Genetic factors contribute both to the development and the course of Rheumatoid Arthritis (RA). The contribution of inherited genetic variability has been estimated 60%. Moreover, stochastic processes during the development of the T and B lymphocytes repertoire or so-called somatic genetic diversity may be responsible for an as yet unknown fraction of the remaining 40% of the factors contributing to the pathogenesis of RA.
Thus far, the only known inherited genetic factors are encoded by the HLA system. These factors contribute about 40% of the inherited genetic variability and also contribute to the somatic genetic diversity. The main contribution of the HLA system is conferred by the HLA class II region and HLA-DR genes are certainly involved but HLA-DQ genes also may have a contribution. Perhaps most importantly: certain HLA-DR genes may provide dominant protection. HLA genes not only contribute to the development but also the course and severity of RA. There is also evidence for dominant protection against the development of erosions. We observed that this effect may be relatively short-lasting and overruled by a very early start of treatment with DMARDS (Yard et al., submitted for publication). These observations suggest that pharmacogenomics may offer possibilities for a tailor-made optimal treatment for individual RA patients. The standard hypothesis for an association of an HLA class II allele with an auto-immune disease is that auto-reactive T cells recognise certain self-epitopes that are exclusively or preferentially presented by that particular HLA class II allele. The Shared Epitope (SE) hypothesis (Gregersen et al. 1987) is a paradigm of this. More than 20 years of intensive research along these lines have however yielded little evidence for this concept. Therefore, we have developed an alternative hypothesis. In this hypothesis auto-reactive T cells do not play a role in the initiation but in the regulation of the disease process (Zanelli et al., Rheumatology, in press). Our model is an extension of the one proposed by Thomas and Lipsky (Immunology Today 1996; 17: 559–560). It starts with activation of synoviocytes by a trauma or an infection. Usually this results in a local inflammation that resolves in a few days, but in the presence of one or more (yet to be identified) genetic factors (nót HLA class II) an aberrant activation of synoviocytes results in a chronic inflammation. As proposed by Thomas and Lipsky chemo-attraction of dendritic cells (DC) and/or the transformation of synoviocytes to follicular DC may play a key role in this process. In our model a so-called amplifier gene stimulates this chemo-attraction of and/or the differentiation to DC’s. The DC’s present self-peptides not to disease-inducing but to regulatory auto-reactive T cells that have been recruited also to the inflamed synovium. These regulatory T cells recognise self-peptides such as DERAA peptides from the HV III region of certain HLA-DR alleles presented by DR or DQ molecules. This DC-regulatory T cell interaction is an essential checkpoint for the control of the inflammation and is controlled by HLA class II genes. In the absence of protective HLA alleles and therefore self-reactive regulatory T cells this checkpoint fails and this results in a local loss of tolerance and a (severe) chronic arthritis (RA).
This model has several important implications for the immunotherapy of RA:
We may stop the search for a unique target antigen for disease-inducing T cells
Immunotherapy that is exclusively targeted at T cells may have an adverse effect
Immunotherapy strategies for RA should either be targeted at the re-establishment of a normal phenotype in synoviocytes or on restoring a functional immunoregulatory loop.
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