T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis–associated and nonassociated HLA–DR4 alleles

SUMMARY Transgenic and knockout mouse models have been invaluable for the elucidation of basic mechanisms in autoimmunity and have contributed new experimental models of human autoimmune diseases. Transgenic models of self tolerance have helped to change our view of this state from a process mediated purely by thymic deletion to a more complex process encompassing deletion, peripheral anergy, down‐regulation of receptors and modulation by regulatory cells. Experiments in which the genes for the candidate target antigens in autoimmune disease are over‐expressed or under‐expressed have helped to clarify the targets of attack. Several examples of T cell receptor transgenic mice have been described in which T cells carry the receptor derived from a human or mouse autoimmune T cell clone. Such mice allow the characterization of T cell specificities contributing to disease and of the additional factors and checkpoints influencing disease development. In addition, the expression of disease associated HLA alleles in ‘humanised’ transgenic lines allows the mapping of HLA‐restricted T cell epitopes and investigation of the mechanisms underlying these genetic associations. These approaches are leading to the generation of new disease models, offering hope for the design and testing of novel immunotherapeutic strategies.

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“…Epitopes confirmed in studies of human [45] Differential epitopes between susceptibility (0401) patient T cell responses.…”

Section: Transgenic Expression Of Candidate Autoantigensmentioning

confidence: 83%

Transgenic models of autoimmune disease

Boyton¹,

Altmann

2002

Clinical and Experimental Immunology

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“…Peripheral HC gp-39-specific T cells have been observed in both RA patients (5,7,41) and healthy controls (42). In healthy individuals these cells may have a role in preserving natural immune homeostasis, a function that is suppressed in RA (42).…”

Section: Discussionmentioning

confidence: 99%

“…T cell hybridomas were obtained as described by Cope et al (7). Briefly, mice transgenic for human CD4 and HLA-DR␣ and ␤ (B1*0401), and devoid of I-A␤ were immunized with 50 g of purified HC gp-39 (derived from MG63 supernatants) or purified recombinant MIA mixed in Freund's incomplete adjuvant.…”

Section: Methodsmentioning

confidence: 99%

“…After 42 hours of incubation, 200 l of supernatant was carefully collected from each well and stored in 2 aliquots of 100 l each at Ϫ20°C. The amount of IL-2 produced by the T cell hybridomas upon antigen-specific activation was measured in these supernatants (in duplicate) with a Europium-based immunoassay (PharMingen, San Diego, CA) and expressed as fluorescence units, as previously described by Cope et al (7).…”

Section: Methodsmentioning

confidence: 99%

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Endogenous HLA–DR–restricted presentation of the cartilage antigens human cartilage gp‐39 and melanoma inhibitory activity in the inflamed rheumatoid joint

Lierop¹,

Hoed²,

Houbiers³

et al. 2007

Arthritis & Rheumatism

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Objective. The cartilage proteins melanoma inhibitory activity (MIA) and human cartilage gp-39 (HC gp-39) are candidate autoantigens in rheumatoid arthritis (RA). The present study was undertaken to investigate the endogenous HLA-DR4-restricted presentation of these self proteins, in order to seek in vivo evidence in support of their potential immunologic role. The mechanisms that cause and sustain rheumatoid arthritis (RA) remain poorly elucidated. The association of the disease with certain class II major histocompatibility complex (MHC) haplotypes, however, strongly suggests that specific antigens are presented by antigen-presenting cells (APCs) to CD4ϩ T lymphocytes (1,2). Previous studies indicate that cartilage could be the source of some of these antigens in RA (3-7). In the present study we investigated the local presence and presentation of 2 cartilage-derived proteins that have distinct properties: human cartilage gp-39 (HC gp-39) and a protein called melanoma inhibitory activity (MIA).

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“…Considering the growing evidence that HC gp-39 might play a central role in antigen-specific immune processes in RA (8,9,(17)(18)(19)(20), analysis of the MHCrestricted presentation of specific HC gp-39 peptides, including the immunodominant epitope 263-275, is an important step in the evaluation of the role of HC gp-39 in the pathogenesis of the disease. In vitro, specific epitopes can be presented, in the context of specific HLA-DR alleles, by dendritic cells, activated macrophages, and B cells (21,22), and the HLA-DR␣␤1*0401/HC gp-39 263-275 complex can stimulate HC gp-39-specific T cell hybridomas (12).…”

Section: Discussionmentioning

confidence: 99%

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

Baeten¹,

Steenbakkers²,

Rijnders³

et al. 2004

Arthritis & Rheumatism

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Clinically, there were no correlations between mAb 12A staining and clinical or biologic parameters in RA. However, positive staining was observed in 61.5% of the inflamed RA synovial samples compared with only 3.0% of the control samples (P < 0.001). This mAb 12A staining was not related to intracellular citrullinated peptides, which are another specific histologic marker for RA.Conclusion. Presentation by synovial dendritic cells of the immunodominant epitope of HC gp-39, in the context of the shared epitope, is associated with characteristic histologic features of follicular synovitis and is highly specific for RA. This suggests a contribution to the autoimmune-related tissue inflammation and provides a new and independent tool for the immunopathologic diagnosis of RA.

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T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis–associated and nonassociated HLA–DR4 alleles

Cited by 93 publications

References 41 publications

Transgenic models of autoimmune disease

Transgenic models of autoimmune disease

Endogenous HLA–DR–restricted presentation of the cartilage antigens human cartilage gp‐39 and melanoma inhibitory activity in the inflamed rheumatoid joint

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

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