title: Loss of tolerance of anti-dsDNA B cells in mice overexpressing CD19.
abstract: Mice transgenic for the R4A-Cmu heavy chain of an anti-dsDNA antibody, maintain tolerance by anergy and deletion. In C57BL/6 mice overexpressing CD19, a molecule, which lowers the threshold for B cell activation, elevated levels of serum autoantibodies have been observed. In the present study, we wished to determine whether CD19 overexpression could alter the induction of tolerance in R4A-Cmu mice and lead to the secretion of transgenic anti-dsDNA antibodies. We, therefore, bred R4A-Cmu transgenic mice-to-mice transgenic for human CD19 (hCD19) and generated R4A-Cmu mice heterozygous and homozygous for hCD19. We, now report the spontaneous secretion of transgenic IgM anti-dsDNA antibody in the sera of R4A-Cmu mice overexpressing CD19, indicative of a loss of B cell tolerance. We observe that transgenic B cells secreting anti-dsDNA antibody in these mice are T independent and display a marginal zone like phenotype althought they do not reside in the MZ. In addition, they appear to be derived from the conventional B2 subset rather than the B1 subset. Interestingly, a subset of the anti-dsDNA B cells in these mice still display the phenotype and functional characteristics of anergic B cells. These B cells cannot be activated to secrete antibody following BCR crosslinking, however, they are hyper-responsive to activation by innate signaling mechanisms. This suggests that CD19 overexpression may promote anergic B cells to escape tolerance by converging with BCR independent pathways, thereby rendering these B cells hyper-responsive to innate signaling.
authors.affiliation: Department of Biochemistry, The Graduate Program in Biochemistry, The City College of New York, The Graduate Center, CUNY, New York, NY 10016, USA.
authors.forename: Devon K
authors.initials: DK
authors.lastname: Taylor
authors.forename: Emi
authors.initials: E
authors.lastname: Ito
authors.forename: Mitchell
authors.initials: M
authors.lastname: Thorn
authors.forename: Krishnan
authors.initials: K
authors.lastname: Sundar
authors.forename: Thomas
authors.initials: T
authors.lastname: Tedder
authors.forename: Linda A
authors.initials: LA
authors.lastname: Spatz
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D017635:Clonal Anergy / Q000276:immunology; D004247:DNA / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010537:Peritoneum / Q000166:cytology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology
chemical_list: D000906:Antibodies; D018941:Antigens, CD19; D007075:Immunoglobulin M; D004247:DNA