Differential properties of peripheral versus central nervous system (CNS) antigen-presenting cells: relevance for antigen-presenting cell T cell interactions and implications for the pathogenesis and therapy of CNS inflammation

CNS中的抗原呈递被认为在神经炎症的起始和持续中起关键作用。越来越明显的是，小胶质细胞在它们对炎症刺激的反应和它们调节免疫反应的能力方面与外周抗原呈递细胞有很大不同。拟议的项目旨在确定相关的功能差异，存在于专业的抗原呈递细胞在外周（单核细胞，B细胞，差异成熟的树突状细胞）与小胶质细胞之间的贡献，中枢神经系统炎症。该项目包括研究自体和潜在的自身反应性T细胞活化如何被外周与CNS抗原呈递细胞控制或调节，以及这些发现如何与多发性硬化的免疫发病机制和治疗相关。特别考虑到这些差异可能会影响疾病的启动，传播和慢性化的步骤。特别是，MHC 11类抗原加工机制的表达和调节之间的差异，共刺激分子B7家族成员的新成员，（B7-H2（ICOS-L）/ICOS，B7-H1（PD-L1）/PD-1非PD-1，B7-DC（PD-L2）/PD 1-非PD 1，B7-H3/X，B7-H4（B7HS1）/BTLA-4），将研究免疫球蛋白家族成员和不同抗原呈递细胞亚群上的非经典MHC分子。

Antigen presentation in the CNS is thought to play a critical role in the initiation and perpetuation of neuroinflammation. It is becoming apparent that microglial cells differ considerably from peripheral antigen-presenting cells in terms of their responses to inflammatory stimuli and their abilities to modulate immune responses. The proposed project aims at defining the relevant functional differences that exist between professional antigen-presenting cells in the periphery (monocytes, B cells, differentially matured dendritic cells) versus microglial cells with respect to their contributions to CNS inflammation. The project includes the investigation of how autologous and potentially autoreactive T cell activation is controlled or modulated by peripheral versus CNS antigenpresenting cells and how these findings might be relevant for the immunopathogenesis and the therapy of multiple sclerosis. Special consideration is given to how these differences might impact the steps of disease initiation, propagation and chronicity. Specifically, differences between the expression and regulation of the MHC class 11 antigen-processing machinery, novel members of the B7 family members of costimulatory molecules (B7-H2 (ICOS-L)/ICOS, B7-Hl (PD-L1)/PD-1non-PD-1, B7-DC (PD-L2)/PD1-non-PD1, B7-H3/X, B7-H4 (B7HSl)/BTLA-4), members of the immunoglobulin family and non-classical MHC molecules on distinct antigen-presenting cell subsets will be studied.