Elsevier

Human Immunology

Volume 60, Issue 2, February 1999, Pages 152-158
Human Immunology

Original Articles
HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis

https://doi.org/10.1016/S0198-8859(98)00101-3Get rights and content

Abstract

We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.

Introduction

Rheumatoid arthritis (RA) is a long-lasting progressive disease which affects about 1% of the population in developed countries. It is characterised by synovial infiltration’s of lymphocytes, monocytes and granulocytes, and often leads to the irreversible destruction of cartilage and bone, resulting in at least a moderate disability in 80% of the patients and in early mortality. Existing treatments essentially aim at slowing down the inflammatory process using non-steroidal anti-inflammatory drugs and disease-modifying drugs such as methotrexate [1]. The classification criteria as defined by the American Rheumatism Association (ARA) in 1987 emphasise the heterogeneity of RA evidenced by the important differences in disease progression among patients [2].

Predicting at an early stage of arthritis which patients are most likely to develop severe RA would be of great clinical value for rheumatologists [3]. In this regard, the role of the Human Leukocyte Antigen (HLA) class II region in RA has been the subject of intense investigations and debates 4, 5, 6. HLA class II heterodimers present antigenic peptides for recognition by specific CD4-positive T cells. Three molecules, HLA-DP, -DQ and -DR, are respectively encoded by DPA1 and DPB1, DQA1 and DQB1, DRA and DRB1 (and DRB3, DRB4 or DRB5). Most of these genes are highly polymorphic. Low frequency of recombination among them, especially between DQ and DR loci, creates a linkage disequilibrium which in turn distributes the alleles of the different loci into HLA class II haplotypes.

Since the early observations by Stastny, it has been clear that some HLA-DRB1 alleles, i.e. DRB1∗01, ∗04 and ∗1001, or their corresponding haplotypes predispose to RA 7, 8, 9, 10. All these alleles share the similar motifs QKRAA, QRRAA or RRRAA in their third hypervariable (HV3) region 7, 8, 9, 10. This observation has been the basis of the Shared Epitope (SE) hypothesis [11]. In this model, the motifs QK(R)RAA and RRRAA predispose to RA by influencing antigenic peptide presentation as part of the HLA-DR peptide-binding groove [12]. As an alternative explanation, the SE motif has been considered as part of a self-peptide able to modulate disease predisposition through its effect during T cell education [13]. However, the SE hypothesis has left several questions unanswered: (1) Why do different SE-positive DRB1 alleles provide different strengths of predisposition 14, 15, 16, 17, 18, 19, 20, 21, 22? (2) Why does HLA-related predisposition behave as a recessive trait 20, 21, 22? (3) Does HLA predispose to RA or only to severe RA 5, 14, 16, 17? Without an answer to these questions, the diagnostic and prognostic values of HLA markers in RA remain limited in clinical practice [23].

Due to linkage disequilibrium, DQB1∗0501/DQA1∗01 and DQB1∗03/DQA1∗03 alleles are respectively found in DRB1∗01- and DRB1∗1001-, and in DRB1∗04- and DRB1∗0901-positive haplotypes, including DRB1∗0103- and ∗0402 which are not associated with RA (Table 1 and ref. [10]). Noticeably, DRB1∗0103 and ∗0402 alleles share with each other a common motif DERAA in their HV3 region, instead of the SE motif. Because of this observation and on the basis of a series of investigations in mice, one of us (EZ) has recently proposed a new hypothesis to explain the HLA and RA association. In this model, hereafter referred to as RAP (RA Protection), the predisposing molecules are DQB1∗0501/DQA1∗01 and DQB1∗03/DQA1∗03 while the HV3 motif DERAA of some DRB1 alleles acts as a self-determinant able to modulate this predisposition through its binding to predisposing DQ molecules 24, 25, 26. Thus, the combination of DQ and DR alleles of both haplotypes plays a crucial role in disease predisposition. To test this model, we have analysed in the present study the distribution of DQ and DR alleles in 155 early RA patients and 306 controls.

Section snippets

Controls

In 1993, a special Early Arthritis Clinic (EAC) was started at the Department of Rheumatology of the Leiden University Medical Centre, the only centre for arthritis in a health care region of more than 300,000 inhabitants [27]. Its protocol was designed as a population based study on arthritic patients. To this end, patients enrolled in this program must have had an arthritis diagnosed by a rheumatologist in the department, and the symptoms must have lasted less than two years. In the period

Two doses of predisposing DQ alleles strongly predispose to RA, even in individuals with a single dose of SE

Table 2 summarises the distribution of Dutch RA patients and controls based on their SE, DQRA and DERAA alleles. One hundred and eight out of 155 RA patients (70%) were both SE- and DQRA-positive compared to 127 out of 306 controls (42%), while only 6 of the patients (4%) and 19 of the controls (7%) were DQRA-positive without SE. None of the patients nor the controls were SE-positive without DQRA. Thus, although DR1- and DR4-related haplotypes clearly predispose to RA, the strong linkage

Discussion

The SE hypothesis is not able to explain several reported observations in humans. Thus, a more complex model has to be put forward. After extensive studies on the role of class II genes in arthritis susceptibility in mice and looking into their analogy in humans, we have proposed that the HLA and RA association was the result of DQ and DR allele combinations 24, 25, 26. In this model DQ predisposes while some DRB1 alleles protect. For instance, DRB1∗0402 which only differs from RA-predisposing

Acknowledgements

The authors are grateful to the technicians in the HLA-typing laboratory for their skills and conscientiousness. The authors would also like to thank Drs F. Claas and M. Giphart for critically reading the manuscript. This work was supported by The Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) and The Nederlandse Vereniging voor Reumabestrijding (NVR).

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