Antigenic complementarity between coxsackie virus and streptococcus in the induction of rheumatic heart disease and autoimmune myocarditis

Abstract

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.

T Cell Receptor Variable Regions in Diabetes Bind to Each Other, to Insulin, Glucagon or Insulin Receptor, and to Their Antibodies

“…In sum, we propose that all autoimmune diseases are basically driven by the immune system attacking itself and only secondarily by the attack on a particular host tissue or organ. [25,29,[46][47][48][49] ACT, like AIT, is also consistent with the complementary antibody and TCR interactions characterized here, but assumes that these complementary immune responses arise concurrently as independent responses to multiple, complementary antigens rather than as antiidiotype responses. Thus, ACT requires that there be both an insulin mimic and an IR or glucagon mimic to induce T1DM.…”

“…We [25,29,[46][47][48][49] and others [54][55][56][57] have suggested that the simultaneous activation of two sets of complementary T-cell clones (or antibodies) by complementary antigens (as might occur in a mixed infection) would trigger each clone to recognize not only its respective antigen, but also its complementary T cell, as targets. Such T-cell targeting of other T cells would create an immunological civil war that could lead to the kind of immunological confusion typifying autoimmune diseases, including loss of the self-nonself distinction [25,29,[46][47][48][49]. Labeling one set of TCR and antibodies as primary and the complementary set as being "antiidiotypes" would then be misleading, since a key characteristic of antiidiotypes is that they arise significantly after the primary immune response and as a direct response to it.…”

Revisiting the old link between infection and autoimmune disease with commensals and T helper 17 cells

“…Consistent with the importance of type I IFNs in these events, four rare polymorphisms in the gene encoding MDA-5, Ifih1 (interferon induced with helicase C domain 1), which confers recognition of RNA from picornaviruses (the class to which enteroviruses belong), were predicted to reduce MDA-5 function and were associated with lowered risk of developing T1D [53]. Besides T1D, several other human autoimmune diseases are thought to arise from viral infection, including cardiomyopathy (myocarditis), also from infection with group B (B3) Coxsackie viruses and group A streptococci [54], as well as acute disseminating encephalomyelitis and MS, which have been associated with viral pathogens such as EBV, measles virus, and HHV-6 [30]. In MS, clinical studies have shown that infection with EBV is a consistent and strong risk factor.…”

Advances in monoclonal antibody application in myocarditis

“…In two weeks, with the virus removed from the body, results show an increase of infiltration of the inflammatory cells and a decrease of necrotic myocardium with subsequent fibrosis and calcification in the surface by degrees on Day 7, and most animals were rehabilitated. However, the body has produced myocardial ingredient antibodies after that infection (Schulze and Schultheiss, 1995;Caforio et al, 2008;Root-Bernstein et al, 2009;Zhang et al, 2010). Autoimmune inflammation continued without the virus for weeks and months, eventually resulting in dilated cardiomyopathy which presents itself as diffuse myocardial necrosis with multinucleated giant cell infiltration.…”