Autoantigenic HCgp39 epitopes are presented by the HLA-DM-dependent presentation pathway in human B cells

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• Autoimmune diseases occur when the immune system loses tolerance to self-antigens (self-Ags).
• Altered self-Ag presentation by antigen-presenting cells (APCs) is a potential mechanism for breaking self-tolerance.
• The intracellular molecule HLA-DM typically edits and selects stable MHC-peptide complexes for cell surface presentation.

Purpose of the Study:

• To test the hypothesis that autoreactive MHC-peptide complexes can bypass HLA-DM editing and reach the cell surface via an alternative pathway.
• To investigate the role of HLA-DM in the presentation of human cartilage glycoprotein 39 (hCG39), a candidate autoantigen in rheumatoid arthritis (RA).

Main Methods:

• Generated human B lymphoblastoid cell lines expressing specific HLA-DRB1 alleles (DRB1(*)0401 and DRB1(*)0402) with or without intracellular HLA-DM.
• Assessed the presentation of hCG39 by these cell lines to CD4(+) T cell hybridomas derived from DR(*)04-transgenic mice.

Main Results:

• The presence of intracellular HLA-DM was essential for the presentation of the autoantigen hCG39.
• HLA-DM-dependent presentation of hCG39 was observed, suggesting that the traditional pathway is critical for this autoantigen.

Conclusions:

• Intracellular HLA-DM plays a critical role in the presentation of the cartilage autoantigen hCG39.
• The findings suggest that the traditional, HLA-DM-dependent antigen presentation pathway is important in the context of RA.