title: Intrinsic molecular factors cause aberrant expansion of the splenic marginal zone B cell population in nonobese diabetic mice.
abstract: Marginal zone (MZ) B cells are an innate-like population that oscillates between MZ and follicular areas of the splenic white pulp. Differentiation of B cells into the MZ subset is governed by BCR signal strength and specificity, NF-κB activation through the B cell-activating factor belonging to the TNF family (BAFF) receptor, Notch2 signaling, and migration signals mediated by chemokine, integrin, and sphingosine-1-phosphate receptors. An imbalance in splenic B cell development resulting in expansion of the MZ subset has been associated with autoimmune pathogenesis in various murine models. One example is the NOD inbred mouse strain, in which MZ B cell expansion has been linked to development of type 1 diabetes and Sjögren's syndrome. However, the cause of MZ B cell expansion in this strain remains poorly understood. We have determined that increased MZ B cell development in NOD mice is independent of T cell autoimmunity, BCR specificity, BCR signal strength, and increased exposure to BAFF. Rather, mixed bone marrow chimeras showed that the factor(s) responsible for expansion of the NOD MZ subset is B cell intrinsic. Analysis of microarray expression data indicated that NOD MZ and precursor transitional 2-MZ subsets were particularly dysregulated for genes controlling cellular trafficking, including Apoe, Ccbp2, Cxcr7, Lgals1, Pla2g7, Rgs13, S1pr3, Spn, Bid, Cd55, Prf1, and Tlr3. Furthermore, these B cell subsets exhibited an increased steady state dwell time within splenic MZ areas. Our data therefore reveal that precursors of mature B cells in NOD mice exhibit an altered migration set point, allowing increased occupation of the MZ, a niche favoring MZ B cell differentiation.
authors.affiliation: Garvan Institute of Medical Research, Immunology Program, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Stolp
authors.forename: Eliana
authors.initials: E
authors.lastname: Mariño
authors.forename: Marcel
authors.initials: M
authors.lastname: Batten
authors.forename: Frederic
authors.initials: F
authors.lastname: Sierro
authors.forename: Selwyn L
authors.initials: SL
authors.lastname: Cox
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Silveira
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000172:deficiency / Q000502:physiology*; D053265:B-Cell Activation Factor Receptor / Q000502:physiology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D043484:Proprotein Convertases / Q000502:physiology; D051883:Receptor, Notch2 / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D012697:Serine Endopeptidases / Q000502:physiology; D013154:Spleen / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; D011947:Receptors, Antigen, B-Cell; D049349:Receptors, Lysosphingolipid; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1