Production of autoantibodies is the hallmark of many autoimmune diseases. To understand how these self-destructive antibodies are controlled, we generated transgenic mice where the majority of B cells express disease-associated anti-DNA antibodies. We have shown that anti-DNA B cells are eliminated by deletion, functional silencing (anergy) and revision of self-reactive receptors (receptor editing). Paradoxically, although auto reactive B cells are strictly regulated, a substantial proportion of circulating antibodies in normal sera exhibits self- reactivity. Such antibodies, referred as natural autoantibodies (NAA), often have weak reactivity toward conserved cell components such as DNA, nucleoproteins and phospholipids that are also the common targets seen in autoimmune diseases. The function of NAA is presently unknown, as is their relationship to pathologic autoantibodies. Here, we propose two fundamentally different but not mutually exclusive roles of NAA in autoimmunity: 1) they may be a major source of pathological autoantibodies; 2) they may play a central role in maintaining self-tolerance. To test these hypotheses, a new immunoglobulin knock-in mouse model will be generated, where the B cells express a typical NAA. Unlike conventional transgenes, the knock-in gene is able to undergo receptor editing, somatic mutation and isotype switching, all of which are important in development of pathologic antibodies. Using this model, we will define the nature of B cells that produce NAA, and determine whether these B cells will participate in T cell-independent and T cell- dependent antigen responses. Next, by crossing the NAA knock-in mice to an autoimmune-prone background, the relationship between natural and pathologic autoantibodies will be determined, and the molecular mechanisms by which NAA acquire pathogenicity will be explored. Finally, by co-expression of natural autoantibodies and pathologic anti-DNA antibodies in a single animal, we will determine whether NAA can suppress pathologic autoantibody production, and determine whether NAA can alleviate autoimmune diseases. Results from these studies will provide great insight into the etiology of autoimmunity and may lead to new therapeutic strategies for autoimmune diseases.
