To provide effective host defense, a healthy immune system must recognize microbial threats and coordinate a protective inflammatory response. Yet the maintenance of overall homeostasis also dictates an absolute requirement for the efficient recognition and clearance of the host’s own dead and dying cells, and these functions must somehow also be balanced to avoid autoimmune disease. In recent studies we have characterized a class of naturally arising regulatory antibodies (NAbs) to oxidation-associated phospholipid antigens on apoptotic-cell (AC) membranes that discriminate apoptotic from healthy cells. When augmented by appropriate constant region effector functions, these antibodies enhance the phagocytic clearance of ACs, blunt inflammatory responses transduced by membrane and endosomal Toll-like receptors (TLRs), and block the development of inflammatory arthritis. These NAbs have also been implicated in lupus as well as atherosclerosis. We describe a model of immune homeostasis, termed the inhibitory dual receptor hypothesis, in which NAbs to ACs oppose the development of autoimmune and inflammatory disease.
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