title: Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo.
abstract: Autoreactive B lymphocytes first encountering self-antigens in peripheral tissues are normally regulated by induction of anergy or apoptosis. According to the "two-signal" model, antigen recognition alone should render B cells tolerant unless T cell help or inflammatory signals such as lipopolysaccharide are provided. However, no such signals seem necessary for responses to T-independent type 2 (TI-2) antigens, which are multimeric antigens lacking T cell epitopes and Toll-like receptor ligands. How then do mature B cells avoid making a TI-2-like response to multimeric self-antigens? We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid-binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid "missing self"-responses to unsialylated multimeric antigens. The results suggest use of siglec ligand antigen constructs as an approach for inducing tolerance.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Bao Hoa
authors.initials: BH
authors.lastname: Duong
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.forename: Gladys
authors.initials: G
authors.lastname: Completo
authors.forename: Shoufa
authors.initials: S
authors.lastname: Han
authors.forename: José Luis
authors.initials: JL
authors.lastname: Vela
authors.forename: Miyo
authors.initials: M
authors.lastname: Ota
authors.forename: Michael
authors.initials: M
authors.lastname: Kubitz
authors.forename: Nicolai
authors.initials: N
authors.lastname: Bovin
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.forename: James
authors.initials: J
authors.lastname: Paulson
authors.forename: David
authors.initials: D
authors.lastname: Nemazee
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000502:physiology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D037102:Lectins / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics / Q000276:immunology*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; C497868:Cd22 protein, mouse; D037102:Lectins; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse