title: Multiple checkpoint breach of B cell tolerance in Rasgrp1-deficient mice.
abstract: Lymphopenic hosts offer propitious microenvironments for expansion of autoreactive B and T cells. Despite this, many lymphopenic hosts do not develop autoimmune disease, suggesting that additional factors are required for breaching self-tolerance in the setting of lymphopenia. Mice deficient in guanine nucleotide exchange factor Rasgrp1 develop a lymphoproliferative disorder with features of human systemic lupus erythematosus. Early in life, Rasgrp1-deficient mice have normal B cell numbers but are T lymphopenic, leading to defective homeostatic expansion of CD4 T cells. To investigate whether B cell-intrinsic mechanisms also contribute to autoimmunity, Rasgrp1-deficient mice were bred to mice containing a knockin autoreactive BCR transgene (564Igi), thereby allowing the fate of autoreactive B cells to be assessed. During B cell development, the frequency of receptor-edited 564Igi B cells was reduced in Rasrp1-deficient mice compared with Rasgrp1-sufficient littermate control mice, suggesting that tolerance was impaired. In addition, the number of 564Igi transitional B cells was increased in Rasgrp1-deficient mice compared with control mice. Immature 564Igi B cells in bone marrow and spleen lacking RasGRP1 expressed lower levels of Bim mRNA and protein, suggesting that autoreactive B cells elude clonal deletion during development. Concomitant with increased serum autoantibodies, Rasgrp1-deficient mice developed spontaneous germinal centers at 8-10 wk of age. The frequency and number of 564Igi B cells within these germinal centers were significantly increased in Rasgrp1-deficient mice relative to control mice. Taken together, these studies suggest that autoreactive B cells lacking Rasgrp1 break central and peripheral tolerance through both T cell-independent and -dependent mechanisms.
authors.affiliation: Department of Microbiology and Immunology, University of South Alabama, Mobile, AL 36688;
authors.forename: Amber
authors.initials: A
authors.lastname: Bartlett
authors.forename: Janet E
authors.initials: JE
authors.lastname: Buhlmann
authors.forename: James
authors.initials: J
authors.lastname: Stone
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.forename: Robert A
authors.initials: RA
authors.lastname: Barrington
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics*; D007108:Immune Tolerance / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C112278:Rasgrp1 protein, mouse; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors