"Natural" antibodies are antibodies produced in the absence of apparent stimulation by specific antigens. Most of these antibodies are of IgM class. Natural IgM is thought to function in the innate immune response, in immune regulation, and in autoimmune processes because of its natural presence, polyreactivities with high avidities, and the exquisite ability to activate complement. However, the physiological role of natural IgM in these processes is not completely understood due to the lack of a suitable model system. To overcome this limitation, we have constructed a novel mouse strain that is completely deficient in circulating IgM. But this mouse strain still maintains a normal preimmune B cell compartment that can initiate an antibody response by secreting other IG isotypes. Utilizing this new mouse strain, this proposal outlines experiments aimed at elucidating the role of natural IgM in the immediate immune response against bacterial infection, in enhancing the ensuing antibody response, and in autoantibody production and autoimmune pathogenesis. We propose to: (1) determine the susceptibility of mutant mice to challenges by exogenous bacteria such as group B streptococcus (GBS), endogenous intestinal bacteria, or bacterial endotoxin; (2) measure the antibody response in mutant mice immunized with T-dependent and T-independent antigens and determine the effect of the absence of IgM on b cell activation, somatic hypermutation, antibody affinity maturation, and memory b cell differentiation and maintenance; (3) introduce the targeted mutation onto the lymphoproliferation (lpr) background and determine the effect of the absence of IgM on autoantibody production and autoimmune-mediated glomerulonephritis and vasculitis. GBS is the leading cause of bacterial sepsis and meningitis among newborns in the United States and endotoxin shock is an urgent medical problem. Elucidation of the role of natural IgM in protection against these pathogens may provide a basis for the development of IgM antibody for their treatment. Autoantibodies, including IgM rheumatoid factor, are often associated with human rheumatoid disease. Clarification of the role of autoreactive IgM in autoimmune responses and pathogenesis will help to reveal the etiology of human rheumatoid diseases.