Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris.
Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris.
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DOI：
10.1073/pnas.92.25.11935
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发表时间：
1995-12
影响因子：
11.1
通讯作者：
Kai W. WUCHERPFENNIGt;Bei Yut;Kailash BHOLt;Dimitri S. Monos;Elias Argyris;W. Robert;Karr;A. R. AHMEDt;J. L. STROMINGERt
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文献类型：
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作者：
Kai W. WUCHERPFENNIGt;Bei Yut;Kailash BHOLt;Dimitri S. Monos;Elias Argyris;W. Robert;Karr;A. R. AHMEDt;J. L. STROMINGERt
人类T细胞介导的自身免疫性疾病在遗传上与MHC II类基因的特定等位基因相关。寻常天疱疮（PV）是一种皮肤自身免疫性疾病，其易感性与HLA-DR 4的一种罕见亚型（DRB 1 *0402，22种已知DR 4亚型之一）有关。PV连锁的DR 4亚型与类风湿性关节炎相关的DR 4亚型（DRB 1 *0404）仅在三个残基（DR β 67、70和71）处不同。这种疾病是由抗桥粒芯糖蛋白3（DG）的自身抗体引起的，T细胞被认为是触发抗这种角质形成细胞粘附分子的自身抗体产生的。基于DRB 1 *0402结合基序，鉴定了DG自身抗原的7个候选肽。来自四名患有活动性疾病的PV患者的T细胞对这些DG肽之一（残基190-204）有反应;两名患者也对DG-（206-220）有反应。DG-（190-204）特异性的T细胞克隆分泌高水平的白细胞介素4和10，表明它们可能在触发DG特异性自身抗体的产生中是重要的。DG-（190-204）肽由疾病相关的DRB 1 *0402分子呈递，而不是由其他DR 4亚型呈递。DRB 1 *0402的定点诱变证明，在P4位置携带正电荷的DG-（190-204）的选择性呈递是由于P4口袋（DR β 70和71）的带负电荷的残基。DR β 71在DRB 1 *0402中具有负电荷，但在其他DR 4亚型中具有正电荷，包括与类风湿性关节炎相关的DR 4亚型。因此，DR 4肽结合位点中P4口袋的电荷似乎是MHC连锁的PV和类风湿性关节炎易感性的关键决定因素。
Human T-cell-mediated autoimmune diseases are genetically linked to particular alleles of MHC class II genes. Susceptibility to pemphigus vulgaris (PV), an autoimmune disease of the skin, is linked to a rare subtype of HLA-DR4 (DRB1*0402, 1 of 22 known DR4 subtypes). The PV-linked DR4 subtype differs from a rheumatoid arthritis-associated DR4 subtype (DRB1*0404) only at three residues (DR beta 67, 70, and 71). The disease is caused by autoantibodies against desmoglein 3 (DG), and T cells are thought to trigger the autoantibody production against this keratinocyte adhesion molecule. Based on the DRB1*0402 binding motif, seven candidate peptides of the DG autoantigen were identified. T cells from four PV patients with active disease responded to one of these DG peptides (residues 190-204); two patients also responded to DG-(206-220). T-cell clones specific for DG-(190-204) secreted high levels of interleukins 4 and 10, indicating that they may be important in triggering the production of DG-specific autoantibodies. The DG-(190-204) peptide was presented by the disease-linked DRB1*0402 molecule but not by other DR4 subtypes. Site-directed mutagenesis of DRB1*0402 demonstrated that selective presentation of DG-(190-204), which carries a positive charge at the P4 position, was due to the negatively charged residues of the P4 pocket (DR beta 70 and 71). DR beta 71 has a negative charge in DRB1*0402 but a positive charge in other DR4 subtypes, including the DR4 subtypes linked to rheumatoid arthritis. The charge of the P4 pocket in the DR4 peptide binding site therefore appears to be a critical determinant of MHC-linked susceptibility to PV and rheumatoid arthritis.