title: HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD.
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.
authors.affiliation: 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
authors.forename: Umesh S
authors.initials: US
authors.lastname: Deshmukh
authors.forename: Davis L
authors.initials: DL
authors.lastname: Sim
authors.forename: Chao
authors.initials: C
authors.lastname: Dai
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Kannapell
authors.forename: Felicia
authors.initials: F
authors.lastname: Gaskin
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Shu Man
authors.initials: SM
authors.lastname: Fu
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015803:HLA-DR3 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D010455:Peptides / Q000276:immunology*; D011485:Protein Binding; D013292:Streptococcus agalactiae / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014734:Vibrio cholerae / Q000276:immunology / Q000378:metabolism; D055517:snRNP Core Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015803:HLA-DR3 Antigen; D010455:Peptides; D055517:snRNP Core Proteins