title: Integrin-α FG-GAP repeat-containing protein 2 is critical for normal B cell differentiation and controls disease development in a lupus model.
abstract: The phenylalanyl-glycyl-glycyl-alanyl-prolyl (FG-GAP) domain plays an important role in protein-protein interactions, including interaction of integrins with their ligands. Integrin-α FG-GAP repeat-containing protein 2 (Itfg2) is a highly conserved protein in vertebrates that carries two FG-GAP domains, but its role in mammalian physiology is unknown. In this article, we show that Itfg2 is an intracellular protein and it plays a critical role in B cell differentiation and development of autoimmunity. Itfg2-deficient mice displayed a phenotype consistent with retention of B cells in the spleen and had a lower concentration of IgG in the blood when compared with wild-type littermates. Itfg2-deficient splenocytes also showed a defect in cell migration in vitro. After immunization with a thymus-dependent Ag, the absence of Itfg2 caused a shift in B cell maturation from the germinal centers to the extrafollicular regions of the spleen and blocked deposition of Ag-specific plasma cells in the bone marrow. In support of hematopoietic cell intrinsic activity of Itfg2, bone marrow transplantation of Itfg2-deficient cells was sufficient to impair germinal center development in wild-type mice. Furthermore, Itfg2 deficiency exacerbated development of autoimmune disease in MRL/lpr lupus-prone mice. These results identify Itfg2 as a novel contributor to B cell differentiation and a negative regulator of the autoimmune response during lupus.
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381.
authors.forename: Amin
authors.initials: A
authors.lastname: Al-Shami
authors.forename: Jeannette
authors.initials: J
authors.lastname: Crisostomo
authors.forename: Carrie
authors.initials: C
authors.lastname: Wilkins
authors.forename: Nianhua
authors.initials: N
authors.lastname: Xu
authors.forename: Juliane
authors.initials: J
authors.lastname: Humphries
authors.forename: Wei C
authors.initials: WC
authors.lastname: Chang
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Anderson
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D023061:Gene Order; D018390:Gene Targeting; D005838:Genotype; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007136:Immunoglobulins / Q000097:blood; D039001:Integrin alpha Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D016415:Sequence Alignment; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D007136:Immunoglobulins; D039001:Integrin alpha Chains; C584572:Itfg2 protein, mouse