Hla class II association with rheumatoid arthritis: Facts and interpretations
Introduction
Rheumatoid arthritis (RA) remains a syndrome. Its heterogeneity and complex genetic susceptibility strongly suggest that RA is more than one disease [1]. Consequently, it is not surprising that more than 20 years after the original report by Stastny [2], we are still debating on the meaning of the association of certain HLA class II alleles with RA. The ever-growing complexity of HLA, both in numbers of alleles and haplotype configurations, does not help in resolving this issue.
One debate is about the significance of this association. Because HLA class II molecules are presenting peptides to specific T cells, the simplest explanation would be that the pathology of RA involves autoreactive T cells recognizing self-determinants in the context of RA-associated alleles. However, the actual determinants recognized by these T cells remain speculative and the question whether T cells are involved in the initiation or perpetuation of RA is yet unanswered [3]. In the present essay, we will only briefly discuss the possible mechanisms behind the association of HLA class II with RA.
Another debate is about the association itself. Nobody would argue that DR4 alleles and related haplotypes are not associated with severe, persistent, rheumatoid factor-positive polyarthritis with extraarticular manifestations [4]. However, the question whether DR4 influences disease severity or susceptibility is still a matter of debate. Even less understood is the actual contribution of DR1 and DR10 alleles and related haplotypes to RA 5, 6, 7. A possible confounding effect of HLA-DQ alleles in RA association has also been regularly suggested and disputed 8, 9. This latter issue is due to the fact that DQ and DR alleles are not distributed randomly but rather constitute haplotypes that are well preserved inside ethnic groups, and even in the whole human population. The protective effect of some DR alleles has also been described 10, 11. Hereafter, we will review what we have learned in the last 20 years on the individual contribution of HLA class II alleles to RA. From these observations, we will discuss the need for a better model of HLA and RA association.
Section snippets
DRB1∗0401
Initially named DR4Dw4, the DRB1∗0401 allele encoding the almost unique motif 70QKRAA74 in its third hypervariable (HV3) region is the most common DR4 allele in the Northern European and North American populations. For instance, in a group of 306 Dutch cadaveric organ donors that we have used as controls in the past [12], the allele DRB1∗0401 constituted 54 of the 84 (64%) observed DR4 alleles. This allele is mostly in linkage disequilibrium with either DQB1∗0301-DQA1∗03 (DQ7) or
The shared epitope hypothesis
In 1987, Gregersen and colleagues [33] published an article proposing a model to account for the role of the HLA class II region in RA. The so called shared epitope (SE) hypothesis insists on the contribution of the third hypervariable (HV3) region of DRB1 in disease susceptibility. It underlines the fact that RA-associated alleles encode either the HV3 motif 70QKRAA74, i.e., DRB1∗0401, or 70QRRAA74, i.e., DRB1∗0101, ∗0404, and ∗0405. From the original description of the SE model, a particular
Need for a better model
None of the two models (SE and RAP) can account for all the observations published in the field for the last 20 years. We think that HLA-DQB1 and DQA1 are the primary susceptibility loci because they offer a simple explanation for the dichotomy between DQ3 (DQB1∗03 and ∗04 combined with DQA1∗03) and DQ5 (DQB1∗0501 combined with DQA1∗0101 and ∗0104). DQ3 predisposes more strongly to RA and to a more severe disease while DQ5 is weakly associated with RA and often with a mild form of
Acknowledgements
The authors would like to acknowledge the contributions of D. Bontrop-Elferink, A. Snijders, L. Morgan, L. van der Zanden, K. Vos, M. Pascual, M. Giphart, G. M. Th. Schreuder, W. Verduyn, T. W. J. Huizinga, J. M. W. Hazes, H. Visser, and I. van der Horst-Bruinsma (Leiden University Medical Centre, The Netherlands) to the work described in this article. This work was supported by The Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) and The Nederlandse Vereniging voor
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