Knock-out of the histidine decarboxylase gene modifies the repertoire of natural autoantibodies

Natural antibodies (NA) are antibodies produced in the absence of known immunization with specific antigens. NA are found in the blood of healthy humans and mice. Histamine influences many aspects of the immune response, including antibody production. However, the role of histamine in the generation of NA has not yet been studied. In this work, we used an ELISA assay to characterize the self-antigen binding repertoires of NA in wild type (WT) mice and in histidine decarboxylase knock-out (HDC-KO) mice, unable to synthesize histamine: We now report that HDC-KO and WT mice differed in the patterns of autoreactivity of their IgM and IgG NA. The NA in HDC-KO sera manifested a larger repertoire of IgM autoantibodies than did the WT sera. The self-antigens bound by IgM from HDC-KO mice included structural proteins, enzymes associated with cellular metabolism, double-stranded and single-stranded DNA, and tissue-specific antigens like insulin. There were relatively fewer differences in the NA repertoire of IgG autoantibodies of the mice: notably, the HDC-KO sera reacted with glutamic acid decarboxylase (GAD), an antigen associated with autoimmune diabetes. These results demonstrate that endogenous histamine can influence the self-reactivity of the NA repertoire. (C) 2004 Elsevier Ltd. All rights reserved.