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

Abstract

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).

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…The most accepted concept is that the presence of synovial T cell expansions reflects activation and/or proliferation in response to a local antigen (54)(55)(56). This would be consistent with our finding that the profiles identified in synovium are not merely a reflection of peripheral blood alterations, as well as with our previous demonstrations of HLA-DRB-restricted presentation of autoantigens in RA synovitis (17)(18)(19).…”

“…First, the fact that ACPA are classed-switched antibodies directed against a peptide antigen suggests T cell help. Second, the association with the HLA-DRB1 shared epitope alleles supports the concept that specific antigenic epitopes could be presented to T cells in an HLA-restricted manner (17)(18)(19). Whether such epitopes should be citrullinated or not remains unclear.…”

Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis

“…Using model antigens, we demonstrate that tolDCs are unaffected by antigen loading and mediate antigen-specific hyporesponsiveness without inducing proliferation of ‘bystander’ T cells with low affinity for the antigen, all of which are important features of targeted antigen-specific therapy. The pathogenic autoantigen in RA is unknown, however; future studies will reveal the tolerising effects of tolDCs to non-characterised RA autoantigen(s) present within synovial fluid 58–60…”

Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial

“…Epitopes of HC gp-39 are recognised by peripheral blood mononuclear cells of patients with RA 4. HC gp-39 protein was detected in RA synovial tissue and its epitopes are made available by antigen-presenting cells in inflamed joints of patients with RA 6–8. The relevance of HC gp-39 in joint pathology was strongly supported by the demonstration that HC gp-39 induces arthritis in Balb/c mice.…”