EditorialInfluence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis*
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).
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)
References (48)
- et al.
Population genetics of rheumatoid arthritis
Rheum Dis Clin North Am
(1992) - et al.
The genetic basis of rheumatoid arthritis. The shared epitope hypothesis
Rheum Dis Clin North Am
(1992) - et al.
Shared epitope and rheumatoid arthritis: Disease associations in Greece and meta-analysis of Mediterranean European populations
Semin Arthritis Rheum
(2002) Rheumatoid arthritis in the elderly
Clin Rheum Dis
(1986)- et al.
Could HLA-DRB1 be the protective locus in rheumatoid arthritis?
Immunol Today
(1995) - et al.
Repeated therapy with monoclonal antibody to tumor necrosis factor alpha (cA2) in patients with rheumatoid arthritis
Lancet
(1994) - et al.
Highly informative typing of the human TNF locus using adjacent polymorphic markers
Genomics
(1993) - et al.
What is the natural history of rheumatoid arthritis?
Baillieres Best Pract Res Clin Rheumatol
(2001) - et al.
Twin concordance rates for rheumatoid arthritis: Results from a nationwide study
Br J Rheumatol
(1993) Association of the B-cell alloantigen DRw4 with rheumatoid arthritis
N Engl J Med
(1978)
Association of HLA-Dw16 with rheumatoid arthritis in Yakima Indians. Further evidence for the “shared epitope” hypothesis
Arthritis Rheum
Is rheumatoid arthritis in Indians associated with HLA antigens sharing a DR beta 1 epitope?
Ann Rheum Dis
Association of HLA-DR4-Dw15 (DRB1*0405) and DR10 with rheumatoid arthritis in a Spanish population
Arthritis Rheum
Different gene loci within the HLA-DR and TNF regions are independently associated with susceptibility and severity in Spanish rheumatoid arthritis patients
Tissue Antigens
The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis
Arthritis Rheum
Does the HLA-DRB1 shared epitope really contribute that much to the development or severity of rheumatoid arthritis? In: Controversies in Rheumatology
Association of HLA-DR4/Dw4 and DR2/Dw2 with radiologic changes in a prospective study of patients with rheumatoid arthritis. Preferential relationship with HLA-Dw rather than HLA-DR specificities
Arthritis Rheum
HLA and rheumatoid arthritis: A combined analysis of 440 British patients
Ann Rheum Dis
HLA and rheumatoid arthritis: Susceptibility or severity?
Dis Markers
The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis
Ann Intern Med
Association of the shared epitope with radiological severity of rheumatoid arthritis
J Rheumatol
HLA markers and prediction of clinical course and outcome in rheumatoid arthritis
Arthritis Rheum
HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis
J Rheumatol
HLA-DRB1 genotype influences risk for severity of rheumatoid arthritis
J Rheumatol
Cited by (0)
- *
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]