Weissert R, Svenningsson A, Lobell A, de Graaf K L, Andersson R, Olsson T
Neuroimmunology Unit, Center of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
J Immunol. 1998 Jan 15;160(2):681-90.
The underlying mechanisms behind the preferential expression of select TCRBV products in certain autoimmune illnesses, such as multiple sclerosis and some models of experimental autoimmune encephalomyelitis (EAE), have principally remained enigmatic. In this study, we examined the mutual role of nonself- vs self-origin of antigenic myelin basic protein (MBP) peptides and given MHC haplotypes in relation to the relative frequency of activated TCRBV8S2+ T lymphocytes in the Lewis (LEW) rat EAE model. Inbred MHC (RT1) congenic LEW rats (LEW (RT1l), LEW.1AV1 (RT1av1), and LEW.1W (RT1u)) were immunized with the 63 to 88 peptide of the guinea pig MBP (MBPGP63-88). Additionally, LEW rats were immunized with the corresponding autologous rat sequence (MBPRAT63-88). Although EAE ensued in all MBP peptide/LEW rat strain combinations, only LEW rats immunized with the heterologous MBPGP63-88 peptide elicited T cell responses encompassing a bias toward TCRBV8S2 expression, as determined by flow cytometric analyses. Reduction of TCRBV8S2+ T cells led to mitigation of disease severity in LEW rats immunized with MBPGP63-88, but not with MBPRAT63-88, indicating that critical encephalitogenic characteristics are associated with this T cell subset. We conclude that the preferential recruitment of TCRBV8S2+ T cells in the LEW rat EAE model is due to selective, high-avidity recognition of the nonself-MBPGP63-88 in the context of the RT1.Bl molecule. This inference lends support to the notion that the highly restricted TCR repertoire of the self-MBP-reactive T cells in certain genetically predisposed multiple sclerosis patients may have its source in a multistep molecular mimicry event.
在某些自身免疫性疾病中,如多发性硬化症和一些实验性自身免疫性脑脊髓炎(EAE)模型,特定TCRBV产物优先表达背后的潜在机制主要仍不明确。在本研究中,我们研究了抗原性髓鞘碱性蛋白(MBP)肽的非自身与自身来源以及特定MHC单倍型在Lewis(LEW)大鼠EAE模型中与活化的TCRBV8S2 + T淋巴细胞相对频率的相互作用。用豚鼠MBP的63至88肽(MBPGP63 - 88)免疫近交MHC(RT1)同源LEW大鼠(LEW(RT1l)、LEW.1AV1(RT1av1)和LEW.1W(RT1u))。此外,用相应的自体大鼠序列(MBPRAT63 - 88)免疫LEW大鼠。尽管在所有MBP肽/LEW大鼠品系组合中都发生了EAE,但通过流式细胞术分析确定,仅用异源MBPGP63 - 88肽免疫的LEW大鼠引发了T细胞反应,且这种反应存在对TCRBV8S2表达的偏向性。TCRBV8S2 + T细胞的减少导致用MBPGP63 - 88免疫的LEW大鼠疾病严重程度减轻,但用MBPRAT63 - 88免疫的大鼠则不然,这表明关键的致脑炎性特征与该T细胞亚群相关。我们得出结论,在LEW大鼠EAE模型中TCRBV8S2 + T细胞的优先募集是由于在RT1.B1分子背景下对非自身MBPGP63 - 88的选择性、高亲和力识别。这一推断支持了这样一种观点,即在某些遗传易感性多发性硬化症患者中,自身MBP反应性T细胞高度受限的TCR库可能源于多步骤分子模拟事件。