Elsevier

Advances in Immunology

Volume 68, 1998, Pages 315-332
Advances in Immunology

Major Histocompatibility Complex-Directed Susceptibility to Rheumatoid Arthritis

https://doi.org/10.1016/S0065-2776(08)60563-5Get rights and content

Publisher Summary

The human major histocompatibility complex (MHC) region includes at least 6 human leukocyte antigen (HLA) class I genes and 14 HLA class II loci within a 4-megabase region. The complex also includes several other genes functionally related to pathways of antigen presentation and processing. HLA-DRB1 molecules, like all class II MHC molecules, bind antigenic peptides and present these peptides for recognition to antigen-specific T lymphocytes. This chapter discusses several different molecular mechanisms envisioned to account for the association between rheumatoid arthritis (RA) and the specific shared epitope sequence on DRB class II susceptibility molecules. In one of the mechanisms, the HLA-DR molecules associated with RA are presumed to bind a specific pathogenic peptide. Peptides with neutral and small amino acids at residue are capable of binding to the same class II molecules albeit with lower avidity. Thus, the restricted motif for peptide residue 4 may be favored for antigens bound by RA-associated class II molecules. Another model suggests that the basis for the shared epitope association with RA is that the DRB1 molecule itself is an antigen, in which proteolysis leads to presentation of peptides derived from the DRB1-encoded protein.

References (72)

  • BreedveldF.C.

    New perspectives on treating rheumatoid arthritis

    N. Engl. J. Med.

    (1995)
  • CalinA. et al.

    Destructive arthritis, rheumatoid factor, and HLA-DR4

    Arthritis Rheum.

    (1989)
  • ChiezR.M. et al.

    Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles

    J. Exp. Med.

    (1993)
  • CombeB. et al.

    Prognostic factors in rheumatoid arthritis. Comparative study of two subsets of patients according to severity of articular damage

    Br. J. Rheum.

    (1995)
  • DavenportM.P. et al.

    Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DRβ chain

    Proc. Natl. Acad. Sci. USA

    (1995)
  • DavenportM.P. et al.

    A distinctive peptide binding motif for HLA-DRB1°0407, an HLA-DR4 subtype not associated with rheumatoid arthritis

    Immunogenetics

    (1997)
  • DemotzS. et al.

    The set of naturally processed peptides displayed by DR molecules is tuned by polymorphism of residue 86

    Eur. J. Immunol.

    (1996)
  • FuX. et al.

    Pocket 4 of the HLA-DR(α,β1°0401) molecule is a major determinant of T cell recognition of peptide

    J. Exp. Med.

    (1995)
  • GaoX. et al.

    HLA-DR alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis

    Arthritis Rheum.

    (1990)
  • GaurL.K. et al.

    Ancestral major histocompatibility complex DRB genes beget conserved patterns of localized polymorphisms

    Proc. Natl. Acad. Sci. USA

    (1996)
  • GaurL.K. et al.

    MHC-DRB allelic sequences incorporate distinct intragenic trans-specific segments

    Tissue Antigens

    (1997)
  • GhoshP. et al.

    The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3

    Nature

    (1995)
  • GoughA. et al.

    Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome

    Arthritis Rheum.

    (1994)
  • GregersenP.K. et al.

    The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

    Arthritis Rheum.

    (1987)
  • GyllenstenU.B. et al.

    Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates

    Proc. Natl. Acad. Sci. USA

    (1991)
  • HammerJ. et al.

    Precise prediction of major histocompatibility complex class II-peptide interaction based on peptide side chain scanning

    J. Exp. Med.

    (1994)
  • HammerJ. et al.

    Peptide binding specificity of HLA-DR4 molecules: Correlation with rheumatoid arthritis association

    J. Exp. Med.

    (1995)
  • HiraiwaA. et al.

    Structural requirements for recognition of the HLA-Dw14 class II epitope: A key HLA determinant associated with rheumatoid arthritis

    Proc. Natl. Acad. Sci. USA

    (1990)
  • KellyA. et al.

    Novel genes in the human major histocompatibility complex class II region

    Int. Arch. Allergy Immunol.

    (1994)
  • KirschmannD.A. et al.

    Naturally processed peptides from rheumatoid arthritis associated and non-associated HLA-DR alleles

    J. Immunol.

    (1995)
  • KraulisP.J.

    MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures

    J. Appl. Crystallogr.

    (1991)
  • KwokW.W. et al.

    HLA-DQB1 codon 57 is critical for peptide binding and recognition

    J. Exp. Med.

    (1996)
  • LundbergA.S. et al.

    Evolution of major histocompatibility complex class II allelic diversity: Direct descent in mice and humans

    Proc. Natl. Acad. Sci. USA

    (1992)
  • MatsushitaS. et al.

    Allele specificity of structural requirement for peptides bound to HLA-DRB1°0405 and -DRB1°0406 complexes: Implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndrome

    J. Exp. Med.

    (1994)
  • McDanielD.O. et al.

    Most African-American patients with rheumatoid arthritis do not have the rheumatoid antigenic determinant (epitope)

    Ann. Intern. Med.

    (1995)
  • McNichollJ.M. et al.

    Structural requirements of peptide and MHC for DR(α,β1°0401)-restricted T cell antigen recognition

    J. Immunol.

    (1995)
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