Current concepts of innate immune responses to bacterial stimuli such as lipopolysaccharides (e.g., the LPS from S. typhimurium used here) are largely based on data from in vitro stimulation of spleen cells taken from unstimulated mice. However, our recent findings with LPS stimulation in an in vivo mouse model demonstrate that much of this in vitro data is not suitable for modeling innate responses, which occur perforce in vivo. Similarly, our findings raise questions about the how to relate data from in vivo models (B-cell transgenic, TLR- deficient, parasite infection, etc.) to LPS responses in normal (genetically intact) animals. Specifically, we find that the majority of the LPS-stimulated plasma cell response in vivo is produced by B-1a (CD5+ B-1) cells, most of which only migrate into the spleen after LPS injected. Further, we find that the immediate response to LPS in vivo is produced by the B-1a cells that are resident in the spleen and surprisingly differentiate into plasma cells within 1-2 days without undergoing cell division. This initial wave of plasma cell differentiation accounts for a relatively small proportion of the overall in vivo response, which peaks at day 3 and is largely produced by immigrant B-1a cells that divide before (or while) differentiating to plasma cells. However, the rapid response capabilities of the early responders, which can be likened to primitive immunologic memory, may be key to the ability to use the innate immune system to """"""""fill in the gap"""""""" until the adaptive immune system can take over. Studies proposed here are designed to provide a clear view of the B cells and mechanisms that participate in innate antibody responses to invading pathogens, including but not restricted to LPS. Our findings to date demonstrate that we can work effectively with the tiny functional B cell subsets that mediate these responses (0.1-3% of spleen cells from unstimulated or LPS-stimulated mice, respectively). Thus, we now propose to further define the cellular, anatomical and molecular mechanisms that distinguish resident B-1 responses from those of immigrant B-1 cells, and to determine the extent to which other B cell compartments and receptor interactions contribute to the innate response. Together, these studies will provide grounds for developing a comprehensive and informative model of the complex innate immunity mechanisms involved in natural antibody responses that must be produced rapidly to minimize damage due to invading pathogens. Public Health Relevance: Studies proposed here are designed to provide a clear view of the B cells and mechanisms that participate in innate antibody responses to invading pathogens. Our findings to date demonstrate that we can work effectively with the tiny functional B cell subsets that mediate these responses. These studies will provide grounds for developing a comprehensive and informative model of the complex innate immunity mechanisms involved in natural antibody responses that must be produced rapidly to minimize damage due to invading pathogens.
Studies proposed here are designed to provide a clear view of the B cells and mechanisms that participate in innate antibody responses to invading pathogens. Our findings to date demonstrate that we can work effectively with the tiny functional B cell subsets that mediate these responses. These studies will provide grounds for developing a comprehensive and informative model of the complex innate immunity mechanisms involved in natural antibody responses that must be produced rapidly to minimize damage due to invading pathogens.
| Herzenberg, Leonore A (2015) Layered evolution in the immune system: a view from history. Ann N Y Acad Sci 1362:1-5 |
| Yang, Yang; Ghosn, Eliver Eid Bou; Cole, Leah E et al. (2012) Antigen-specific memory in B-1a and its relationship to natural immunity. Proc Natl Acad Sci U S A 109:5388-93 |
| Ghosn, Eliver Eid Bou; Yamamoto, Ryo; Hamanaka, Sanae et al. (2012) Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells. Proc Natl Acad Sci U S A 109:5394-8 |
| Grant, Jacqueline L; Ghosn, Eliver Eid Bou; Axtell, Robert C et al. (2012) Reversal of paralysis and reduced inflammation from peripheral administration of ?-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med 4:145ra105 |
| Kusy, Sophie; Ghosn, Eliver E B; Herzenberg, Leonore A et al. (2012) Development of B cells and erythrocytes is specifically impaired by the drug celastrol in mice. PLoS One 7:e35733 |
| Yang, Yang; Ghosn, Eliver Eid Bou; Cole, Leah E et al. (2012) Antigen-specific antibody responses in B-1a and their relationship to natural immunity. Proc Natl Acad Sci U S A 109:5382-7 |
| Ghosn, Eliver Eid Bou; Sadate-Ngatchou, Patricia; Yang, Yang et al. (2011) Distinct progenitors for B-1 and B-2 cells are present in adult mouse spleen. Proc Natl Acad Sci U S A 108:2879-84 |
| Ghosn, Eliver Eid Bou; Cassado, Alexandra A; Govoni, Gregory R et al. (2010) Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc Natl Acad Sci U S A 107:2568-73 |
| Cole, Leah E; Yang, Yang; Elkins, Karen L et al. (2009) Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge. Proc Natl Acad Sci U S A 106:4343-8 |
| Yang, Yang; Tung, James W; Ghosn, Eliver E B et al. (2007) Division and differentiation of natural antibody-producing cells in mouse spleen. Proc Natl Acad Sci U S A 104:4542-6 |
