Autoimmune Encephalitis Related to Cancer Treatment With Immune Checkpoint Inhibitors: A Systematic Review.

OBJECTIVE: To determine the clinical and laboratory features of immune checkpoint inhibitor (ICPI)-associated autoimmune encephalitis (ICPI-AIE), an increasingly recognized adverse event with ICPI treatment. METHODS: We searched PubMed, The Cochrane Library, and Embase for ICPI-AIE cases from the first description in 2015 until January 2020 using standard bibliographic measures including PRISMA guidelines and preregistration with PROSPERO. RESULTS: Thirty-nine studies met inclusion criteria, resulting in 54 patients with ICPI-AIE (mean age 58.6 years; 43% female). Common cancers included melanoma (30%) and non-small cell lung cancer (30%). Brain metastases were found in 16 patients (30%). The most frequent ICPI was nivolumab (61%). Onset of ICPI-AIE occurred after a median of 3.0 treatment cycles, but very early and late presentations were common. Nonlimbic AIE was roughly twice as frequent as limbic AIE (p < 0.05). The most common laboratory abnormalities included bitemporal fluid-attenuated inversion recovery lesions on MRI, continuous slow waves and diffuse slowing on EEG, and monocytic pleocytosis on CSF analysis. Intraneuronal antibodies were more frequent than neuronal surface antibodies and a significant predictor for lack of improvement after first-line immunotherapy (p < 0.05). CONCLUSIONS: ICPI-AIE consists of a heterogenous group of conditions. Neurologists will likely encounter ICPI-AIE more often in the future, but important unresolved questions include the pathophysiologic mechanisms, the epidemiology, and the best treatment approaches associated with ICPI-AIE.

MAIT cell subtypes in multiple sclerosis.

In patients with multiple sclerosis (MS) and healthy controls (HC) we studied circulating MAIT cells and MAIT cell subtypes expressing CXCR3 and CCR6 by flow cytometry. Absolute numbers of MAIT cells and specifically Tc17-like MAIT cells were lower in patients with primary progressive MS (PPMS) than in controls. Low numbers of Tc17-like MAIT cells were associated with smoking and high concentrations of myelin basic protein in the cerebrospinal fluid. Treatment with alemtuzumab and dimethyl fumarate decreased MAIT cell frequencies. Altogether, we have identified specific MAIT cell subtypes related to PPMS, smoking and demyelination, and MAIT cell effects of MS therapies.

GPR15+ T cells are Th17 like, increased in smokers and associated with multiple sclerosis.

Smoking is a risk factor for the development and progression of multiple sclerosis (MS); however, the pathogenic effects of smoking are poorly understood. We studied the smoking-associated chemokine receptor-like molecule GPR15 in relation to relapsing-remitting MS (RRMS). Using microarray analyses and qPCR we found elevated GPR15 in blood cells from smokers, and increased GPR15 expression in RRMS. By flow cytometry we detected increased frequencies of GPR15 expressing T and B cells in smokers, but no difference between patients with RRMS and healthy controls. However, after cell culture with the autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein, frequencies of MBP-reactive and non-proliferating GPR15+CD4+ T cells were increased in patients with RRMS compared with healthy controls. GPR15+CD4+ T cells produced IL-17 and were enriched in the cerebrospinal fluid (CSF). Furthermore, in the CSF of patients with RRMS, GPR15+ T cells were associated with CCR6+CXCR3+/CCR6-CXCR3+ phenotypes and correlated positively with concentrations of the newly identified GPR15-ligand (GPR15L), myelin degradation and disability. In conclusion, we have identified a proinflammatory cell type linking smoking with pathogenic immune cell functions in RRMS.

Statin treatment before stroke reduces pro-inflammatory cytokine levels after stroke.

OBJECTIVE: In this clinical case-control study, we investigated statin treatment in stroke patients on a range of inflammatory effectors in peripheral blood. We focus on RhoA GTPase and its downstream effectors as a future inflammatory target in stroke treatment. METHODS: Data from 10 patients already on statins at stroke onset (Pre-S group) was compared with data from both 29 patients starting statin treatment right after stroke onset (Post-S group) and with 8 healthy controls. In T-cells isolated from stroke patients, we analyzed the activity of the main cytoskeletal regulator RhoA GTPase and its downstream effectors: rho-associated protein kinase (ROCK), myosin phosphatase targeting protein subunit 1 (pMYPT1), myosin light chain kinase (pMLC) and cofilin. In the blood samples, we further determined levels of 12 key plasma cytokines as well as C-reactive protein (CRP) and kallikrein. RESULTS: Compared to healthy controls, the Post-S group achieved significantly higher RhoA and ROCK activities, while the Pre-S did not differ from controls. Levels of pMYPT1, pMLC and cofilin did not differ from controls in the Pre-S and Post-S groups. At day 90 after stroke, interferon γ and IL-18 were significantly increased in the Post-S group compared to the Pre-S group. We found a positive correlation between CRP and NIHSS, whereas kallikrein levels showed no correlation with NIHSS at any of the days. CONCLUSION: Stroke induces changes in the RhoA-ROCK pathway in T-cells. CRP and NIHSS score correlated positively in the study. Statins may have an anti-inflammatory effect as statin treatment before stroke reduces post-stroke pro-inflammatory levels. RhoA GTPase and its downstream effectors are possibly the key to improve statin treatment in stroke.

B cells from patients with multiple sclerosis have a pathogenic phenotype and increased LTα and TGFß1 response.

The contribution of B cells to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is currently of great interest due to the positive outcomes of treatment with B cell-depleting monoclonal antibodies. In this exploratory study we examined the phenotype and cytokine response of B cells from untreated patients with RRMS and healthy controls. The CNS migration potential of the individual blood B cell subpopulations was evaluated according to the expression of CD49d, ALCAM, CXCR3, and CCR7, and cerebrospinal fluid (CSF) samples were analyzed to establish the phenotype of migrated B cells. The frequency of the individual blood B cell subsets expressing CD5, CD43, CD69, CD80, CD83, DC-SIGN and CD138 was similar in patients with RRMS and healthy controls. However, a higher percentage of CD27-IgD-IgM+ memory B cells were found in the blood of patients with RRMS, a population also identified in the CSF samples. We also observed an increased percentage of B cells producing LTα and a higher level of TGFß1 in patients with RRMS. Altogether, we found that patients with RRMS have an increased frequency of blood CD27-IgD-IgM+ memory B cells that are recruited to the CSF together with other memory B cell populations. Furthermore, we report an increased B cell production of LTα and TGFß1 in patients with RRMS.