T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the HLA class II haplotype DRB1*0301/DQB1*0201

Nadine L. Dudek, Shannon Maier, Zhen Jun Chen, Philip A. Mudd, Stuart I. Mannering, David C. Jackson, Weiguang Zeng, Catherine L. Keech, Kassie Hamlin, Zi Jian Pan, Karen Davis-Schwarz, Jennifer Workman-Azbill, Michael Bachmann, James McCluskey, A. Darise Farris

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17 Scopus citations

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 Sjögren'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.

Original languageEnglish
Pages (from-to)3387-3398
Number of pages12
JournalArthritis and rheumatism
Volume56
Issue number10
DOIs
StatePublished - Oct 2007

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    Dudek, N. L., Maier, S., Chen, Z. J., Mudd, P. A., Mannering, S. I., Jackson, D. C., Zeng, W., Keech, C. L., Hamlin, K., Pan, Z. J., Davis-Schwarz, K., Workman-Azbill, J., Bachmann, M., McCluskey, J., & Farris, A. D. (2007). T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the HLA class II haplotype DRB1*0301/DQB1*0201. Arthritis and rheumatism, 56(10), 3387-3398. https://doi.org/10.1002/art.22870