The National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the Office of Research on Women’s Health (ORWH) of the National Institutes of Health (NIH) and the National Multiple Sclerosis Society (NMSS) invite applications to identify, characterize, and define differences in the immune response between males and females, including responses to exogenous and self-antigens, the innate and adaptive immune response, systemic and mucosal immune response, and regulation of the immune system by hormonal and non-hormonal sex differences. The intent of this Request for Applications (RFA) is to support multidisciplinary research on sex-based differences in immune responses that may be important in autoimmune diseases, including multiple sclerosis (MS), rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), as well as other immune mediated diseases, and the underlying mechanisms and clinical significance of such differences. Collaborative multidisciplinary research, involving investigators with expertise in various scientific disciplines and clinical specialties is encouraged. Both human studies and animal models with relevance to human disease are appropriate. Research that expands basic and clinical knowledge of the effect of sex, including hormonal and non-hormonal differences, on the immune response will facilitate development of improved therapeutic and preventive strategies for autoimmune diseases and other immune-mediated disorders. The focus of this RFA is the biological or physiological sex differences between males and females; studies of the cultural, social, and historical differences between males and females ("gender differences") are not responsive to this RFA.