title: Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production.
abstract: B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic (NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh-expressing B cells compared with C57BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) trait was confirmed using double congenic NOD.B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand (APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor (BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse.
authors.affiliation: Department of Clinical Microbiology, Division of Immunology, Umeå University, Umeå, Sweden.
authors.forename: Viqar S
authors.initials: VS
authors.lastname: Banday
authors.affiliation: Department of Clinical Microbiology, Division of Immunology, Umeå University, Umeå, Sweden.
authors.forename: Radha
authors.initials: R
authors.lastname: Thyagarajan
authors.affiliation: Department of Clinical Microbiology, Division of Immunology, Umeå University, Umeå, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Sundström
authors.affiliation: Department of Clinical Microbiology, Division of Immunology, Umeå University, Umeå, Sweden. kristina.lejon@umu.se.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lejon
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010950:Plasma Cells / Q000276:immunology*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C486361:Tnfrsf13b protein, mouse; C491959:Tnfsf13 protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: B cells; B-cell activating factor; affinity maturation; non-obese diabetic mouse; transmembrane activator, calcium modulator and cyclophilin ligand interactor