A receptor presentation hypothesis for T cell help that recruits autoreactive B cells.
To uncover mechanisms that drive spontaneous expansions of autoreactive B cells in systemic lupus erythematosus, we analyzed somatic mutations in variable region genes expressed by a panel of (NZB x SWR)F(1) hybridomas representing a large, spontaneously arising clone with specificity for chromatin. A single mutation within the Jkappa intron that was shared by all members of the lineage indicated that the clone emanated from a single mutated precursor cell and led to the prediction that a somatic mutation producing a functionally decisive amino acid change in the coding region would also be universally shared. Upon cloning and sequencing the corresponding germline V(H) gene, we found that two replacement somatic mutations in FR1 and CDR2 were indeed shared by all seven clone members. Surprisingly, neither mutation influenced Ab binding to chromatin; however, one of them produced a nonconservative amino acid replacement in a mutationally "cold" region of FR1 and created an immunodominant epitope for class II MHC-restricted T cells. The epitope was restricted by IA(q) (SWR), and the SWR MHC locus is associated with systemic lupus erythematosus in (NZB x SWR)F(1) mice. These, and related findings, provoke the hypothesis that autoreactive B cells may be recruited by a "receptor presentation" mechanism involving cognate interactions between T cells and somatically generated V region peptides that are self-presented by B cells.
Zhang
X
X
Department of Immunology, National Jewish Medical and Research Center, and the University of Colorado School of Medicine, Denver, CO 80206.
Smith
D S
DS
Guth
A
A
Wysocki
L J
LJ
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D001483:Base Sequence; D001666:Binding Sites, Antibody / Q000235:genetics; D002459:Cell Fusion; D002843:Chromatin / Q000276:immunology / Q000378:metabolism; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D018095:Germ-Line Mutation; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006657:Histones / Q000276:immunology / Q000378:metabolism; D006825:Hybridomas; D016056:Immunodominant Epitopes / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008211:Lymphocyte Cooperation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D017354:Point Mutation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001323:Autoantibodies; D001324:Autoantigens; D002843:Chromatin; D000949:Histocompatibility Antigens Class II; D006657:Histones; D016056:Immunodominant Epitopes; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell