Observations that antibodies from rheumatic fever patients recognize both N-acetylglucosamine (GlcNAc), a saccharide found in GAC, and components of human heart, brain, and other tissues raised concerns that immunization with GAC could induce the crossreactive autoantibodies associated with rheumatic fever.
We conducted a detailed literature review of the specificities of polyclonal and monoclonal antibodies elicited by exposure to GAC and other GAS antigens. We found no compelling evidence that GAC induces the crossreactive antibodies in question.
We propose that crossreactive antibodies arise from polyclonal B cell activation in response to GAS membrane fractions with exposure to potent B cell mitogens (including pokeweed mitogen in the case of human mAbs). This process resulted in crossreactive, near germline antibodies, some of which bind GlcNAc.
A similar mechanism may contribute to the pathogenesis of acute rheumatic fever (ARF) with repeated GAS infections driving B cells secreting cross-reacting antibody targeting a variety of lipid, protein and polysaccharide antigens.