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J Autoimmun. 2011 Nov;37(3):254-62. doi: 10.1016/j.jaut.2011.07.002. Epub 2011 Aug 24.

HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD.

Author information

1
Division of Rheumatology and Immunology, Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA. usd7w@virginia.edu

Abstract

Although systemic lupus erythematosus (SLE) is a multigenic autoimmune disorder, HLA-D is the most dominant genetic susceptibility locus. This study was undertaken to investigate the hypothesis that microbial peptides bind HLA-DR3 and activate T cells reactive with lupus autoantigens. Using HLA-DR3 transgenic mice and lupus-associated autoantigen SmD protein, SmD(79-93) was identified to contain a dominant HLA-DR3 restricted T cell epitope. This T cell epitope was characterized by using a T-T hybridoma, C1P2, generated from SmD immunized HLA-DR3 transgenic mouse. By pattern search analysis, 20 putative mimicry peptides (P2-P21) of SmD(79-93,) from microbial and human origin were identified. C1P2 cells responded to SmD, SmD(79-93) and a peptide (P20) from Vibro cholerae. Immunization of HLA-DR3 mice with P20 induced T cell responses and IgG antibodies to SmD that were not cross-reactive with the immunogen. A T-T hybridoma, P20P1, generated from P20 immunized mice, not only responded to P20 and SmD(79-93), but also to peptides from Streptococcus agalactiae (P17) and human-La related protein (P11). These three T cell mimics (P20, P11 and P17) induced diverse and different autoantibody response profiles. Our data demonstrates for the first time molecular mimicry at T cell epitope level between lupus-associated autoantigen SmD and microbial peptides. Considering that distinct autoreactive T cell clones were activated by different microbial peptides, molecular mimicry at T cell epitope level can be an important pathway for the activation of autoreactive T cells resulting in the production of autoantibodies. In addition, the novel findings reported herein may have significant implications in the pathogenesis of SLE.

PMID:
21868195
PMCID:
PMC3372418
DOI:
10.1016/j.jaut.2011.07.002
[Indexed for MEDLINE]
Free PMC Article

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