T Cell Mimicry and Epitope Specificity of Cross-Reactive T Cell Clones from Rheumatic Heart Disease

Abstract

Mimicry between streptococcal M protein and cardiac myosin is important in the pathogenesis of rheumatic heart disease. M protein-specific human T cell clones derived from rheumatic carditis were cross-reactive with human cardiac myosin, and laminin, a valve protein. Among the 11 CD4+ and CD8+ cross-reactive T cell clones, at least 6 different reactivity patterns were distinguished, suggesting different degrees of cross-reactivity and a very diverse T cell repertoire. The latter was confirmed by a heterogeneous Vβ gene and CDR3 usage. HLA restriction and Th1 cytokine production in response to rM6 protein were preserved when the T cell clones were stimulated by human cardiac myosin or other α-helical proteins, such as tropomyosin and laminin. The cross-reactive human T cell clones proliferated to B2 and B3A, dominant peptide epitopes in the B repeat region of streptococcal M protein. In human cardiac myosin, epitopes were demonstrated in the S2 and light meromyosin regions. In our study, T cell mimicry was defined as recognition of structurally related Ags involved in disease and recognized by the same T cell. Mimicry in our study was related to α-helical coiled coil proteins which have a repetitive seven-aa residue periodicity that maintains α-helical structure and thus creates a high number of degenerate possibilities for recognition by T cells. The study of human T cell clones from rheumatic heart disease revealed potential sites of T cell mimicry between streptococcal M protein and human cardiac myosin and represents some of the most well-defined T cell mimicry in human autoimmune disease.

Identification of a Streptococcal Octapeptide Motif Involved in Acute Rheumatic Fever

“…For GAS, epidemiological data suggest that M proteins may have a crucial role in their common pathogenesis since rheumatic potential can be attributed to certain M serotypes (14). This was corroborated by the finding that M proteins of ARFassociated strains such as M5 and M6 can cause autoimmune responses in the host through molecular mimicry by reacting against cardiac myosin and other extracellular matrix proteins with a coiled-coil structure (17,33). ARF-associated strains of serotype M3 bind collagen directly via M3 protein, thereby inducing autoimmunity against collagen IV.…”

“…Rheumatogenicity of Streptococcus pyogenes strains, which are also referred to as group A streptococci (GAS), was found to correlate with certain M serotypes in different parts of the world (12)(13)(14), indicating that such M proteins may be directly involved in the pathogenesis of ARF/RHD. Different autoimmune mechanisms have been proposed for pathogenesis of ARF (3,8,15) that bases on M proteins and other surface components of GAS as causative agents and results in autoimmune response against host proteins of cardiac tissues (3,4,8,(15)(16)(17). One recent hypothesis is that human collagen IV, a major component of subendothelial basement membranes (18,19), acts as such an autoantigen after forming a complex with S. pyogenes strains, which have a potential of causing ARF (15).…”

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

“…The pathogenesis of RHD is autoimmune in nature, with both Abs and T cells playing important roles (15)(16)(17)(18). Various studies have identified the surface M protein of GAS as one such likely target (19)(20)(21)(22), inducing Abs and T cells capable of cross-reacting with cardiac myosin and tropomyosin (23)(24)(25)(26).…”

Molecular Mimics Can Induce Novel Self Peptide-Reactive CD4+ T Cell Clonotypes in Autoimmune Disease

“…self-cardiac myosin than to the streptococcal M protein (5). This may indicate that the PLP 139 -151 -specific T cells are of lower frequency and/or of lower avidity.…”

“…Mimicry between self-Ags and Ags found in infectious agents is postulated to either precipitate autoimmune disease or exacerbate already established disease symptoms (1)(2)(3)(4). For example, there is compelling evidence indicating that rheumatic heart disease is caused by molecular mimicry between T cell epitopes derived from streptococcal M proteins and epitopes from cardiac myosin (5,6). In the autoimmune disease Multiple Sclerosis (MS), 3 disease relapses or flares have long been associated with upper respiratory and other infections (7)(8)(9).…”