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

Umesh S. Deshmukh, Davis L. Sim, Chao Dai, Carol J. Kannapell, Felicia Gaskin, Govindarajan Rajagopalan, Chella S. David, Shu Man Fu

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22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)254-262
Number of pages9
JournalJournal of Autoimmunity
Volume37
Issue number3
DOIs
StatePublished - Nov 1 2011

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Keywords

  • Epitope
  • HLA-DR3
  • Mice
  • Molecular mimicry
  • SmD
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Deshmukh, U. S., Sim, D. L., Dai, C., Kannapell, C. J., Gaskin, F., Rajagopalan, G., David, C. S., & Fu, S. M. (2011). HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD. Journal of Autoimmunity, 37(3), 254-262. https://doi.org/10.1016/j.jaut.2011.07.002