Pruksakorn S, Currie B, Brandt E, Phornphutkul C, Hunsakunachai S, Manmontri A, Robinson J H, Kehoe M A, Galbraith A, Good M F
Molecular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
Int Immunol. 1994 Aug;6(8):1235-44. doi: 10.1093/intimm/6.8.1235.
Rheumatic fever (RF) follows a throat infection with different M-serotypes of beta-hemolytic group A streptococci (GAS) and can affect different tissues, predominantly the heart. It is thought to be an autoimmune illness. Although histological examination of affected heart shows an infiltrate consisting mainly of T cells, antigens or epitopes that could be putative targets of autoimmune T cells have not been identified. We have examined the T cell response to the conserved C-terminal region of the M protein--a streptococcal surface coiled-coil protein which is the target of opsonic antibodies and antibodies which cross-react with human heart tissue. Australian Aborigine, Caucasian and Thai patients, controls and mice were studied to define regions of the protein immunogenic for T cells, and T cell lines and clones were tested for cross-reactivity to myosin as well as an extract of RF-diseased mitral heart valve. Murine (B10, B10.D2, B10.BR) M peptide-specific T cells were often cross-reactive for other M peptides but did not cross-react with human heart antigens. Patients with RF or other heart diseases, or control subjects exposed more commonly to GAS were more likely to have T cell responses to the M protein, with many regions of the C-terminus being recognized. T cell lines and a clone specific for different M peptides were generated from five donors. Cross-reactivity could be shown between different M peptides, but unlike murine M peptide-specific T cells three of the human T cell lines reacted strongly to peptides representing homologous regions of cardiac and skeletal muscle myosins, and two of these lines also responded to porcine myosin and an extract of human rheumatic mitral valve. However, these last two lines were derived from a normal donor without history of RF or other heart disease. Our data demonstrate that regions of the M protein, including regions that are being considered as subunit vaccines, have the potential to stimulate pre-existing heart cross-reactive T cells, but that the ability of such T cells to cross-react (as measured in vitro) is not in itself sufficient to lead to disease.
风湿热（RF）继发于由不同M血清型的A组β溶血性链球菌（GAS）引起的咽喉感染，可累及不同组织，主要是心脏。它被认为是一种自身免疫性疾病。尽管对受累心脏的组织学检查显示主要由T细胞组成的浸润，但尚未确定可能是自身免疫性T细胞假定靶点的抗原或表位。我们研究了T细胞对M蛋白保守C末端区域的反应——M蛋白是一种链球菌表面卷曲螺旋蛋白，是调理素抗体和与人心脏组织交叉反应抗体的靶点。我们对澳大利亚原住民、白种人和泰国患者、对照者及小鼠进行了研究，以确定该蛋白对T细胞具有免疫原性的区域，并检测T细胞系和克隆对肌球蛋白以及风湿性二尖瓣心脏瓣膜提取物的交叉反应性。鼠源性（B10、B10.D2、B10.BR）M肽特异性T细胞通常对其他M肽具有交叉反应性，但不与人心脏抗原发生交叉反应。患有RF或其他心脏病的患者，或更常接触GAS的对照受试者，更有可能对M蛋白产生T细胞反应，C末端的许多区域都能被识别。从五名供体中产生了针对不同M肽的T细胞系和一个克隆。不同M肽之间可显示交叉反应性，但与鼠源性M肽特异性T细胞不同，五个人类T细胞系中的三个对代表心肌和骨骼肌肌球蛋白同源区域的肽有强烈反应，其中两个系也对猪肌球蛋白和人类风湿性二尖瓣提取物有反应。然而，最后这两个系来自一名没有RF或其他心脏病病史的正常供体。我们的数据表明，M蛋白的区域，包括被视为亚单位疫苗的区域，有可能刺激预先存在的心脏交叉反应性T细胞，但这种T细胞的交叉反应能力（在体外测量）本身并不足以导致疾病。
