Activation and migration of marginal zone B (MZB) cells into follicular (FO) regions of the spleen has been proposed as one of the mechanisms that regulate the development of autoreactive B cells. The mer receptor tyrosine kinase (Mertk) mediates apoptotic cell clearance and regulates activation and cytokine secretion. In the well-studied class II chronic GVH model of bm12 cells into B6 hosts, we observed that Mertk deficient B6 mice did not generate autoantibodies in response to this allogeneic stimulus. We posited that Mertk is important in MHC-II-mediated B cell signaling. In the present study, we show that B cells from Mertk(-/-) mice but not WT B6 mice exhibited decreased calcium mobilization and tyrosine phosphorylation when stimulated by MHC-II cross-linking. The finding that Mertk was important for class II signaling in B cells was further supported by the preponderance of a-allotype autoantibodies in cGVH in RAG-KO mice reconstituted with a mixture of bone marrow from Mertk(-/-) mice (b-allotype) and C20 mice (a-allotype). MZB cells from Mertk(-/-) mice were unable to down regulate surface CD1d expression and subsequent inclusion in the MZ, associated with significantly lower germinal center responses compared to MZB cells from WT. Moreover, Mertk(-/-) mice treated with an anti-CD1d down regulating antibody responded significantly to bm12 cells, while no response was observed in Mertk(-/-) mice treated with control antibodies. Taken together, these findings extend the role of Mertk to include CD1d down regulation on MZB cells, a potential mechanism limiting B cell activation in cGVH.
[Show abstract][Hide abstract] ABSTRACT: Mer receptor tyrosine kinase is a member of the Tyro-3/Axl/Mer (TAM) subfamily of receptor tyrosine kinases, and its expression on phagocytes facilitates their clearance of apoptotic cells (ACs). Mer expression in germinal centers (GCs) occurs predominantly on tingible body macrophages. B and T cells do not express Mer. In this study, we show that Mer deficiency ((Mer(-/-)) resulted in the long-term accumulation of ACs primarily in GCs and not in the T cell zone, marginal zone, or red pulp areas of the spleen. AC accumulation in GCs led to augmented Ab-forming cell, GC, and IgG2 Ab responses in Mer(-/-) mice, which were sustained for at least 80 d. Enhanced responses in Mer(-/-) mice were due to increased activation and proliferation of B cells and CD4(+) Th cells, including follicular helper T cells, which resulted in high titers of anti-nuclear Abs in Mer(-/-) mice compared with wild-type controls. Secondary IgG-producing Ab-forming cell, total IgG, and IgG2 Ab responses were also increased in Mer(-/-) mice. Finally, compared with wild-type controls, Mer(-/-) mice had increased percentage of IFN-γ-producing CD4(+) Th cells and elevated levels of Th1 (i.e., IL-2 and IFN-γ) and proinflammatory (i.e., TNF and IL-6) cytokines, consistent with elevated levels of Th1-biased IgG2 Abs in Mer(-/-) mice. Together, our results demonstrate that Mer deficiency induces prolonged accumulation of ACs in GCs, resulting in dysregulation of GC B cell and CD4(+) Th cell responses and Th1 cytokine production, leading to alteration of B cell tolerance and the development of autoantibodies.
The Journal of Immunology 01/2013; 190(4). DOI:10.4049/jimmunol.1200824 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Induced mouse models of systemic lupus erythematosus (SLE) have been developed to complement the spontaneous models. This chapter describes the methods used in the pristane-induced model and the chronic graft-versus-host disease (cGVHD) model, both of which have been extensively used. We will also outline the specific mechanisms of systemic autoimmunity that can be best characterized using each of these models.
[Show abstract][Hide abstract] ABSTRACT: The Mertk receptor tyrosine kinase facilitates macrophage and DC apoptotic-cell clearance and regulates immune tolerance. Mertk may also contribute to B-cell activation, because Mertk-KO mice fail to develop autoantibodies when allo-activated by T cells. We investigated this possibility with a well-characterized model in which injection of mice with goat anti-IgD antibody causes membrane IgD cross-linking that induces T-independent B cell activation and antigen presentation to T cells. Goat anti-mouse IgD antibody-injected C57BL/6 Mertk-KO mice had normal initial B cell activation and proliferation, but significantly lower T cell activation and proliferation, as well as lower IgE and IgG anti-goat IgG responses, as compared to C57BL/6 WT controls. B cell antigen processing, analyzed by evaluating B cell fluorescence following injection of monoclonal anti-IgD antibody labeled with biotin or FITC, was comparable between Mertk-KO mice and WT mice. IgD Ab primed B cells from Mertk-KO mice exhibited significantly lower ability in activating memory T cells isolated from WT mice injected with the same antigen 10 days before. These observations suggest that Mertk expression is required for optimal B-cell antigen presentation, which is, in turn, required in this model for optimal T cell activation and subsequent T cell-dependent B cell differentiation.
Journal of Autoimmunity 04/2014; 53. DOI:10.1016/j.jaut.2014.03.004 · 8.41 Impact Factor
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