Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin

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121

109

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.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Ellis

Hildebrand

et al. 2005

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“…Competitive-inhibition ELISA was performed in triplicate as described previously (35). Inhibitor solutions (five subpeptides of the hNC16A, fulllength hNC16A, and GST protein) were double serially diluted in 0.5% BSA and mixed with equal volumes of the IgG1 mAb 3.B6 (2.5 mg/ml), then incubated at 37˚C for 1 h. One hundred microliters of the mixtures was added to the wells coated with hCOL17 NC16A.…”

Section: Competitive-inhibition Assaymentioning

confidence: 99%

Human IgG1 Monoclonal Antibody against Human Collagen 17 Noncollagenous 16A Domain Induces Blisters via Complement Activation in Experimental Bullous Pemphigoid Model

Ujiie

Shibaki

et al. 2010

“…The Ags identified for polyreactive Abs were generally intracellular cytoskeletal proteins or DNA (1,2). However, work on cross-reactive or polyreactive Abs has progressed, and it is becoming increasingly clear that they may cause disease by cross-reaction with extracellular Ags at the cell surface (3,4). The reaction with the cell surface or entrapment in the extracellular matrix may lead to inflammatory responses targeting the tissue for autoimmune disease.…”

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confidence: 99%

“…In this study, we focus on autoantibodies from acute rheumatic fever (ARF) 3 which follows a group A streptococcal infection and is an autoimmune inflammatory disease affecting the heart, joint, skin, or brain (5,6) In susceptible individuals, an immune response to streptococcal Ags appears to initiate events that result in development of the different clinical manifestations of ARF. It has been well-documented that group A streptococci promote the generation of cross-reactive or polyreactive Abs through molecular mimicry between streptococcal and host Ags (5,7).…”

mentioning

confidence: 99%

Tubulin Is a Neuronal Target of Autoantibodies in Sydenham’s Chorea

Kirvan

Cox

Swedo

et al. 2007

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108

Sydenham’s chorea is a CNS disorder and sequela of group A streptococcal infection where deposition of Abs in brain may result in movement and neuropsychiatric abnormalities. We studied human mAbs 24.3.1, 31.1.1, and 37.2.1 derived from chorea and selected for cross-reactivity with group A streptococci and brain Ags. Our novel findings reveal that Sydenham’s chorea mAbs target a 55-kDa brain protein with an N-terminal amino acid sequence of MREIVHLQ corresponding to β-tubulin. Chorea mAb specificity for purified brain tubulin was confirmed in ELISA and Western immunoblot, and significant levels of anti-tubulin IgG were found in acute chorea sera and cerebrospinal fluid. Lysoganglioside GM1 inhibited binding of chorea mAbs to tubulin and mAb reactivity with human caudate and putamen brain sections was blocked by anti-tubulin mAb. The chorea mAbs labeled both intra- and extracellular Ags of a neuronal cell line providing evidence suggesting mimicry between intracellular brain protein tubulin and extracellular lysoganglioside. In addition, chorea mAb 24.3.1 and acute chorea sera induced calcium/calmodulin-dependent protein kinase II activity in human neuronal cells. Nucleotide sequence analysis of the chorea mAb VH genes revealed that mAb 24.3.1 VH gene was encoded by the VH1 germline gene family which encodes other anti-ganglioside VH genes associated with motor neuropathies. mAb recognition of tubulin and the neuronal cell surface with initiation of cell signaling and dopamine release supports an emerging theme in autoimmunity whereby cross-reactive or polyreactive autoantibodies against intracellular Ags recognize cell surface epitopes potentially leading to disease.