Disease-associated human histocompatibility leukocyte antigen determinants in patients with seropositive rheumatoid arthritis. Functional role in antigen-specific and allogeneic T cell recognition.

Weyand, Cornelia M.; Goronzy, Jörg J.

doi:10.1172/jci114535

Cited by 23 publications

(14 citation statements)

References 34 publications

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“…Thus, the biological effects of a particular superantigen on an adult immune system are essentially influenced by the composition of the TCR repertoire. We have recently postulated that the HLA-DR association of RA can be explained by the regulatory role of HLA molecules in the formation of the patient's T cell repertoire (36). HLA determinants associated with RA are expressed on the a-helical portion of the HLA-DR molecule surrounding the antigen binding groove (37).…”

Section: Discussionmentioning

confidence: 99%

Selective induction of rheumatoid factors by superantigens and human helper T cells.

Goronzy²,

Weyand

1992

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Selective induction of rheumatoid factors by superantigens and human helper T cells.

Goronzy²,

Weyand

1992

J. Clin. Invest.

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“…The DR4 restrictions of most T-cell clones studied have correlated with the classical T-cell-defined subtypes of DR4 (30). Although a contribution from position 86 has been suggested by results from some other T-cell clones (31,32), it may have been overlooked with others.…”

mentioning

confidence: 87%

Critical role for the Val/Gly86 HLA-DR beta dimorphism in autoantigen presentation to human T cells.

Ong

Willcox

Wordsworth

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Helper T lymphocytes recognize fragments of foreign (or self) antigens in the peptide-binding clefts of major histocompatibility complex class II molecules; their activation is a crucial step in the induction of many immune and autoimmune responses. While studying the latter, we raised a T-cell line from the thymus of a myasthenia gravis patient against recombinant a subunit of the human acetylcholine receptor, the target of this autoimmune disease. The line responds to the 144-156 region of the human sequence and not to the same region of the electric fish homolog, which differs by only three residues. These CD4' T cells recognize this epitope only in the context of HLA-DR4 class II molecules, of which the variants with Gly86 are absolutely required. Thus the naturally occurring alternatives Dw14.2 (Gly56) and Dw14.1 (Val ¶*-which differ only at this one position in the entire antigen-binding region-show an all-or-nothing difference in presenting activity. This dimorphism at position 86 is widespread, occurring in subtypes of DR1, DR2, DR3, DR5, and DR6 alleles as well as DR4. Since other DR4 subtypes with substitutions at positions 70-74 also fail to present this peptide, and glycine residues can be uniquely flexible, we suggest that this replacement at position 86 acts locally or at a distance by altering the conformation of the peptide-binding cleft. Such profound functional consequences for T-cell recognition as we report here may explain this example of conserved major histocompatibility complex diversity.The striking polymorphism of the major histocompatibility complex (MHC) in most vertebrate species implies strong selection for diversity. As functional and crystallographic studies show (for class I molecules), the role of these MHC heterodimers is to bind peptide fragments of processed antigens in a cleft formed by the folding of their two membrane-distal domains (1, 2) and to present them to T lymphocytes. [For CD4' helper T cells, the class II molecules on specialized antigen-presenting cells (APCs) fulfill this role.] Specific recognition of the MHC and peptide components of the resulting composite by T lymphocytes underlies the phenomenon of MHC restriction whereby most peptides are recognized in the context of only some of the class II alleles. Thus, the diversity of the MHC molecules probably ensures that the population as a whole maintains responsiveness to a broad repertoire of foreign antigens.Many autoimmune diseases show associations with particular MHC alleles or haplotypes (reviewed in ref.3).

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“…In the current paradigm, HLA molecules in RA function by binding and presenting arthritogenic antigens (20). Alternatively, we have hypothesized that disease-linked HLA-DR molecules could shape the repertoire of mature T cells thus having effects on the immunoresponsiveness (21). Available data on the peptide binding function of HLA-DR4 allelic variants are limited.…”

Section: Introductionmentioning

confidence: 99%

Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis.

Weyand¹,

McCarthy²,

Goronzy³

1995

J. Clin. Invest.

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Disease-associated human histocompatibility leukocyte antigen determinants in patients with seropositive rheumatoid arthritis. Functional role in antigen-specific and allogeneic T cell recognition.

Cited by 23 publications

References 34 publications

Selective induction of rheumatoid factors by superantigens and human helper T cells.

Selective induction of rheumatoid factors by superantigens and human helper T cells.

Critical role for the Val/Gly86 HLA-DR beta dimorphism in autoantigen presentation to human T cells.

Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis.

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