T cell Epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the HLA class II haplotype DRB1*0301/DQBI*0201

Dudek, NL; Maier, S; Chen, ZJ; Mudd, PA; Mannering, SI; Jackson, DC; Zeng, WG; Keech, CL; Hamlin, K; Pan, ZJ; Davis-Schwarz, K; Workman-Azbill, J; Bachmann, M; McCluskey, J; Farris, AD

Author(s): Dudek, NL; Maier, S; Chen, ZJ; Mudd, PA; Mannering, SI; Jackson, DC; Zeng, WG; Keech, CL; Hamlin, K; Pan, ZJ; Davis-Schwarz, K; Workman-Azbill, J; Bachmann, M; McCluskey, J; Farris, AD;
Details: Publication Year 2007-10,Volume 56,Issue #10,Page 3387-3398
Journal Title: ARTHRITIS AND RHEUMATISM
Publication Type: Journal Article
Abstract: Objective. T cells are implicated in the production of anti-La/SSB and anti-Ro/SSA autoantibodies commonly associated with the DR3/DQ2 haplotype in systemic lupus erythematosus and Sjogren's syndrome. This study was undertaken to investigate the DR3/DQ2-restricted T cell response to wild-type human La (hLa) and a truncated form of mutant La. Methods. Humanized transgenic mice expressing HLA-DRB1*0301/DQB1*0201 (DR3/DQ2) were immunized with recombinant antigen and examined for development of autoantibodies and T cell proliferation against overlapping peptides spanning the La autoantigen. HLA restriction and peptide binding of identified T cell epitopes to DR3 or DQ2 were determined using blocking monoclonal antibodies and a direct binding assay. Results. DR3/DQ2-transgenic mice generated an unusually rapid class-switched humoral response to hLa with characteristic spreading to Ro 52 and Ro 60 proteins following hLa protein immunization. Seven T cell determinants in hLa were restricted to the HLA-DR3/DQ2 haplotype. Six epitopes tested were restricted to HLA-DR and bound DR3 with semiconserved DR3 binding motifs. No DQ restriction of these epitopes was demonstrable despite efficient DQ binding activity in some cases. No neo-T cell epitopes were identified in mutant La; however, T cells primed with mutant La exhibited a striking increase in proliferation to the epitope hLa(151-168) compared with T cells primed with hLa. Conclusion. Multiple DR3-restricted epitopes of hLa have been identified. These findings suggest that truncation of La produced by somatic mutation or possibly granzyme B-mediated cleavage alters the immunodominance hierarchy of T cell responsiveness to hLa and may be a factor in the initiation or maintenance of anti-La autoimmunity.
Publisher: WILEY-LISS
Keywords: LA SS-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PRIMARY SJOGRENS-SYNDROME; IMMUNE-RESPONSE; EXPERIMENTAL AUTOIMMUNITY; SELF-ANTIGENS; GRANZYME-B; RO; AUTOANTIBODIES; APOPTOSIS
Publisher's Version: https://doi.org/10.1002/art.22870
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Creation Date: 2007-10-01 12:00:00