. Hartung, Infect. Immun. 69:687-694, 2001). Here, we further characterize Borrelia-induced immunomodulation in order to develop a model of this anergy. We observed that the different Borrelia preparations that we tested, i.e., live, heat-inactivated, and sonicated Borrelia, could desensitize human blood monocytes, as shown by attenuated cytokine release upon restimulation with any of the different preparations. Next, we investigated whether these Borrelia-specific stimuli render monocytes tolerant, i.e. hyporesponsive, towards another Toll-like receptor 2 (TLR2) agonist, such as lipoteichoic acid from gram-positive bacteria, or towards the TLR4 agonist lipopolysaccharide. Cross-tolerance towards all tested stimuli was induced. Furthermore, using primary bone marrow cells from TLR2-deficient mice and from mice with a nonfunctional TLR4 (strain C3H/HeJ), we demonstrated that the TLR2 was required for tolerance induction by Borrelia, and using neutralizing antibodies, we identified interleukin-10 as the key mediator involved. Although peripheral blood mononuclear cells tolerized by Borrelia exhibited reduced TLR2 and TLR4 mRNA levels, the expression of the respective proteins on monocytes was not decreased, ruling out the possibility that tolerance to Borrelia is attributed to a reduced TLR2 expression. In summary, we characterized tolerance induced by B. burgdorferi, describing a model of desensitization which might mirror the immunosuppression recently attributed to the persistence of Borrelia in immunocompetent hosts.
Department of Microbiology and Immunology, School of Medicine, University of Louisville, Kentucky 40292.
Zones of beta-hemolysis occurred around colonies of Borrelia burgdorferi grown on Barbour-Stoenner-Kelly medium containing agarose and horse blood. Blood plates were inoculated with either the infective strain Sh-2-82 or noninfective strain B-31 in an overlay and incubated in a candle jar. Both strains of B. burgdorferi displayed beta-hemolysis after 1 to 2 weeks of incubation. The hemolytic activity diffused out from the borrelial colonies, eventually resulting in lysis of the entire blood plate. Hemolysis was most pronounced with horse blood and was less intense with bovine, sheep, and rabbit blood. Hemolysis was enhanced by hot-cold incubation, which is typical of phospholipase-like activities in other bacteria. Further characterization of the borrelial hemolysin by using a spectrophotometric assay revealed its presence in the supernatant fluids of stationary-phase cultures. Detection of the borrelial hemolytic activity was dependent on activation of the hemolysin by the reducing agent cysteine. This study provides the first evidence of hemolytic activity associated with B. burgdorferi.
In vitro and in vivo induction of tumor necrosis factor alpha by Borrelia burgdorferi.
Defosse DL, Johnson RC.
Department of Microbiology, University of Minnesota, Minneapolis 55455.
Tumor necrosis factor alpha (TNF-alpha) is an immunoregulatory cytokine with many biological activities including the mediation of inflammation. We examined sera and synovial fluids from patients seropositive for infection with Borrelia burgdorferi using a radioimmunoassay specific for TNF-alpha. Significant elevation of TNF-alpha was found in the sera and synovial fluids of patients examined, while controls showed no elevation. Sera of mice infected with B. burgdorferi contained elevated levels of TNF-alpha which varied during the course of a 24-day infection. To determine whether B. burgdorferi is capable of inducing TNF-alpha production, spirochetes were added to adherent human peripheral blood mononuclear cells or mouse peritoneal exudate cells and 24 h later supernatants were assayed. TNF-alpha induction occurred in a dose-dependent manner. The maximum stimulation occurred when a ratio of 1 to 10 spirochetes per mononuclear cell was used. At optimal concentrations, induction was not diminished by inactivation of spirochetes or pretreatment with polymyxin B. These results suggest that an increase in TNF-alpha production may occur as a result of infection with B. burgdorferi.
Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens.
de Souza MS, Fikrig E, Smith AL, Flavell RA, Barthold SW.
Section of Comparative Medicine; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510.
Proliferative responses of naive splenocytes to Borrelia burgdorferi antigens from mice susceptible (C3H) and resistant (BALB) to Lyme borreliosis were investigated. B. burgdorferi spirochetes and recombinant outer surface proteins, OspA and OspB, were found to induce nonspecific proliferation of naive splenocytes from both strains of mice. Cell purification studies localized nonspecific proliferation to the B cell-enriched fraction. B. burgdorferi, OspA, and OspB were found to induce IgM and IgG synthesis in vitro. The mitogenic effect of B. burgdorferi was dissimilar to that of lipopolysaccharide (LPS), in that B cells from C3H/HeJ mice (LPS-unresponsive) responded at levels comparable to those from C3H/HeNCrlBr mice. These results emphasize the need for caution in the study of antigen-specific proliferation for B. burgdorferi.
Cytokines and the pathogenesis of neuroborreliosis: Borrelia burgdorferi induces glioma cells to secrete interleukin-6.
Habicht GS, Katona LI, Benach JL.
Department of Pathology, State University of New York, Stony Brook 11794-8691.
Lyme disease is a multisystemic disease caused by a tickborne spirochete, Borrelia burgdorferi. Neuroborreliosis is characterized by intrathecal production of antibodies specific for the spirochete. This suggests that spirochetal infection of the central nervous system produces conditions that support the maturation of B lymphocytes to immunoglobulin-secreting cells. Interleukin 6 (IL-6) stimulates B cell differentiation into antibody-secreting cells. The present study was undertaken to determine whether B. burgdorferi can stimulate cells of central nervous system origin to secrete IL-6. C6 rat glioma cells cultured with spirochetes induced secretion of IL-6 activity. Peak stimulation was achieved at 24 h with 25 spirochetes per glioma cell. Glioma cells were also stimulated to produce IL-6 by interleukin 1 and tumor necrosis factor. That very few spirochetes are found in Lyme disease patients suggests that biologic amplification factors derived from the organism or the host, or both, are responsible for the pathogenesis of this disease. IL-6 can now be added to the growing list of such factors.
Plagues--what's past is present: thoughts on the origin and history of new infectious diseases.
Ampel NM.
Medical Service, Tucson Veterans Affairs Medical Center, Arizona 85723.
Medical science has made tremendous strides in overcoming infectious diseases in the 20th century. Despite this, several epidemics of previously unrecognized diseases have occurred during the last 15 years. These diseases include Lyme disease, Legionnaires' disease, toxic shock syndrome, and AIDS. Examination of past epidemics, including the plague of Athens, the black death, syphilis, and influenza, suggests that the sudden occurrence of diseases that were previously unrecognized is not unusual. Analysis of the new infectious disease indicates that while all four appeared suddenly, isolated cases of the disease occurred before the actual epidemic. Further, all four new diseases were found to be due to agents or toxins that were not previously recognized. Epidemics due to new infectious diseases may arise by several mechanisms, including mutation of the pathogen to a virulent form and introduction of an infectious agent into a nonimmune population. Environmental and behavioral factors may play an important role, as illustrated by toxic shock syndrome, Legionnaires' disease, and AIDS. On the other hand, epidemic diseases tend to abate over time because of changes in the infecting pathogen and in the host. Hence, epidemics can be seen as cycles; new diseases will arise periodically, occasionally with a devastating outcome. With time the effects of these diseases on the population will ameliorate. The cycle will begin again when a new disease emerges.
17: FEMS Microbiol Immunol. 1991 Feb;3(1):33-8. Related Articles, Links
Evidence for (lipo) oligosaccharides in Borrelia burgdorferi and their serological specificity.
Cinco M, Banfi E, Balanzin D, Godeas C, Panfili E.
Istituto di Microbiologia, Universita degli Studi, Trieste, Italy.
SDS-PAGE and Western immunoblot profiles have been determined for different strains of Borrelia burgdorferi. Major proteins of 60 kDa, 41 kDa corresponding to flagellin, 34-36 kDa and 30-31 kDa corresponding to OspB and OspA respectively, and 18-20 kDa corresponding to 'pC' fractions were detected. A "rough" lipopolysaccharide which we called lipooligosaccharide (LOS) of 8-11 kDa appeared to be present, being detected by specific silver staining, as in crude Borrelia lysates as in proteinase K digested Borrelia strains, quite similar in shape among the different strains examined. The LOS reacted in Western blotting with immune anti-B. burgdorferi rabbit serum and also with sera collected from humans affected by Lyme borreliosis. The LOS did not react with sera positive for syphilis or leptospirosis, and their immunological specificity is discussed.
Endotoxicity associated with the Lyme disease Borrelia: recent findings.
Fumarola D, Munno I, Marcuccio C, Miragliotta G.
The endotoxicity of Borrelia burgdorferi, the causative agent of Lyme Disease, a tick-borne spirochetosis, was studied using Limulus assay and pyrogen test in rabbit. Some suspensions of Ixodes ricinus and Ixodes dammini associated Borrelia were able to gelify Limulus lysate and demonstrated a febrile response in rabbit. These findings and other recent data demonstrating an endotoxin-like activity of the Lyme Disease agent are discussed in the context of the pathogenic mechanisms of the illness.
Chemical and biologic characterization of a lipopolysaccharide extracted from the Lyme disease spirochete (Borrelia burgdorferi).
Beck G, Habicht GS, Benach JL, Coleman JL.
A lipopolysaccharide (LPS) was isolated from the Lyme disease spirochete by a modification of the hot phenol-water method. The material was composed of 45% carbohydrate, 8% protein, 44% lipid A, and 1% 3-deoxy-D-mannooctulosonic acid and accounted for approximately 1.5% of the cellular dry weight. The isolated LPS possessed several biologic activities characteristic of endotoxins. The LPS was pyrogenic for rabbits, mitogenic for human mononuclear cells and murine splenocytes, capable of clotting limulus lysate, and cytotoxic for murine macrophages. LPS extracted from Borrelia burgdorferi by the petroleum-ether:chloroform:liquid-phenol procedure was also characterized. The results show that the Lyme disease spirochete contains a hitherto unknown LPS that is biologically active in vitro, and the expression of such activities in vivo may play an important role in the pathogenesis of Lyme disease. Some of the clinical manifestations of other spirochetal disease may be explained by similar endotoxins in those organisms. To our knowledge this is the first report of an LPS extracted from a spirochete that is known to be a human pathogen.
Meptazinol diminishes the Jarisch-Herxheimer reaction of relapsing fever.
Teklu B, Habte-Michael A, Warrell DA, White NJ, Wright DJ.
Naloxone, an opioid antagonist, and meptazinol, an opioid antagonist with agonist properties, were tested in a double-blind placebo-controlled trial in 24 Ethiopian patients with louse-borne relapsing fever. The potentially fatal Jarisch-Herxheimer reaction (J-HR), which invariably follows tetracycline treatment of the disease, was unaffected by naloxone, 30-40 mg intravenously, but was diminished by meptazinol, 300-500 mg intravenously. Compared with naloxone and placebo, meptazinol reduced the clinical severity of the reaction, significantly delayed and shortened its chill phase, delayed the rise in temperature, and reduced peak temperature and changes in pulse and respiratory rates and leucocyte count. High-dose corticosteroids given before or at the time of tetracycline treatment failed to alter the reaction, which is thought to result from release of endotoxin-like substances. Meptazinol is the first effective treatment for the J-HR of louse-borne relapsing fever. This finding suggests a role for endogenous opioids in the pathogenesis of the J-HR.
Reaction following treatment of murine borreliosis and Shwartzman type reacion with borrelial sonicates.
Wright DJ.
Treatment of experimental murine borreliosis induced an acute transient fall in temperature, leucopenia and thrombocytopenia with appearance of circulating 'endotoxin-like' material. This reaction to treatment could be reproduced by the inoculatioh of borrelial sonicates into infected mice or by two injections of the same sonicate given 24 hours apart, into normal mice. Sensitization or precipitation of the reaction could not be induced by E. coli lipopolysaccharide, although a reaction indistinguishable from the reaction to treatment could be provoked in mice by two successive injections of lipopolysaccharide given 24 hours apart. The nature of this reaction in mice was investigated and the relation of both reactions to the Shwartzman reaction, Endotoxin.
Fifteen patients with Borrelia recurrentis infection were studied to evaluate the role of certain plasma proteins and endotoxin in the pathophysiology of both the acute illness and the Jarisch-Herxheimer-like reaction. The causative spirochetes disappeared from the blood during the Jarisch-Herxheimer-like reaction, which occurred about 2 hours after antibiotic therapy. The mean titers of Hageman factor, plasma prekallikrein and serum hemolytic complement activity were decreased at the time of admission and 2 hours after treatment, and rose to normal values during convalescence. Serum properdin titers were decreased in 14 patients at the time of admission, in 12 patients 2 hours after treatment, and in none during convalescence. The frequency of elevated levels of fibrinogen-related antigens increased from three patients at the time of admission to 12 patients 2 hours after treatment. Results of plasma limulus tests for endotoxin-like material were positive in 11 patients at the time of admission and in 13 patients 2 hours after treatment. These findings demonstrated that Hageman factor, prekallikrein and proteins of the complement system are activated in B. recurrentis infection and that endotoxin may play a role in both the acute illness and in the development of the Jarisch-Herxheimer-like reaction after treatment.
Clinical pathology of the Jarisch-Herxheimer reaction.
Bryceson AD.
The Jarisch-Herxheimer reaction is a complication that can follow treatment of several infectious diseases. Its most severe form is in louse-borne relapsing fever; in this syndrome the reaction can cause death. Information from studies in Ethiopia during the past eight years is presented, and clinical, physiological, pathological, and immunological features of the reaction are described. Possible causative mechanisms of the reaction are discussed, especially in relation to the role of endotoxin, and an attempt is made to consider this reaction in relation to other endotoxin-associated states.
PMID: 932495 [PubMed - indexed for MEDLINE]
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Posted by clairenotes (Member # 10392) on :
Marnie -- will try to find out about trivalence. Still looking into it. If trivalent, does that mean it is more difficult to deal with?
David -- you said...
"I can only speculate as to why but my guess is that it has to do with the ability of the bacteria to enter a dormant state (like some mycobacterial infections (ie TB)) but somehow while in this state gets forced into the open every few weeks, likely with a changed skin that may or may not be sensed by the body as a foriegn entity and may or may not have some protein structures that look like the bodies own tissue (and thus the apparent autoinflamatory cycles)"
I thought this had to do with Bb going in and out of cyst forms and replication cycles? Does not some abx and other remedies cause Bb to 'hide' in cyst form where they are more protected, while killing others that are not so lucky? Isn't there a four week cycle of replication?
Also you said...
"On top of all that it seems (at least with me and some others that i know) that when the lyme emerges, it somehow distracts the immune system and allows other things that are normally silent to crop up. Things like warts, deep absesses and cutaneous as well as mucous membrane infections. These then clear up in a few days only to occur again right after the lyme symptoms flare up."
I do know that whenever the immune system is suppressed it can allow things that have been dormant to come to life, so to speak. This is the frustration. Still wonder why it has the strength to bring the immune system down so dramatically.
Note... I am still learning. There is so much to know about this complicated illness and probably still have many 'holes' in my understanding.
Treepatrol -- Whew! I am totally overwhelmed! I am sure it will be very useful... but it will take me days to get through that material.
I do understand that endotoxins are cell-wall fragments of bacteria that have been lysed, but are still somehow pathogenic and can cause herx reactions. I do understand that exotoxins are toxins released from a bacteria with the same result. I think I am most interested in the make-up of those pathogens/toxins, if that makes sense, in order to determine how best to clear them.
Bea provided a great resource in this respect. With the TCM (Traditionel Chinese Remedies), one probably does not need to know the 'make-up' of the toxins or pathogens in order to have success with the remedies. But we do need help with choosing which ones are best for us according to our constitutions, so we probably still need to see a TCM practitioner/acupuncturist/herbalist.
Still... it would be nice to be able to identify exactly what is going on.
Also... if possible can you provide summaries of the material? That would really help. I understand it may not be possible.
Thanks.
Claire
Posted by micul (Member # 6314) on :
Claire wrote:
One time I took some ozonated water and suddenly I was stricken with inflammation and dehydration. After much research, I am starting to conclude that it had to do with a sudden and strong parasitic 'die off' and consequent endotoxins. It took months to clear. Just didn't understand, at all,
IMO it's not a die off that you are getting. It's a flair up because you are giving an aerobic pathogenic bacteria a big burst of oxygen down in your gut which gave it a boost.
Ozone will kill Bb because it's anerobic, but Bart and Babs are both aerobic, so you could have triggered a growth spurt, or revitalized them. If it was truly a die off, it only would have lasted a short time untill the dead organisms were cleared. That is unless you had continued to drink ozonated water for an extended period. But it sounds like you only took it short term.
Posted by trails (Member # 1620) on :
woah---too much information. but I would like to ask if anyone knows what the difference is between endo toxin and ritchie shoemaker's assertion of biotoxins?
Posted by seibertneurolyme (Member # 6416) on :
Tree,
Thanks so much for putting all that info in one spot. Haven't had time to read and absorb it all yet.
And thanks to Marnie and everyone else for contributing to this very informative discussion.
Trails,
Don't remember Dr S ever specifying endotoxin or exotoxin -- just remember the word toxin. Maybe someone else will know more.
Bea Seibert
Posted by clairenotes (Member # 10392) on :
Thanks Micul.
It has been almost one year since the ozone incident and this makes sense. Something was activated and I am almost positive it was babs (sudden severe headaches) and quintana fever due to five day cycles, a relative of bart.
Still, endotoxins continued to show up for months afterward, as did an inflammatory response that occurs after almost every anti-microbial protocol I have ever used. So if endotoxins are part of the die-off, they are not easy to clear. At least they weren't in my case and the end result was that there was a lot going on that was difficult to sort out.
Looks like a die-off and flare-up all at once. Don't recommend this to anyone.
Hope everyone is careful with the whole process of die-off and clean-up.
Claire
Posted by Marnie (Member # 773) on :
Trivalent means it has 3 charges...O3 is ozone.
OUR OWN ANTIBODIES PRODUCE OZONE.
Bb alters its protein expression in response to various levels of CO2. (Since ticks are attracted to CO2, this makes sense.) Find the relationship that exists between CO2 levels and O3.
Some minerals can have one, two, or three charges too.
Read the following VERY carefully and watch for my ***
A relatively recent discovery is that the
Fab portion of all antibodies, regardless of antigenic specificity, catalyze a reaction between singlet oxygen and water,
***yielding the toxic oxidative species hydrogen peroxide, ozone, and hydroxide radials (reviewed in Ref. 61).***
The reaction rate is fastest for antibodies with highest UV absorption. It is hypothesized that this activity may represent an ancient mechanism of protection against infection.
B. burgdorferi may be particularly vulnerable to oxidative damage, as it grows best in environments with limited oxygen, and its genome does not encode a catalase (62).
OUR OWN ANTIBODIES yield ozone...specifically the "fab" portion, which incidentally is damaged due to Mg deficiency. Restoring Mg, restored the "health" of our OWN antibodies.
Documentation follows:
Our own antibodies are not "perfect" fighters against Bb, why? Characterization of the physiological requirements for the bactericidal effects of a monoclonal antibody to OspB of Borrelia burgdorferi by confocal microscopy.
The bactericidal effect of Fab-CB2 is not dependent on the induction of spirochetal proteases but is dependent on the presence of Ca2+ and Mg2+.
***Supplementation of Ca2(+)- and Mg2(+)-free medium with these cations restored the bactericidal effects of Fab-CB2.***
The mechanism by which a Fab fragment of an antibody destroys a bacterium directly may represent a novel form of antibody-organism interaction.
PMID: 9125579
A ``novel form of antibody-organism interaction?'' I don't THINK so!!!
E. Required by immunological process. Magnesium, immunity, and allergy: Mg is required for several steps of immunological reactions 1. Lymphoblastic transformation, a prerequisite of secretion of antibodies by lymphoblasts, requires Ca2+ and Mg2+ 2. Mg is required for synthesis of proteins, immunoglobulins included 3. Antibody-induced complement activation is Mg dependent 4. The antigen-immunoglobulin-complement reaction induces degranulation of the mastocyte
Aerobic...so are we (!) i.e. oxygen breathers. But we can't BREATHE ozone (there is a LITTLE present at all times in the air, but most is shielded from us because it does tremendous lung damage).
It is curious that persons who once came to this board and were discussing ozone saunas (as being very effective) never once talked about herxes after the saunas (unlike Rife which does lead to a herx response).
Think about the above ozone discussion and how it might also apply to "aerobic" pathogens.
To protect itself from oxidative damage, it looks like Bb is "upregulating" MnSOD which impacts CoQ10 levels.
It looks like we need a LOT of CoQ10...ongoing for many months (likely) to correct this situation. If you combine abx. with this, you are defeating the purpose. Abx. deplete specific nutrients we need to FIGHT. And it is bad enough that for many reasons, Mg levels are ALREADY low and continue to be driven lower.
We KNOW Bb can be destroyed by NO (nitric oxide) AND the powerful (damaging) free superoxide radical.
For more on ozone (you will be blown away), go here:
PMID: 11548286 and PMID: 15770062 and PMID: 12438699 and PMID: 11799239 and PMID: 16712921
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