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.

Increased Levels of Type 1 Interferon in a Type 1 Diabetic Mouse Model Induce the Elimination of B Cells from the Periphery by Apoptosis and Increase their Retention in the Spleen

“…An imbalance in splenic B cell development resulting in expansion of the MZ subset has been associated with autoimmune pathogenesis in various murine models [39], including the NOD inbred mouse strain, in which splenic marginal zone (MZ) B cell expansion has been linked to the development of T1D [40]. Therefore, the numbers of CD20-positive B cells in the spleens of control, diabetic and anti-IFNAR1-treated mice were estimated.…”

“…An imbalance in splenic B cell development resulting in the expansion of the MZ subset has been associated with autoimmune pathogenesis in various murine models [39]. For example, in the NOD inbred mouse strain, splenic MZB cell expansion has been linked to the development of T1D [40]. MZB cells are suggested to be enriched in autoreactive specificities, and an enlargement of the MZB compartment has been implicated in T1D [20,39].…”

An update on the biology of sphingosine 1-phosphate receptors

“…Additionally, traffi cking of marginal zone (MZ) B cells between the MZ and the follicle is regulated by S1P 1 , which maintains these cells in the MZ in order for them to capture blood-borne antigens (86)(87)(88). Studies of nonobese diabetic mice have shown that upregulation of S1P 3 by MZ B cells and their T2 MZ precursors may also play a role in enhancing MZ retention in these mice ( 89,90 ). S1P 3 has already been shown to regulate B cell migration in vitro, but not in vivo, in WT mice ( 83,87 ).…”

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…RGS13 is one of the smallest members of the RGS family of proteins, containing 159 amino acids, 157 amino acids, the mouse counterpart, and a predicted molecular weight of 19 kDa Sethakorn and Dulin, 2013;Shi et al, 2002;Stolp et al, 2013;Wang et al, 2013a;Xie et al, 2010b). Human RGS13 was cloned in 2002 from lung cDNA and exhibits relatively restricted tissue expression, most prominently in T and B lymphocytes, as well as mast cells, of immune tissues such as tonsil, thymus, lymph node, and spleen (Johnson and Druey, 2002;Larminie et al, 2004;Shi et al, 2002).…”