MITOCHONDRIAL ANTIGENS, MOLECULAR MIMICRY AND AUTOIMMUNE-DISEASE
MITOCHONDRIAL ANTIGENS, MOLECULAR MIMICRY AND AUTOIMMUNE-DISEASE
复制标题
DOI：
10.1016/0925-4439(95)00017-x
复制
发表时间：
1995-05-24
影响因子：
6.2
通讯作者：
BAUM, H
中科院分区：
文献类型：
--
作者：
BAUM, H
免疫系统通常对线粒体自身抗原具有耐受性，但对细菌有反应。低滴度抗线粒体抗体（AMA）可能与这种歧视有关。以高滴度 AMA 为特征的疾病会破坏耐受性。其中一些 AMA 针对心磷脂，与 DNA 发生交叉反应。研究最多的 AMA 是那些表征原发性胆汁性肝硬化 (PBC) 的 AMA。它们针对矿石酸脱氢酶复合物的 E2 亚基，也针对丙酮酸脱氢酶复合物的 E1 α、E1 β 和 X 亚基。 PBC 患者的 AMA 也会与细菌 E2 发生反应。反应性主要是肽特异性的，但在线粒体和微生物抗原之间以及各自复合物的 E2 之间具有交叉反应性。抗 E2 AMA 的免疫显性表位包括硫辛酰附着位点侧翼的保守序列。有人提出，抗体产生的最初刺激是慢性尿路感染。 AMA 本身并不致病，但 CD4(+) T 细胞会被启动，识别与 II 类 HLA 相关的硫辛酰结构域表位。胆管上皮上 II 类抗原的不适当表达（如在 PBC 中发现的）可能会导致 HLA-DR α 特定片段的呈递，已知该片段是小鼠中主要 MHC 呈递的自肽。该序列强烈模仿硫辛酰结构域，可能会被引发的 T 细胞识别，从而启动自身免疫级联反应。在小鼠体内，复合物 I 的 ND1 肽与 I 类 MHC 相关联。因此，表现出这种肽的体细胞突变的细胞可能会受到CD8(+) T细胞的攻击。如果此类肽由 II 类 HLA 呈递，则可能会出现与此类肽和微生物序列和/或自身抗原之间的拟态有关的自身免疫性疾病。这些考虑因素可能适用于莱伯氏病和与年龄相关的病理学。
The immune system is normally tolerant to mitochondrial self-antigens, but responsive against bacteria. Low-titre anti-mitochondrial antibodies (AMA) might be involved in this discrimination. Tolerance is broken in diseases characterised by high titre AMA. Some of these AMA, against cardiolipin, cross-react with DNA. The best studied AMA are those characterising primary biliary cirrhosis (PBC). These are directed against E2 subunits of the ore-acid dehydrogenase complexes, and also against subunits E1 alpha, E1 beta and X of the pyruvate dehydrogenase complex. AMA of PBC patients also react with bacterial E2s. Reactivities are primarily peptide-specific but with cross-reactivity between mitochondrial and microbial antigens and between E2s of respective complexes. Immunodominant epitopes, for anti E2 AMA, include the conserved sequence flanking the site of lipoyl attachment. It is proposed that the initial stimulus for antibody production is chronic urinary tract infection. AMA themselves are not pathogenic, but CD4(+) T-cells would be primed, recognising the lipoyl domain epitope in association with class II HLA. Inappropriate expression of class II antigens on bile duct epithelia, (as found in PBC), might lead to presentation of a particular fragment of HLA-DR alpha, known to be a major MHC presented self-peptide in the mouse. That sequence strongly mimics the lipoyl domain and might be recognised by primed T-cells, initiating the autoimmune cascade. Tn the mouse, a peptide of ND1 of Complex I is presented in association with class I MHC. Cells exhibiting somatic mutation of such a peptide might thus be subject to attack by CD8(+) T-cells. If such peptides were presented by class II HLA, autoimmune diseases might arise, related to mimicry between such peptides and microbial sequences and/or self-antigens. These considerations might apply in Leber's disease and in age-related pathology.