Molecular basis for the association between HLA DR4 and rheumatoid arthritis. From the shared epitope hypothesis to a peptidic model of rheumatoid arthritis

doi:10.1016/0009-9120(92)90328-P

Clinical Biochemistry

Volume 25, Issue 3, June 1992, Pages 209-212

https://doi.org/10.1016/0009-9120(92)90328-P Get rights and content

Susceptibility to rheumatoid arthritis (RA) maps to residues QKRAA/QRRAA in the third hypervariable region of the HLA DRβ1 chain. Peptides from the same area of MHC class II molecules are able to modulate the T-cell repertoire by deleting self-reactive T-cells. The Epstein Barr virus glycoprotein gp110 and the dna J heat-shock protein from E. coli mimic the third hypervariable region of HLA-Dw4DRβ1. Thus, the same area of HLA DRβ1 carries susceptibility to RA, modulates the T-cell repertoire and is mimicked by human pathogens. RA may originate from a particular shape imposed on the T-cell repertoire by the QKRAA/QRRAA sequence in the third hypervariable region of HLA DRβ1.

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Cited by (17)

Autoimmunity versus tolerance: Analysis using transgenic mice
2000, Human Immunology
On the basis of our extensive studies on collagen induced arthritis in HLA class II transgenic mice, we proposed a hypothesis to explain role of shared epitope in rheumatoid arthritis (RA) association. According to our hypothesis, complementation between both DQ and DR molecules is required for susceptibility or protection from disease. While certain DQ alleles predispose individuals to RA, DRB1 molecule can modulate disease by shaping T-cell repertoire in the thymus by providing self-peptides and presented by DQ molecules. Using Aβo.DQ8 transgenic mice, we tested ability of peptides derived from HV3 of DR molecules, implicated in RA positively or negatively, to activate T cells. While the peptides derived from RA susceptible DR molecule were poor binders and poor in activating T cells, the peptides derived from RA resistant DR molecules were high affinity binders and efficient T-cell activators. Our experiments suggest that high affinity DR peptides could induce tolerance to autoimmunity while the low affinity peptides could be permissive to autoimmunity. Using peptide from DRB1∗0402 molecule, known to be associated with resistance to RA, prior to induction of collagen induced arthritis prevents the onset of disease. Thus, self-peptides derived from HLA molecules could potentially generate tolerance or autoimmunity depending on their binding affinity with HLA molecules.
Vaccine-induced autoimmunity
1996, Journal of Autoimmunity
HLA-DQ Associations in Type 1 Autoimmune Hepatitis
1995, Mayo Clinic Proceedings
To determine whether, in patients with type 1 autoimmune hepatitis and human leukocyte antigen (HLA) DR3 and DR4 positivity, any DQ antigen is disease-specific.
HLA class II typing was performed by restriction fragment length polymorphism in 103 patients with type 1 autoimmune hepatitis, 104 patients with chronic viral hepatitis, and 80 normal subjects. A shared association with a disease-specific DQ antigen was sought in patients with HLA-DR3, DR4, and DR3-DR4.
Patients with HLA-DR3 and DR4 shared positivity for DQ2, DQ4, DQ5, DQ6, and DQ7, but the associations reflected established linkages or were of low frequency. Patients heterozygous for DR3-DR4 or homozygous for either DR3 or DR4 did not have a shared DQ antigen. Only the DR3-DQ2 haplotype distinguished patients with autoimmune hepatitis from normal subjects or those with chronic viral hepatitis.
The DR3 and DR4 antigens are not associated with a single disease-specific DQ antigen in type 1 autoimmune hepatitis. The DR3-DQ2 haplotype is the principal risk factor for the disease at our referral center. Analyses by restriction fragment length polymorphism do not implicate a single susceptibility gene at the DQ locus.
Infection and autoimmunity: A story of the host, the pathogen, and the copathogen
1995, Clinical Immunology and Immunopathology
Immunogenetics of chronic liver diseases
1994, Gastroenterology
The genetic background of autoimmune diseases becomes more and more evident. Immunogenetics comprises the analysis of genes and their products located at the region 6p21 on the short arm of chromosome 6, which is also known as the major histocompatibility complex (MHC). MHC class I and II genes are highly polymorphic. The complement genes C2, C4A, C4B, and BF, which are also polymorphic, became known as MHC class III genes. In autoimmune hepatitis type 1, there is a dual association for white persons with either HLA-A1-B8-DR3 or HLA-DR4. In patients from Japan, autoimmune hepatitis type 1 is predominantly associated with HLA-DR4. This dual association is confirmed at the DNA level. Whereas only limited data are available for autoimmune hepatitis type 2, the association of primary biliary cirrhosis with HLA-DR8 is based on several studies. Primary sclerosing cholangitis is associated with HLA-B8-DR3 and -DR52a. This association was confirmed at the DNA level because of a significant increase of the DRB3*0101 allele. For DRB3*0101-negative individuals, a second association with DRB5*0101 (=DR2) was described. Further analysis of the hypervariable region of the HLA class II molecule indicates that lysine at position 71 is crucial for autoimmune hepatitis type 1 in white persons, whereas position 13 is important for people from Japan. In contrast, leucine at position 35 is important for patients with primary biliary cirrhosis, whereas leucine at position 38 is an important risk factor for primary sclerosing cholangitis. The MHC class III allele C4A-QO is significantly increased in autoimmune hepatitis type 1 and 2 and in primary biliary cirrhosis. Advances in immunogenetics will certainly increase our knowledge of the etiology and pathogenesis of immune-mediated liver diseases, which hopefully will lead to more specific therapeutic interventions.
Reduced Fas ligand-expressing splenic CD5 <sup>+ </sup>B lymphocytes in severe collagen-induced arthritis
2009, Arthritis Research and Therapy

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Molecular basis for the association between HLA DR4 and rheumatoid arthritis. From the shared epitope hypothesis to a peptidic model of rheumatoid arthritis

Hum Immunol

Clin Immunol Immunopathol

Association of the B cell alloantigen DRw4 with rheumatoid arthritis

N Engl J Med

DR antigens and rheumatoid arthritis: a study of two populations

Br Med J

The molecular basis for HLA class II associations with Rheumatoid Arthritis

J Clin Immunol

Identification of HLA Dw14 genes in DR4 + rheumatoid arthritis

Lancet

Molecular diversity of HLA DR4 haplotypes

The shared epitope hypothesis

An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

Arthritis Rheum