Formation of peripheral immunoreceptor repertoire for antigens: Potential relationship to the pathogenesis of rheumatoid arthritis

Kohsaka, Hitoshi; Carson, Dennis A.; Miyasaka, Nobuyuki

doi:10.1002/1529-0131(199811)41:11<1911::aid-art4>3.0.co;2-s

Cited by 4 publications

References 49 publications

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T-cell responses in rheumatoid arthritis

Weyand

Goronzy

1999

Current Opinion in Rheumatology

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One manifestation of rheumatoid arthritis (RA) is a destructive inflammation of the joint, but many other organs can be targeted by this disease, classifying it as a truly systemic disorder. Accordingly, pathogenic models have to account for the multiorgan character of RA. This article proposes that the primary abnormalities in RA lie in the assembly of the T-cell pool and in the maintenance of T-cell homeostasis. Evidence has accumulated that the repertoire of CD4 T cells in RA patients is distinct and includes a high frequency of disease-relevant T cells. Emergence of T cells with self-aggressive potential could indicate a failure of negative selection in the thymus. Also, the turnover of mature T cells in the periphery is altered in RA patients with a sharp contraction in diversity. Loss of diversity results from the replacement of rare T-cell specificities by multiplying T-cell clones. Large clonal T-cell populations in RA patients acquire a distinct phenotype (CD4+CD28null) and functional profile (overproduction of interferon-gamma, cytotoxicity), giving them the ability to function as proinflammatory cells. Optimal conditions for T-cell stimulation are encountered in the synovium, where ectopic lymphoid tissue with germinal centers is formed. Considering the systemic nature of RA, therapeutic strategies suppressing synovial inflammation while ignoring systemic abnormalities could lack the potential of a curative intervention.

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T-cell responses in rheumatoid arthritis

Weyand

Goronzy

1999

Current Opinion in Rheumatology

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T Cell Homeostasis and Autoreactivity in Rheumatoid Arthritis

Goronzy

Weyand

2000

Current Directions in Autoimmunity

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Roudier

2000

Arthritis Res

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Most patients with rheumatoid arthritis (RA) express HLA-DR4, HLA-DR1 or HLA-DR10. These alleles share a common amino acid motif in their third hypervariable regions: the shared epitope. In normals and patients with RA, HLA-DR genes exert a major influence on the CD4 αβ T-cell repertoire, as shown by studies of AV and BV gene usage and BV BJ gene usage by peripheral blood CD4 αβ T cells. However, the rheumatoid T-cell repertoire is not entirely under HLA-DR influence, as demonstrated by discrepancies in VB JB gene usage between identical twins discordant for RA and by contraction of the CD4 αβ T-cell repertoire in RA patients. Shared epitope positive HLA-DR alleles may shape the T-cell repertoire by presenting self peptides to CD4 T cells in the thymus. Peptides processed from HLA-DR molecules and encompassing the shared epitope may also be presented by HLA-DQ and select CD4 αβ T cells in the thymus. Thus, shared epitope-positive alleles impose a frame on the T-cell repertoire. This predisposing frame is further modified (by unknown factors) to obtain the contracted rheumatoid repertoire.

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Formation of peripheral immunoreceptor repertoire for antigens: Potential relationship to the pathogenesis of rheumatoid arthritis

Cited by 4 publications

References 49 publications

T-cell responses in rheumatoid arthritis

T-cell responses in rheumatoid arthritis

T Cell Homeostasis and Autoreactivity in Rheumatoid Arthritis

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