Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis
Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis
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DOI：
10.1093/brain/aws082
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发表时间：
2012-05-01
期刊：
影响因子：
14.5
通讯作者：
Bauer, Jan
中科院分区：
文献类型：
--
作者：
Bien, Christian G.;Vincent, Angela;Bauer, Jan
典型的副肿瘤性脑炎综合征与针对细胞内抗原的“肿瘤神经”抗体，以及最近描述的副肿瘤性或非副肿瘤性脑炎和针对神经表面抗原（电压门控钾通道复合物，N-甲基-d-天冬氨酸受体）和细胞内抗原（谷氨酸脱羧酶-65）的抗体，构成了一组日益被认可的免疫介导的脑疾病。然而，特异性免疫机制的证据很少。在这里，我们报告定性和定量免疫病理学在脑组织（活检或尸检材料）的17例脑炎和抗体的细胞内（胡，马2，谷氨酸脱羧酶）或表面抗原的目标（电压门控钾通道复合物或N-甲基-d-天冬氨酸受体）。我们假设，脑炎抗体对细胞内抗原（细胞内抗原onconeural和细胞内抗原谷氨酸脱羧酶组）将显示神经变性介导的T细胞的细胞毒性和脑炎抗体对表面抗原将抗体介导的，将显示较少的T细胞参与。我们发现，与表面抗原（抗-N-甲基-d-天冬氨酸受体和抗电压门控钾通道复合物）患者相比，细胞内抗原-神经元组（抗-Hu和抗-Ma 2病例）的CD 8/CD 3比值更高，颗粒酶-B+细胞毒性T细胞与神经元的贴壁更频繁，并伴有相关的神经元丢失。其中一例谷氨酸脱羧酶抗体脑炎（细胞内抗原-谷氨酸脱羧酶组）显示GrB阳性T细胞与神经元的多处并列。然而，一般来说，与细胞内抗原肿瘤神经病例相比，谷氨酸脱羧酶抗体病例的炎症不太严重，CD 8/CD 3比率也相对较低。相反，我们发现补体C9 neo沉积在神经元上与急性神经元细胞死亡相关的表面抗原组，特别是在电压门控钾通道复合物抗体患者。N-甲基-d-天冬氨酸受体抗体病例显示没有抗体和补体介导的组织损伤的证据，并且与所有其他脑炎的区别在于没有明确的神经元病理学和低密度的炎性细胞。虽然组织样本的位置和疾病的阶段各不相同，我们的研究结果强烈支持T细胞介导的神经元细胞毒性在脑炎与细胞内抗原的抗体的核心作用。在电压门控钾通道复合物脑炎，表面抗原抗体脑炎的一个子集，抗体和补体介导的免疫反应似乎是负责神经元的损失和脑萎缩; N-甲基-d-天冬氨酸受体抗体脑炎这些机制的明显缺乏是耐人寻味的，需要进一步研究。
Classical paraneoplastic encephalitis syndromes with 'onconeural' antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N-methyl-d-aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage-gated potassium channel-complex or N-methyl-d-aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B+ cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti-N-methyl-d-aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo deposition on neurons associated with acute neuronal cell death in the surface antigen group only, specifically in the voltage-gated potassium channel-complex antibody patients. N-methyl-d-aspartate receptors-antibody cases showed no evidence of antibody and complement-mediated tissue injury and were distinguished from all other encephalitides by the absence of clear neuronal pathology and a low density of inflammatory cells. Although tissue samples varied in location and in the stage of disease, our findings strongly support a central role for T cell-mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens. In voltage-gated potassium channel-complex encephalitis, a subset of the surface antigen antibody encephalitides, an antibody- and complement-mediated immune response appears to be responsible for neuronal loss and cerebral atrophy; the apparent absence of these mechanisms in N-methyl-d-aspartate receptors antibody encephalitis is intriguing and requires further study.