MHC class II regulation and antigen processing in EAE

描述（由申请人提供）：MHC II类调节对于理解抗原（Ag）呈递和CD4 +T细胞活化在多发性硬化症（MS）和实验性过敏性脑脊髓炎（EAE）中的重要性至关重要。干扰素- γ (ifnγ)是一种多效性细胞因子，被认为是非专业银呈递细胞（APC） U类诱导的必要条件，包括常驻中枢神经系统APC。然而，ifngma缺陷小鼠易患EAE。MHC II类反激活因子（CIITA）是ifγ诱导和组成型II类表达的关键中间体。ciita缺陷小鼠对EAE具有抗性，表明CNS APC中ciita依赖的II类表达是CNS炎症所必需的。CIITA在小胶质细胞（一种有效的中枢神经系统APC） II类表达中的体内作用尚不清楚。CIITA还指导不变性链（Ii）和HLA-DM的表达，这些分子参与内吞Ag加工。对Ii和H-2M缺陷小鼠以及选择性表达Ii p31和p41的小鼠的研究表明，CNS APC对银的加工是初始CNS银呈递所必需的，尽管这种可能性尚未得到直接验证。ip41可以稳定某些肽，为Ag呈递提供优势。Ii p31、p41和野生型小鼠对急性EAE的易感性相似，但Ii p41小鼠的病程更为严重，提示Ii p41可能影响慢性EAE中Ag的呈现。

DESCRIPTION (provided by applicant): MHC class II regulation is central in importance for understanding antigen (Ag) presentation and CD4 +T cell activation in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Interferon-gamma (IFNgamma), a pleiotropic cytokine, is considered a requirement for class U induction on nonprofessional Ag presenting cells (APC), including resident CNS APC. Yet, IFNgamma-deficient mice are susceptible to EAE. The MHC class II transactivator (CIITA) is a key intermediate in IFNgamma-inducible and constitutive class II expression. CIITA-deficient mice are resistant to EAE, indicating that CIITA-dependent class II expression by resident CNS APC is required for CNS inflammation. The in vivo role of CIITA in class II expression by microglia, a potent CNS APC, is not known. CIITA also directs expression of invariant chain (Ii) and HLA-DM, molecules involved in endocytic Ag processing. Studies of Ii and H-2M deficient mice and mice that selectively express Ii p31 and p41 suggest that Ag processing by CNS APC is required for initial CNS Ag presentation, although this possibility has not been tested directly. Ii p41 may stabilize certain peptides, providing advantage in Ag presentation. Ii p31, p41 and wild-type mice are similarly susceptible to acute EAE, but Ii p41 mice have a more severe course, suggesting that Ii p41 may influence Ag presentation in chronic EAE. The principle goals of this research program are to investigate the role of CIITA and gammaIFN class II expression and the role of Ag processing in EAE. We propose to examine the role of CIITA in IFNgamma-dependent and IFN(-independent class II expression by CNS APC. We hypothesize that constitutive CIITA-directed class II by microglia and macrophages in vivo will promote Ag presentation and EAE development, and that when CIITA-directed class II expression is restricted to macrophages and microglia, Ag presentation by these APC alone will be sufficient for initial T cell activation in EAE. We hypothesize that Ag processing is required for initial CNS Ag presentation and that the particular Ii isoform may alter Ag presentation during chronic EAE. The Specific Aims are to: (1) evaluate the role of IFNgamma and IRF-1 on CIITA regulation on class II expression by CNS APC, (2) examine how constitutive CIITA directed class II expression by microglia and macrophages influences susceptibility to CNS inflammation, (3) determine the role of Ag processing in CNS Ag presentation in EAE through use of bone marrow chimera mice constructed from Ii and H-2M deficient mice, and (4) to evaluate how the Ii isoform influences chronic EAE severity through analysis of mice that selectively express Ii p31 or p41. These studies will provide valuable information regarding CNS class II regulation, which may provide insight for development of therapeutic means to modulate class II expression and T cell activation in MS.