title: Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner.
abstract: The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock-in mouse strain, we identify a pathway by which B-cell selection to nucleolar self-antigens is complement dependent. Deficiency in complement component C4 led to a breakdown in the elimination of autoreactive B-cell clones at the transitional stage, characterized by a relative increase in their response to a range of stimuli, entrance into follicles, and a greater propensity to form self-reactive GCs. Using mixed BM chimeras, we found that the myeloid compartment was sufficient to restore negative selection in the autoreactive mice. A model is proposed in which in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells, allowing the maturation and activation of self-reactive B-cell clones leading to increased spontaneous formation of GCs.
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Chatterjee
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.|Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.|MD-PhD Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Amma F
authors.initials: AF
authors.lastname: Agyemang
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marat B
authors.initials: MB
authors.lastname: Alimzhanov
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Degn
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Stefanos A
authors.initials: SA
authors.lastname: Tsiftsoglou
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Alicot
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Minghe
authors.initials: M
authors.lastname: Ma
authors.affiliation: Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.|Department of Pediatrics, Harvard Medical School, Boston, MA, USA.|Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology; D009697:Nucleolus Organizer Region / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D012261:Ribonucleoproteins / Q000276:immunology*
chemical_list: D001324:Autoantigens; C016759:C4b protein, mouse; D003181:Complement C4; D011947:Receptors, Antigen, B-Cell; D012261:Ribonucleoproteins
keywords: Autoimmunity; Germinal center; Lupus nucleolar antigen; Negative selection