A variety of clinical, epidemiological, and experimental data suggest that rheumatic heart disease and autoimmune myocarditis are not only similar in their pathogenesis, but may often be due to combined infections with coxsackie virus (CX) and streptococcus A bacteria (SA). This paper reviews the evidence for this hypothesis, provides some new experimental data supporting the hypothesis, and suggests specific experiments for testing it. While, it is well-established that the M protein of SA mimics myosin, we demonstrate using homology search tools that various CX proteins mimic actin. We further demonstrate that antibody against CX recognizes actin as an antigen, and that anti-actin antibodies recognize CX antigen. Thus, anti-CX antibodies may also target muscle. Moreover, since myosin and actin are molecularly complementary, it follows that some SA and CX proteins may be molecularly complementary. Some antibodies against these complementary proteins in SA and CX should therefore act like idiotype-antiidiotype antibodies. We show that, indeed, CX and SA antibodies precipitate each other. Thus, it is possible that combined CX-SA infections produce more severe disease by producing pairs of idiotypic antibodies that act like antiidiotypic antibodies as well, thereby, disregulating immune control and triggering an autoimmune reaction against both myosin and actin simultaneously. We predict that combinations of the appropriate actin- and myosin-like antigens from CX and SA will, therefore, be much more autoimmunogenic than antigens from CX or SA alone, and that the combination will not require use of adjuvants or self-proteins that many current protocols require. It is possible that co-infections involving CX or SA with other infectious agents may produce similarly enhanced disease.

Insulin activity is sensitive to glucose concentration but the mechanisms are still unclear. An unexamined possibility is that the insulin receptor (IR) is sensitive to glucose concentration. We demonstrate here that insulin-like peptides derived from the IR bind glucose at low millimolar, and cytochalasin B at low micromolar, concentrations; several insulin-like IR peptides bind insulin at nanomolar Kd; and this binding is antagonized by increasing glucose concentrations. In addition, glucose and cytochalasin B bind to IR isolated from rat liver and increasing glucose decreases insulin binding to this IR preparation. The presence of GLUT 1 in our IR preparation suggests the possibility of additional glucose-mediated allosteric control. We propose a model in which glucose binds to insulin, the IR, and GLUT; insulin binds to the IR; and the IR binds to GLUT. This set of interactions produces an integrated system of insulin-dependent interactions that is highly sensitive to glucose concentration.

Dwyer suggested that peptide receptors evolved from self-aggregating peptides. Root-Bernstein extended Dwyer's theory to include complementary molecules. Insulin is a self-aggregating peptide. Insulin is also complementary (and therefore binds) to glucagon. We have shown previously using similarities searches that the insulin receptor (IR) has several insulin-like and several glucagon-like sequences associated with insulin-binding regions. We demonstrate here that peptides derived from these insulin-and glucagon-like regions bind insulin with up to high-nanomolar affinity, providing experimental evidence for the evolution of the IR from insulin-and glucagon-like modules. Moreover, we demonstrate that insulin itself binds glucose (and cytochalasin B), and that many of the insulin-like regions of the IR (but not the glucagon-like regions of the insulin receptor) do likewise. These data suggest the function of insulin, and of the IR in glucose regulation has been directed by chemical selection for their mutual set of molecular interactions. This model may be generalizable to the evolution of other receptor and transporter systems. The relationship between molecular structure and function within living systems may be highly constrained by selection for molecular complementarity.