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Reactive Arthritis

The development of a spondyloarthropathy phenotype is the result of a complex interaction between environmental triggers acting on a genetically susceptible individual reactive arthritis, reactive artritis, new treatments. The striking specificity of these diseases for individuals with B-27 remains the single most striking genetic clue to the etiology and the pathogenesis, however it is also quite clear that there are many other genes involved in determining susceptibility. For example, twin studies have shown that HLA-B 27 positive monozygotic twins have a concordance rate of about 75% for disease, whereas this drops to about 25% in B 27 positive dizygotic twins. Again, emphasizing the role of other genes. It’s also been suggested in the past few years that the contribution that B 27 makes to the overall susceptibility is somewhere around 20% or less. There are currently genome-wide surveys going on to try to identify other genes that are involved in susceptibility.

With regard to environmental triggers, there is the obvious well known triggering action of bacterial pathogens, particularly JRAM negative organisms. But there are some rather recent variance modeling studies to suggest that the majority of the susceptibility is actually genetic, implying that whatever the environmental triggers are they are probably relatively ubiquitous.

The predominant hypothesis in the last decade or so to explain the role that HLA-B 27 plays in disease pathogenesis argues that it is a result of its peptide binding specificity. So it is hypothesized that B 27 can select and present arthritogenic peptides and these peptides presumably are arthritogenic because they resemble in some way a pathogen derived peptide and thus can stimulate the proliferation of auto-reactive B 27 restricted T cells. This hypothesis has really not been proven, in fact to date there are no arthritogenic peptides that have been identified and studies looking for auto-reactive CD-8 positive B 27 restricted T cells are fairly limited.

Immuno-histochemical analyses of very early sacroiliac lesions in patients with ankylosing spondylitis reveal a preponderance of CD-4 positive T cells. Lots of CD-14 positive or activated macrophages and increased levels of messenger RNA for TNF alpha, interferon gamma and IL-4. Thus neither a TH-1 or a TH-2 profile. In comparison, peripheral joint fluid more typically will show similar numbers of CD-4 and CD-8 positive T cells and more of a TH-2-like pattern with IL-4 and IL-10.

So what about transgenic animal models? Well, there are three systems where expression of HLA-B 27 in rodents can lead to an inflammatory arthropathy. I really don’t have time to go into each of these model systems in any great detail, so I call your attention to relatively recent review articles for those of you who are interested in further reading on this subject. I do want to make a couple of important points about the model systems. Where it’s been looked at, it does appear that T cells are mediating the disease process. However, in both spontaneous inflammatory disease in rats and spontaneous arthritis in mice it appears that CD-4 positive T cells play a critical role in the disease. In the spontaneous arthritis model in mice, animals that expressed B 27 developed disease in the absence of beta 2 microglobulin. What this means is that cell surface expression of HLA-B 27 in a folded, conformationally correct form that can present peptide, is virtually nonexistent although there are free heavy chains that are expressed. In addition, lack of beta 2 microglobulin causes a defect in the selection of the CD-8 positive T cells. So for example, in this model system, it is extremely unlikely that a straightforward arthritogenic peptide mechanism is working. There are data that support that hypothesis in HLA-B 27 transgenic rats, although there is no direct evidence indicating what the arthritogenic peptides are. There are other components of this system which have not been easily explained. One is the requirement for over-expression of HLA-B 27.

There is sort of a new concept evolving in this field and I want to bring that to your attention today. Normally when class I molecules are synthesized, shortly after the heavy chain is made it folds into a conformation that is capable of binding beta 2 microglobulin and peptide and then makes its way to the cell surface where it can be recognized by T cells. We’ve shown recently that in addition to this normal pathway of B 27 assembly, that B 27 has a tendency to miss-fold. Interestingly this miss-folding is entirely dependent on the B pocket structure and the B pocket of B 27 is critically involved in the peptide selection process, and in fact it is very similar in all of the B 27 subtypes but differs between alleles and has been hypothesized to be critical for the arthritogenicity of HLA-B 27.

So I emphasize right now that this is theoretical, although clearly HLA-B 27 miss-folds, the consequences are unknown and their relation to pathogenesis is unknown. But the main point that I want to leave you with is that miss-folding presents an alternative to the arthritogenic peptide hypothesis and may be important in pathogenesis.

Let me first show you some of the examples that are these diseases. These poor boys got a spondyloarthropathy. All of them are 27 boys. All of them got peripheral arthritis in their initial months of disease and some of them for a few years. Then _ affecting the lower limbs. Throughout the course of their disease they present a series of symptoms that define their final diagnosis. Some of those symptoms were involving the axial joints, specifically the sacroiliac joints and the spinal joints

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