Breakdown of autoreactive tolerance in mice deficient in apoptotic clearance (143.24)

Abstract

Abstract The Mer receptor tyrosine kinase (Mertk) helps in clearance of apoptotic cells through the bridging molecules Gas6 and/or Protein S. Mertk deficient (Mer-KO) mice develop lupus-like autoimmunity with gradual accumulation of apoptotic cells in spleen and thymus. Such Mer-KO mice have two-fold expanded numbers of splenic marginal zone (MZ) B cells, yet, they develop normal response to OVA comparing to B6 control mice. When challenged respectively with type I (NP-LPS) and type II (NP-Ficoll) T-independent antigens, Mer-KO developed greater antibody responses to NP-Ficoll than their B6 counterparts. We further explored the role of the Mertk in regulating autoreactive B cells. Mer-KO mice bearing a DNA-specific immunoglobulin heavy-chain transgene (3H9/Mer-KO) spontaneously produced anti-dsDNA antibodies at the age of 3-5 months. Allotype specific ELISA allowed us to identify the transgene as source of autoantibody in Mer-KO/3H9 mice. We further analyzed MZ and follicular (FO) B cells by ELISPOT. Antibody-secreting cell counts (ASC) of MZ B cells are 70 (3H9/Mer-KO), 40 (Mer-KO), and 20 (3H9), respectively, while ASC counts of FO B cells are all around the baseline level of 20 cells. Taken together, our data show that Mer has a major effect on the development of the marginal zone B-cell compartment. Mer is important in establishing DNA-specific B cell tolerance in 3H9 anti-DNA transgenic mice.