Rethinking Molecular Mimicry in Rheumatic Heart Disease and Autoimmune Myocarditis: Laminin, Collagen IV, CAR, and B1AR as Initial Targets of Disease

Abstract

Rationale: Molecular mimicry theory (MMT) suggests that epitope mimicry between pathogens and human proteins can activate autoimmune disease. Group A streptococci (GAS) mimics human cardiac myosin in rheumatic heart disease (RHD) and coxsackie viruses (CX) mimic actin in autoimmune myocarditis (AM). But myosin and actin are immunologically inaccessible and unlikely initial targets. Extracellular cardiac proteins that mimic GAS and CX would be more likely.Objectives: To determine whether extracellular cardiac proteins such as coxsackie and adenovirus receptor (CAR), beta 1 adrenergic receptor (B1AR), CD55/DAF, laminin, and collagen IV mimic GAS, CX, and/or cardiac myosin or actin.Methods: BLAST 2.0 and LALIGN searches of the UniProt protein database were employed to identify potential molecular mimics. Quantitative enzyme-linked immunosorbent assay was used to measure antibody cross-reactivity.Measurements: Similarities were considered to be significant if a sequence contained at least 5 identical amino acids in 10. Antibodies were considered to be cross-reactive if the binding constant had a Kd less than 10-9 M.Main results: Group A streptococci mimics laminin, CAR, and myosin. CX mimics actin and collagen IV and B1AR. The similarity search results are mirrored by antibody cross-reactivities. Additionally, antibodies against laminin recognize antibodies against collagen IV; antibodies against actin recognize antibodies against myosin, and antibodies against GAS recognize antibodies against CX. Thus, there is both mimicry of extracellular proteins and antigenic complementarity between GAS-CX in RHD/AM.Conclusion: Rheumatic heart disease/AM may be due to combined infections of GAS with CX localized at cardiomyocytes that may produce a synergistic, hyperinflammatory response that cross-reacts with laminin, collagen IV, CAR, and/or B1AR. Epitope drift shifts the immune response to myosin and actin after cardiomyocytes become damaged.

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

“…If anti-cardiac myosin antibodies are actually anti-idiotypic, it would follow that the original receptor for CVB3 would mimic myosin. In fact, both coxsackie-adenovirus receptor (CAR) and decay accelerating factor (DAF) also called CD55, which are used by some strains of CVB3 as receptors, have multiple and statistically significant similarities to cardiac myosin [80]. Several examples are illustrated in Figure 3.…”

“…Finally, a dedicated search for anti-idiotype antibodies directed against CAR, DAF, the β2AR, AChR, and other novel CVB receptor candidates [87, 88] should be undertaken. The possibility that these receptor anti-idiotypes might correspond to anti-cardiac myosin autoAbs should also be considered [80, 81]. …”

“…Several groups extended this work by showing that CVB3 induced antibody and T cell responses against actin, cardiac myosin, tropomyosin, and vimentin during myocarditis [117–121]. Subsequent studies have shown that CVB proteins mimic cardiac actin (Figure 6), that antibodies against CVB3 recognize cardiac actin as an antigen and, conversely, that anti-actin antibodies recognize CVB3 proteins [80, 81]. …”

“…One outstanding question is whether cardiac myosin mimicry is necessary to induce myocarditis or whether CVB and GAS antigens that mimic other cardiac proteins such as the β2AR, CAR, DAF, actin, troponin, laminin, etc., can also induce experimental myocarditis [80]. It is quite possible that the failure to observe clinical correlates of MM in many diseases is due to using too narrow a focus on a single dominant antigen.…”

“…As noted in the discussion of HAT, actin and cardiac myosin are unlikely to be available to the immune system until cellular damage has already commenced, making mimicry to extracellular proteins such as CAR, DAF, laminin, collagen IV, etc. more likely candidates [80]. …”