T cells provide critical immune surveillance to the central nervous system (CNS), and the cerebrospinal fluid (CSF) is thought to be a main route for their entry. Further characterization of the state of T cells in the CSF in healthy individuals is important for understanding how T cells provide protective immune surveillance without damaging the delicate environment of the CNS and providing tissue-specific context for understanding immune dysfunction in neuroinflammatory disease. Here, we have profiled T cells in the CSF of healthy human donors and have identified signatures related to cytotoxic capacity and tissue adaptation that are further exemplified in clonally expanded CSF T cells. By comparing profiles of clonally expanded T cells obtained from the CSF of patients with multiple sclerosis (MS) and healthy donors, we report that clonally expanded T cells from the CSF of patients with MS have heightened expression of genes related to T cell activation and cytotoxicity.

Experimental autoimmune encephalomyelitis (EAE) is a classical murine model for Multiple Sclerosis (MS), a human autoimmune disease characterized by Th1 and Th17 responses. Numerous studies have reported that C-reactive protein (CRP) mitigates EAE severity, but studies on the relevant pathologic mechanisms are insufficient. Our previous study found that CRP suppresses Th1 response directly by receptor binding on naïve T cells; however, we did not observe the effect on Th17 response at that time; thus it remains unclear whether CRP could regulate Th17 response. In this study, we verified the downregulation of Th17 response by a single-dose CRP injection in MOG-immunized EAE mice in vivo while the direct and indirect effects of CRP on Th17 response were differentiated by comparing its actions on isolated CD4+ T cells and splenocytes in vitro, respectively. Moreover, the immune cell composition was examined in the blood and CNS (Central Nervous System), and a blood (monocytes) to CNS (dendritic cells) infiltration pathway is established in the course of EAE development. The infiltrated monocyte derived DCs (moDCs) were proved to be the only candidate antigen presenting cells to execute CRP’s function. Conversely, the decrease of Th17 responses caused by CRP disappeared in the above in vivo and in vitro studies with FcγR2B−/− mice, indicating that FcγR2B expressed on moDCs mediates CRP function. Furthermore, peripheral blood monocytes were isolated and induced to establish moDCs, which were used to demonstrate that the antigen presenting ability of moDCs was attenuated by CRP through FcγR2B, and then NF-κB and ERK signaling pathways were manifested to be involved in this regulation. Ultimately, we perfected and enriched the mechanism studies of CRP in EAE remission, so we are more convinced that CRP plays a key role in protecting against EAE development, which may be a potential therapeutic target for the treatment of MS in human.

Objective:To identify the frequency and clinical spectrum of neuroinflammation associated with exposure to tumor necrosis factor alpha inhibitors (TNFi).Methods:We performed a single-system retrospective cohort study. Adults in the Yale New Haven Health System with documented use of any FDA-approved TNFi between 2007-2017 were identified via automated review of the electronic medical record. Those who also had brain MRIs were identified and categorized as either TNFi exposed or unexposed. Individuals with MRI findings concerning for neuroinflammation were identified and detailed chart reviews were performed.Results:A total of 4391 patients received TNFi and 547 also had brain MRI. After exclusion criteria were applied, 375 MRIs occurred after TNFi exposure and 132 MRIs occurred prior to TNFi. MRIs were normal for 20.8% of exposed patients. The most common abnormal finding was nonspecific, punctate T2 hyperintensities. Seventeen cases (4.5%) among the exposed cohort had findings consistent with neuroinflammation, of which 58.8% required TNFi discontinuation and additional immunotherapy while an additional 23.5% discontinued TNFi alone. After 3 years, 70.6% had stable MRI findings while 11.8% demonstrated progression. 10-year period prevalence of neuroinflammation in all subjects exposed to TNFi was 0.4%.Conclusions:Neuroinflammatory phenomena following TNFi is a common concern for those treating patients with autoimmune disease. This is a large-scale study identifying the epidemiology surrounding this phenomenon. TNFi-associated inflammation was a rare outcome in our cohort. Most treated patients had either normal or nonspecific MRI findings. Further risk stratification parameters need to be identified.

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