Immunological tolerance regulates unwanted responses of B and T cells to self-tissue, reducing the chances of autoimmunity and focusing the immune response on foreign antigens. We review our progress in using transgenic models expressing superAgs that promote either central or peripheral B cell tolerance to study the genetics of the processes. We identified and verified a number of candidate genes whose mutation allowed B cell escape. We propose to find additional candidates, and evaluate existing validated targets in greater depth. To expand the identification of new candidate genes, we will focus on use of CRISPR mediated mutation or knockdown in hematopoietic stem cells. For the detailed mechanistic studies, we will examine in more detail proteins involved in ER stress and oncogenesis. The long-term goal of these studies is to develop a comprehensive understanding of all of the genetic components maintaining immune tolerance at these stages. This knowledge should facilitate treatment of autoimmune disorders and impact vaccine development.
Mice expressing superantigens to B cell receptors reveal tolerance checkpoints in a normal immune system. We have exploited this selection to identify mutations that promote escape with the goal of understanding how autoreactive B cells are regulated. The proposed studies aim to characterize how the genes of interest contribute to tolerance and how their mutation facilitates escape of potentially harmful self-reactive B cells.
| Gavin, Amanda L; Huang, Deli; Huber, Christoph et al. (2018) PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nat Immunol 19:942-953 |
| Nemazee, David (2017) Mechanisms of central tolerance for B cells. Nat Rev Immunol 17:281-294 |
| Martinic, Marianne M; Caminschi, Irina; O'Keeffe, Meredith et al. (2017) The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8+ Thymocyte Selection. J Immunol 198:2649-2660 |
| Lai, Maoyi; Gonzalez-Martin, Alicia; Cooper, Anthony B et al. (2016) Regulation of B-cell development and tolerance by different members of the miR-17?92 family microRNAs. Nat Commun 7:12207 |
| Lang, Julie; Ota, Takayuki; Kelly, Margot et al. (2016) Receptor editing and genetic variability in human autoreactive B cells. J Exp Med 213:93-108 |
| Gonzalez-Martin, Alicia; Adams, Brian D; Lai, Maoyi et al. (2016) The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat Immunol 17:433-40 |
| Aït-Azzouzene, Djemel; Kono, Dwight H; Gonzalez-Quintial, Rosana et al. (2010) Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice. J Immunol 185:1015-27 |
