title: Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evidence of tolerance in a transgenic model.
abstract: Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5-15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Aplin
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Keech
authors.forename: Andrea L
authors.initials: AL
authors.lastname: de Kauwe
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Gordon
authors.forename: Dana
authors.initials: D
authors.lastname: Cavill
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D000915:Antibody Affinity / Q000235:genetics; D000918:Antibody Specificity / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D007136:Immunoglobulins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D012261:Ribonucleoproteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D000097585:SS-B Antigen
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D007075:Immunoglobulin M; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D011947:Receptors, Antigen, B-Cell; D012261:Ribonucleoproteins; D000097585:SS-B Antigen