RESUMO
Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Splenic marginal zone B cells are important producers of autoantibodies, and are subject to stringent tolerance mechanisms to prevent autoimmunity. In this paper, we explore the role of the Mer tyrosine kinase (Mertk) in regulating autoreactive B cells. This receptor tyrosine kinase serves to bind apoptotic cells, to mediate their phagocytosis, and to regulate subsequent cytokine production. Mice lacking Mertk suffer from impaired apoptotic cell clearance and develop a lupus-like autoimmune syndrome. Here we show that such Mertk-KO mice have expanded numbers of splenic marginal zone B cells. Mertk-KO mice bearing a DNA-specific immunoglobulin heavy-chain transgene (3H9) produced anti-DNA antibodies that appeared to be secreted largely by marginal zone B cells. Finally, Mertk-KO mice developed greater antibody responses after NP-Ficoll immunization than their B6 counterparts. Taken together, our data show that Mertk has a major effect on the development of the marginal zone B-cell compartment. Mertk is also important in establishing DNA-specific B-cell tolerance in 3H9 anti-DNA transgenic mice.
Assuntos
Anticorpos Antinucleares/metabolismo , Linfócitos B/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Anticorpos Antinucleares/genética , Apoptose/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Modelos Animais de Doenças , Humanos , Tolerância Imunológica/genética , Cadeias Pesadas de Imunoglobulinas/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fagocitose/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/imunologia , Baço/patologia , c-Mer Tirosina QuinaseRESUMO
The p53 tumor suppressor molecule triggers a key pathway of apoptosis in injured cells, in part through induction of Fas. The importance of Fas as a receptor mediating apoptosis is highlighted by the lupus-like systemic autoimmunity seen in animals and humans with nonfunctional Fas molecules. We set out to see if the absence of p53, superimposed on the Fas defect of lpr mice, might further accelerate or exacerbate their systemic autoimmunity. We generated double mutant mice (p53(-/-) lpr) having defects in both p53- and Fas-dependent pathways, hypothesizing that animals with lesions in both Fas- and p53-dependent pathways would show reduced ability to delete autoreactive or injured cells, thereby producing more severe autoimmune disease. Surprisingly, these mice have lower autoantibody levels than the single mutant lpr mice. These studies suggest an unanticipated role for p53 in the progression of autoimmunity and the production of autoantibodies.
