Editorial
Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis*

https://doi.org/10.1053/sarh.2002.32552Get rights and content

Abstract

Background and Objectives: All human leukocyte antigen (HLA)-DRB1 alleles associated with rheumatoid arthritis (RA) encode a conserved amino acid sequence (QKRAA, QRRAA, or RRRAA) at position 70-74 in the third hypervariable region (HVR3) of the DRβ1 chain, which is commonly called the shared epitope (SE). Several studies, however, have associated the HLA-DRB1 gene in RA severity and progression rather than with susceptibility. Moreover, the association with disease severity and presence of the SE varies among different ethnic populations. HLA-DRB1 alleles also influence the disease onset. In this manuscript, the role of the HLA genes in RA was examined. Methods: A retrospective review of the literature was conducted to analyze the influence of the HLA-class II genes on the susceptibility, severity and protection against RA. Results: The HLA-DRB1*0401/*0404 genotype was associated with a higher risk for early disease onset in more severe forms in patients from the United Kingdom (UK). In northwest Spain, RA onset under 40 years is strongly associated with HLA-DRB1*0401 and *0404. In contrast, RA onset above 60 years is associated with HLA-DRB1*01. The protection against RA linked to some HLA-DRB1 alleles encoding a DERAA sequence of amino acids at position 70-74 in the HVR3 of the DRβ1 chain, and specifically aspartic acid (D) at position 70 of this chain, recently was confirmed in both UK and northwest Spanish populations. Besides HLA-class II, other genes may be implicated in RA. Polymorphism in the tumor necrosis factor (TNF) region seems to be associated with RA, even in patients without the HLA-DRB1 SE. However, other genes such as interleukin-1 (IL-1) and corticotropin-releasing hormone may play a role in susceptibility to RA. Conclusions: The additive effect of various genes may account for the development of RA and its clinical severity. Semin Arthritis Rheum 31:355-360. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Human leukocyte antigen association with RA

Initial studies by Stastny using mixed lymphocyte culture reactions showed an association between human leukocyte antigen (HLA)-Dw4 (HLA-DRB1*0401) and RA. Subsequent studies proved an association between RA and a broad serologically defined HLA-DR4 specificity (2). However, DNA sequence level studies showed that some alleles of the HLA-DRB1 gene could not be discriminated by antibodies used in tissue typing. HLA-DRB1 typing performed on DNA samples using polymerase chain reaction (PCR) based

Shared epitope hypothesis

Most HLA-DRB1 associations with RA have in common a conserved sequence of amino acids at position 70-74 in the third hypervariable region (HVR3) of the DRβ1 chain. This subsequently led to the formulation of the shared epitope (SE) hypothesis, which proposes that all RA-associated HLA-DRB1 alleles (DRB1*0101, *0102, *0401, *0404, *0405, *0408, *1001, *1402) share a conserved motif of amino acid residues (QKRAA/QRRAA/RRRAA) in the HVR3 of the DRB1 molecule 8, 9 (Table 1).

Table 1: Epitope encoded

Are HLA-DRB1 shared epitope alleles associated with disease severity rather than susceptibility?

Several studies have indicated that the influence of HLA-DRB1 molecules on RA is due to effects on disease severity and progression rather than susceptibility. This was initially reported by investigators in the UK for HLA-DR4 and appeared to be related to the extent of bone erosions 11, 12, 13. However, the association with disease severity varies among different ethnic populations. Thus, a well-defined association exists between severe disease outcome and presence of the SE, particularly in

Do late-onset RA and “classic” RA have different HLA-DRB1* genetic susceptibility?

The onset of RA usually occurs in middle age. However, disease onset may start after the age of 60 years, and these cases are defined as having a late or elderly onset (30). Of note, a subset of patients with RA with elderly onset may present with polymyalgia symptoms that may be difficult to differentiate from polymyalgia rheumatica. In this regard, few studies have examined the relationship between HLA and the age of RA onset. In the UK, Jaraquemada et al (12) observed a significantly

RA protective epitope

The concept of joint protection linked to some HLA-DRB1 alleles encoding a DERAA sequence of amino acids at position 70-74 in the HVR3 of the DRβ1 chain, and specifically aspartic acid (D) at position 70 of this chain, was developed from initial observations in the mouse experimental model of arthritis, collagen-induced arthritis. In transgenic and F1 mice, the presence of the Eb(d) gene yielded a significant reduction in the incidence and severity of arthritis 33, 34. As in all protective

Other potential RA susceptibility genes

Besides HLA-class II, other genes may be implicated in RA. Among other potential candidates is tumor necrosis factor (TNF)-α. This proinflammatory cytokine seems to be important in destructive RA, and neutralization of this molecule with monoclonal anti-TNF antibodies is a treatment for RA (40). The TNF region is polymorphic and is located within the HLA class III region. A number of biallelic polymorphisms have been identified within the TNF locus, as well as 5 microsatellite markers (a-e) (41)

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    *

    Address reprint requests to Miguel A. Gonzalez-Gay, MD, Rheumatology Division, Hospital Xeral-Calde, c/ Dr. Ochoa s/n, Lugo, 27004, Spain. E-mail: [email protected]

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