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Autoantigenic HCgp39 Epitopes Are Presented by the HLA-DM-Dependent Presentation Pathway in Human B Cells¹

Namrata S. Patil^2,*, Frances C. Hall, Sheila Drover, David R. Spurrell, Ebo Bos, Andrew P. Cope, Grete Sonderstrup^3, and Elizabeth D. Mellins^3,*

Departments of ^* Pediatric Immunology and Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada; and NV Organon, Oss, The Netherlands

It is hypothesized that autoimmune diseases manifest when tolerance to self-Ags fails. One possible mechanism to break tolerance is presentation of self-Ag in an altered form. Most Ags are presented by APCs via the traditional presentation pathway that includes "epitope editing" by intracellular HLA-DM, a molecule that selects for stable MHC-peptide complexes. We were interested in testing the hypothesis that autoreactive MHC-peptide complexes may reach the cell surface by an alternate pathway without being edited by HLA-DM. We selected a cartilage autoantigen human cartilage glycoprotein 39 to which T cell responses are observed in rheumatoid arthritis (RA) patients and some DR*04 healthy subjects. RA is genetically associated with certain DRB1 alleles, including DRB1*0401 but closely related allele DRB1*0402 is either neutral or mildly protective with respect to RA. We generated human B lymphoblastoid cell line cells expressing DR*0401 or DR*0402 in the presence or absence of intracellular HLA-DM and assessed their ability to present a candidate autoantigen, human cartilage glycoprotein 39. Our results show that the presence of intracellular HLA-DM is critical for presentation of this autoantigen to CD4⁺ T cell hybridomas generated from DR*04-transgenic mice. Presentation of an autoantigen by the traditional HLA-DM-dependent pathway has implications for Ag presentation events in RA.

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