Role of natural immunity to self apoptotic exosomes in maintaining immune homeostasis

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BACKGROUND The immune system distinguishes the self from the non-self, allowing protection against foreign organisms from damaging the body. To ensure of its homeostasis, multiple mechanisms tightly regulate the immune system to avoid autoimmune disease. In contrast to the classical theory that a healthy immune system requires an absolute avoidance of self-reactive lymphocyte clones, the repertoires of innate-like B cells are known to incorporate some level of autoreactivity, and to produce natural antibodies. A significant set of natural antibodies are specific to apoptotic Antigens (NapoAbs) expressed by apoptotic cells. It is suggested that these NapoAbs may play a role in facilitating effective non-inflammatory clearance of apoptotic cells of importance in maintaining immune homeostasis. However, of the mechanisms that regulate the production of NapoAbs is still largely unexplored. Our group was the first to characterize a novel structure reminiscent of exosomes that are released downstream of Caspase-3 activation by apoptotic endothelial cells. These Apoptotic Exosomes (ApoExo) are strikingly different from classical apoptotic bodies. Our observations suggest that B1 cell memory to autoantigens packaged in ApoExo can be found within the normal immune repertoire and that the infusion of ApoExo triggers the production of IgM and IgG Antibodies specific to Apoptotic antigens. HYPOTHESIS We HYPOTHESIZE that newly identified vesicular structures Apoptotic Exosomes stimulate specific B cells that exist in the normal immune repertoire to secrete Natural Apoptotic Antigens autoantibodies of importance in non-inflammatory clearance of apoptotic cells. We also hypothesize that inflammatory signals can regulate these processes. OUR LONG-TERM OBJECTIVE is to delineate the functions of Apoptotic Exosomes in basic immunological processes of importance in maintaining homeostasis AIMS In this research program we propose: AIM 1: To characterize the repertoire of naturally occurring B cells specific to Apoptotic Exosomes (ApoExo) and their autoantibody secretion signature AIM 2: To evaluate ApoExo derived Ig capacity to modulate Non-Inflammatory clearance of apoptotic cells AIM 3: To evaluate how inflammatory context modulates ApoExo immune responses SCIENTIFIC APPROACH This research program, articulated around a well-structured series of complementary descriptive and mechanistic aims, proposes to use an extensive array of `tools' available for our analyses. These includes substantial number of genetically modified mouse strain and state of the art techniques to characterize and isolate exosome, immune cells subsets and antibodies. Importantly, the PI and his team of collaborators have extensive experience with exosomes and immunological approaches. IMPACT This research program will provide, upon completion, great insight on ApoExo contribution to immune homeostasis. This program is, to our knowledge, the first to investigate this appealing direction.