This is the competitive renewal application to extend our work supported by AI51420-01 A. Significant progress has been made that greatly elucidate the mechanism of the unique neonatal autoimmune ovarian disease (nAOD). Autoantibody (Ab) to the ovarian ZP3 led to the formation of ovarian immune complex. This provokes an organ specific autoimmune disease that is regulated by FcgR+, and dependent on de novo activation of pathogenic CD4 T cells (TD-nAOD). Uniquely, nAOD affects only neonatal mice and spares mice beyond 5 days of age;therefore, the understanding neonatal propensity to autoimmunity is our major goal. We discovered that severe nAOD is also induced in the recombinase activating gene (RAG) knockout (KO) mice, thus innate immunity alone is also sufficient to induce nAOD (TI-nAOD). NK cells play multiple and pivotal roles in TI-nAOD. A seminal observation is the ontogenetic regulation of NK cell function in TI- nAOD. RAG KO mice deficient in perforin did not develop TI-nAOD, and the disease was restored by neonatal but not adult (or day 9) NK cells from wild type donors. NK function in TI-nAOD also depended on NKG2D - a major NK cell activating receptor.
In AIM 1, we will test the hypothesis that the late ontogeny of expression of the Ly49 NK cell inhibitory receptors allows neonatal NK cells to escape from regulation between neonatal 1-5 days, and to induce neonatal ovarian injury. The pro-inflammatory cytokine IFNg and also FcgR played non-redundant roles in the pathogenesis of both TI-nAOD and TD-nAOD.
In AIM 2, we will investigate the cellular basis for the IFNg- and NK cell- dependent functions in TI-nAOD of RAG KO mice. And in AIM 3, we will investigate how neonatal NK cells and IFNg promote de novo pathogenic T cell responses in TD-nAOD of wild type mice;in particular, determine the relative contribution of NK cells and dendritic cells in this process. Finally, the NK cell-dependent TI-nAOD was readily suppressed by adult CD4+CD25+ Treg, and it requires IL10. This finding documents, for the first time, Treg suppression of any form of neonatal immune response.
In AIM 4, we will investigate the cellular mechanism of the IL10- dependent Treg suppression. Also, by comparing the mechanism of suppression between the adult and the neonatal hosts, we expect to obtain new insight into the physiology of neonatal immune system, and further elucidate the important observation of neonatal propensity to autoimmune disease.
|Rival, Claudia; Wheeler, Karen; Jeffrey, Sarah et al. (2013) Regulatory T cells and vasectomy. J Reprod Immunol 100:66-75|
|Rival, Claudia; Samy, Eileen; Setiady, Yulius et al. (2013) Cutting edge: Ly49C/I? neonatal NK cells predispose newborns to autoimmune ovarian disease induced by maternal autoantibody. J Immunol 191:2865-9|
|Mauldin, Ileana S; Tung, Kenneth S; Lorenz, Ulrike M (2012) The tyrosine phosphatase SHP-1 dampens murine Th17 development. Blood 119:4419-29|
|Ernst, P B; Erickson, L D; Loo, W M et al. (2012) Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice. Am J Physiol Gastrointest Liver Physiol 302:G105-15|
|Jiang, Chao; Loo, William M; Greenley, Erin J et al. (2011) B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus. J Immunol 186:6136-47|
|Wheeler, Karen; Tardif, Steve; Rival, Claudia et al. (2011) Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy. Proc Natl Acad Sci U S A 108:7511-6|
|Cohen, Jarish N; Guidi, Cynthia J; Tewalt, Eric F et al. (2010) Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med 207:681-8|
|Case, Laure K; Del Rio, Roxana; Bonney, Elizabeth A et al. (2010) The postnatal maternal environment affects autoimmune disease susceptibility in A/J mice. Cell Immunol 260:119-27|
|Wheeler, Karen M; Samy, Eileen T; Tung, Kenneth S K (2009) Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity. J Immunol 183:7635-8|
|Kharel, Yugesh; Lee, Sangderk; Snyder, Ashley H et al. (2005) Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 280:36865-72|