The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

Abstract

The Mer receptor tyrosine kinase mediates apoptotic cell phagocytosis and modulates macrophage cytokine production. Mer−/− mice have defective clearance of apoptotic debris and develop a systemic lupus erythematosus-like autoimmune syndrome. It was surprising then that B6-Mer−/− recipients of bm12 spleen cells failed to develop anti-dsDNA and anti-chromatin autoantibodies, whereas B6 hosts produced the expected autoimmune chronic graft-vs-host (cGVH) reaction. The lack of autoantibody formation in cGVH was not due to the failure of Mer-deficient hosts to provoke alloreactivity, because Mer−/− spleen cells were recognized by bm12 T cells in MLR. Cell transfer experiments in Rag-knockout mice indicated that the lack of autoantibody production in Mer−/− cGVH disease hosts was due to an intrinsic B cell defect. This defect did not cause a global inability to produce autoantibodies, because in vivo exposure to LPS stimulated production of autoantibodies in both B6 and Mer−/− mice. We further observed that wild-type B6 B cells up-regulated Mer upon activation in cGVH, and that B cells from mice lacking Mer showed a decreased up-regulation of activation-associated cell surface markers. These findings indicate that Mer serves an important role in the activation of self-reactive B cells in systemic autoimmunity.

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

“…For example, low doses of lipopolysaccharide in MerTK -/-mice resulted in death from endotoxic shock associated with high levels of TNF-α (30). Failure to dampen acute innate immunity leads to secondary pathological activation of T and B lymphocytes directed at self-antigens (4,26,29,31,32). This is especially important given that apoptotic cells accumulate in the absence of MerTK (23,28), providing an enriched source for intracellular "self" antigens in the context of heightened acute inflammatory signals and enhanced B and T lymphocyte activity.…”

A novel role for c-Src and STAT3 in apoptotic cell–mediated MerTK-dependent immunoregulation of dendritic cells

“…14 In addition to DCs, MerTK is expressed by macrophages (Møs), natural killer cells, natural killer T cells, B cells, and endothelial and epithelial subtypes. [15][16][17][18] Expression of MerTK by Møs is required for efficient phagocytosis of ACs, and defective MerTK expression by retinal pigment epithelial cells leads to the accumulation of apoptotic photoreceptor outer segments and the development of a type of retinitis pigmentosa in rats, mice, and humans. 9,[19][20][21] Phagocytosis of ACs in these cell types is due to MerTKdependent signaling events promoting cytoskeletal reorganization.…”

Genetic and Pharmacological Modulation of Dendritic Cell-T Cell Interactions as a Therapeutic Strategy for Systemic Lupus Erythematosus

“…Thus, immature DC therapy will lead to the production of Tregs with the subsequent downmodulation of CD4-induced B cell responses. However, several individual alterations in B cell from SLE patients have been reported [56,58,[90][91][92]), posing the modulation of B cells as an attractive alternative approach to DC modulation. In this regard, the successful results obtained in rheumatoid arthritis patients with Rituximab, a chimeric monoclonal antibody that selectively deletes CD20-positive B cell, prompted the evaluation of this drug in lupus patients [91,93].…”

“…Because SLE hallmark is the hyper production of autoantibodies, B cells are critical players in SLE pathogenesis and several abnormalities in their function have been described [37,[56][57][58]. One of the stimuli that promotes B cell differentiation into immunoglobulin secreting cells is the B cells activating factor (BAFF), which is significantly increased in the sera of active SLE patients [58].…”