Marnie
Frequent Contributor (5K+ posts)
Member # 773
posted
"Accumulation of iron in the synovium of RA patients is thought to contribute towards tissue damage.1
Iron chelation or deprivation can reduce joint inflammation in both experimental18 and clinical19 situations, suggesting that reducing the amount of iron in the joint can be beneficial, although in the latter case undesirable side effects were observed, making chelation unsuitable for routine clinical purposes.
In vivo, iron is normally present ***intracellularly*** as haem, or stored as ferritin, while ***extracellular iron*** is bound by transferrin or lactoferrin.20
In these forms it is generally harmless, and in particular, transferrin or lactoferrin bound iron cannot catalyse the potentially damaging production of hydroxyl radicals from hydrogen peroxide and superoxide.21
However, in situations where iron levels exceed the binding capacity of these proteins, it may bind non-specifically to molecules such as citrate, or to other proteins.22
This fraction, referred to as "free" iron, can catalyse free radical production.
The rheumatoid joint, where reactive oxygen species are produced by activated neutrophils or macrophages provides an enviroment in which the presence of "free" iron can lead directly to tissue destruction.
In this study it was found that about one third of the synovial fluids examined contained "free" iron, thus confirming earlier reports.15
It should be noted that such iron was only detectable when the assay was performed at pH 5.3, as at pH 7.4 no "free" iron was detectable in any sample.
However, the lower pH is comparable to that found in the microenvironment of an activated macrophage, where concentrations of hydrogen peroxide and superoxide are likely to be highest.
At this pH transferrin is an ineffective iron binder, whereas lactoferrin remains effective.7
Lactoferrin is thus likely to be a key molecule in determining whether "free" iron is present in the synovium in vivo.
Our results provide three pieces of evidence to support this hypothesis.
Firstly, lactoferrin, but not transferrin concentrations were significantly lower in synovial fluids in which "free" iron was present than in those where it was not detected (fig 2).
Secondly, addition of exogenous lactoferrin, but not transferrin, to synovial fluid reduced the "free" iron concentration.
Thirdly, the fact that the transferrin: albumin ratio in synovial fluid is similar to that in serum, whereas the lactoferrin concentration is much high than in serum, suggests that transferrin enters the synovium simply as a result of transudation and is not related to the inflammatory process.
This indicates that relative lactoferrin deficiency, in the context of exigent free iron levels, existed in vivo, which was correctable in vitro and rendered the presence of an alternate competetive inhibitor unlikely.
Transferrin increased the "free" iron concentration in some cases.
This may reflect movement of iron from other molecules, whose iron binding is not pH dependent, to transferrin, which then releases at least some of its iron at pH 5.3.23
Lactoferrin in synovial fluid comes from degranulating neutrophils, where it is stored in secondary granules.24
Neutrophil lactoferrin is thought to function as an antimicrobial and anti-inflammatory agent as a result of its iron scavenging ability,25 but it is evident that the amount produced or released into the synovial fluid is not always sufficient to neutralise all the iron present.
If lactoferrin concentrations in the synovium could be increased, synovial inflammation and tissue destruction might be reduced.
This strategy would avoid the unwanted side effects that accompany use of chelating agents to lower synovial iron concentrations.18
One point needing clarification is the possible adverse role of autoantibodies to lactoferrin.
Lactoferrin is one of the target antigens of antineutrophil cytoplasmic antibodies (ANCA) and these have been detected in a small proportion of synovial fluids from RA patients.26
It is possible that they could affect the ability of lactoferrin to bind synovial iron, as we have found that antilactoferrin IgG causes lactoferrin bound iron to become reactive in the bleomycin assay.27
As well as providing evidence for the importance of lactoferrin in controlling the appearance of "free" iron in the synovium, this work has also considered possible underlying mechanisms for the accumulation of iron in the synovium.
Iron homeostasis is normally tightly controlled by the IRP/IRE system, the presence of excess iron causing conversion of IRPs to the non-RNA binding form, and consequently increasing the availability of ferritin for iron storage while reducing unwanted cellular iron uptake by down regulating transferrin receptor expression.3 4
It might therefore be expected that iron accumulation in the rheumatoid joint would trigger this protective mechanism.
However, H2O2 and NO, both of which are produced by synovial inflammatory cells,28 can have an opposing effect as they can convert IRPs back to the RNA binding form.5
It was found that the proportion of active (that is, RNA binding) IRP in cells from synovial fluid showed no correlation with synovial fluid "free" iron concentrations, but did correlate with serum CRP, an established index of disease activity (fig 4).
This strongly suggests that the effect of inflammatory mediators such as H2O2 and NO on IRP activity overrides that of iron itself.
To our knowledge, this is the first time that the ability of inflammatory stimuli to override the effect of iron on IRP activity has been demonstrated in a clinical setting.
This has important implications for the mechanism of local iron accumulation at inflammatory sites such as the rheumatoid joint and for the anaemia of chronic disease.
It is also compatible with the suggestion29 that ferritin production may fail in synovial macrophages, as active IRP would prevent translation of ferritin mRNA.
Further confirmation that the inflammatory response affects IRP activation comes from the finding that the transcription factor NF B was activated in synovial cells, and that this correlated with increased IRP activity.
NF B is activated by a variety of primary inflammatory mediators such as TNF , IL1, LPS, and thus has been implicated in the pathogenesis of RA.
In particular, H2O2, a product of activated macrophages, can activate both IRP5 and NF B,6 suggesting that it may play an important part in RA.
In conclusion, we have shown that lactoferrin probably fulfills a critical role in reducing the amount of potentially toxic "free" iron in the synovium, and that such iron may accumulate, at least in part, because inflammatory mediators (H2O2, NO) produced locally override the normal iron mediated homeostatic effect of IRP on iron uptake and storage.
Lactoferrin is therefore an attractive potential candidate for gene therapy approaches to the treatment of RA."
posted
Northstar, I'm in the same boat you are... High Hemogloblin... low ferritin...... (9)...
What do we do ?????
I am turning whiter by the day...........and weaker........Seeing my Lyme Doc on Monday, but the ferritin was drawn by my family doc.....
I did test neg for RA.... I was treated for Babs but my test last month came back negative.
Posts: 116 | From state of lyme | Registered: Oct 2006
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