Autoimmune hemolytic anemia (AIHA) is characterized by the production of antibodies directed against self red blood cells. Given the frequent association between AIHA and other autoimmune disorders, generalized immune dysfunction likely plays a role in the disease process. Under normal conditions, self-reactive lymphocytes are killed, inactivated or suppressed by regulatory T cells, resulting in unresponsiveness to selfantigens. Disruption of these control mechanisms results in the survival and pathogenic activation of selfreactive lymphocytes. It is unclear how self-reactive lymphocytes are spontaneously activated in the absence of overt infection or other stimuli, leading to autoimmune disease. If the initiators of activation and subsequent disease can be delineated, and the antigen targets of pathogenic antibodies identified, means of controlling these autoimmune reactions may be uncovered. In this study, we use a mouse model of spontaneous, acute systemic autoimmunity that principally manifests as AIHA to define the stimuli that are required for the development of autoimmune disease. The overall objective of this proposal is to define the immunological abnormalities in a model of spontaneous autoimmunity and to identify the target antigens in this disease. The central hypothesis underlying this proposal is that abnormal cytokine production and uncontrolled activation of dendritic cells due to the absence of regulatory T cell suppression results in autoimmunity. The successful completion of this project will elucidate the immune abnormalities (including the role of dendritic cells, cytokines and antigen-specific lymphocytes) in AIHA development, and strengthen our understanding of what triggers and maintains autoimmunity.
The long-term goals of this project are the identification and blockade of antigen-specific T cells, and the selective expansion of antigen-specific regulatory T cells. By identifying the relevant targets of autoimmune attack in these animals, we can better understand the pathogenic lymphocytes and the mechanisms by which they cause damage.
|Gravano, David M; Al-Kuhlani, Mufadhal; Davini, Dan et al. (2016) CD8+ T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure. J Autoimmun 75:58-67|
|Peiris, T Harshani; Hoyer, Katrina K; Oviedo, Néstor J (2014) Innate immune system and tissue regeneration in planarians: an area ripe for exploration. Semin Immunol 26:295-302|
|Johnson, Larry; Gaab, Erin M; Sanchez, Javier et al. (2014) Valley fever: danger lurking in a dust cloud. Microbes Infect 16:591-600|
|Isakson, Sara H; Katzman, Shoshana D; Hoyer, Katrina K (2012) Spontaneous autoimmunity in the absence of IL-2 is driven by uncontrolled dendritic cells. J Immunol 189:1585-93|