HLA polymorphisms and T cells in rheumatoid arthritis

Cornelia M. Weyand, Jorg J. Goronzy

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

A dense infiltrate of activated T cells, macrophages, and B cells in the synovial membrane is the cardinal pathological feature of rheumatoid arthritis (RA). Frequently, tissue infiltrating cells acquire a morphological organization reminiscent of secondary lymphoid tissue. The composition of the inflammatory lesions, the production of autoantibodies, and the association of disease risk with genes related to the HLA-D region have all been cited as evidence for a critical role of T cells in disease pathogenesis. Investigations on the precise role of HLA genes in RA have confirmed the importance of this genetic risk factor and have identified a consensus sequence within the HLA-DRB1 genes. The observation that HLA polymorphisms are mostly associated with disease progression and severity and that a gene dose effect for HLA-DR genes is operational has challenged the simple model that HLA molecules select and present an arthritogenic antigen. Studies analyzing the repertoire of tissue infiltrating T cells have not been able to identify a dominant and common disease relevant T cell. The infiltrate is diverse in terms of T cell receptor gene usage but consistently includes clonally expanded populations. Recent evidence indicates that RA patients carry expanded CD4 clonotypes which are characterized by deficient CD28 expression and autoreactivity. These autoreactive CD4 T cells are not restricted to the joint, raising the possibility that rheumatoid synovitis is a manifestation of a systemic autoimmune disease. Support for this model has come from studies in T cell receptor (TCR) transgenic animals which develop inflammation of the synovial membrane stimulated by a T cell response to ubiquitously expressed self-MHC molecules. Antigens driving the chronic persistent immune response in RA may not be restricted to the joint but rather may be widely distributed, providing an explanation for the difficulties in identifying arthritogenic antigens directly or indirectly through the selection of joint infiltrating T cells.

Original languageEnglish (US)
Pages (from-to)37-59
Number of pages23
JournalInternational Reviews of Immunology
Volume18
Issue number1-2
DOIs
StatePublished - 1999

Keywords

  • Autoreactivity
  • Clonally expanded CD4 T cells
  • Disease risk genes
  • HLA-DRB1 genes
  • Tissue cytokines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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