Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis.

With the discovery that the highly effective anti-CD20 antibody therapies developed to deplete CD20+ B cells deplete CD20+ T cells equally well, a great interest in the biological properties of CD20+ T cells has emerged. In this study we show that CD20+ T cells have a proinflammatory Th1/Tc1 phenotype with a high proliferative capacity to CNS antigens. We also found that the percentage of CD20+ T cells is increased in the blood of patients with multiple sclerosis and are enriched in the CSF of the patients. Furthermore, we found a positive correlation between CD20+ T cells in the CSF and multiple sclerosis disease severity and see that regulation of CD20+ T cells likely contributes to the positive treatment effect of the multiple sclerosis treatment alemtuzumab. These data represent an important contribution to the understanding of the nature of CD20+ T cells and strongly suggests a role of CD20+ T cells in the pathogenesis of multiple sclerosis.

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.

Differentiating anti-IgLON5 disease and Lewy body dementia: a systematic review.

BACKGROUND: Anti-IgLON5 disease is a rare but potentially reversible cause of cognitive impairment, sleep disturbances, dysautonomia, and movement disorders. It is an autoimmune encephalitis which, due to its insidious onset, could mimic neurodegenerative disorders, and multiple symptoms overlap with those seen in dementia with Lewy bodies (DLB). We hypothesized that the symptomatology and findings in patients with anti-IgLON5 disease overlapped with that of DLB. OBJECTIVES: To assess the commonality of features in anti-IgLON5 disease and DLB and identify potential red flags for anti-IgLON5 disease in patients undergoing diagnostic evaluation for DLB. METHODS: We searched in MEDLINE, Web of Science, and Embase from inception on December the 8th, 2022 with the search term "IgLON5". We performed a systematic review of case reports and case series of anti-IgLON5 disease, and two reviewers independently extracted data on symptoms and findings. Frequencies of symptoms were compared with consensus criteria for DLB. RESULTS: We included 57 studies with 127 individual case reports of anti-IgLON5 disease (mean age 63 years at diagnosis, median symptom duration 2 years). Cognitive dysfunction was reported in 45% of cases, REM-sleep behavioral disorder in 15%, and 14% had parkinsonism. Respiratory insufficiency was reported in 37%, and bulbar symptoms in 67%. CONCLUSIONS: We found a significant overlap between anti-IgLON5 disease and DLB. We propose that anti-IgLON5 disease should be considered in young patients with DLB with chorea, gaze palsy, early dysphagia, or prominent respiratory symptoms. Our study contributes to the emerging knowledge on symptoms and biomarkers in anti-IgLON5 disease.

Christmas article: Christmas lasts a long time, but do Christmas article writers? A bibliometric case-control study.

Introduction Christmas-themed scientific articles are becoming increasingly popular and may represent a shortcut to scientific demise due to their demand for time better spent on "serious" research. We aimed to investigate whether authorship on Christmas-themed medical articles could damage the scientific careers of authors. We hypothesized that Christmas-authorships had a negative impact on core bibliometric outcomes such as publication rates. Methods We extracted demographic and bibliometric data on first- and last authors of medical papers written for the Christmas edition of Journal of The Danish Medical Association through the years 2010-2012. These cases were compared with controls representing authors of original "serious" research papers written in the same years. We performed a negative binomial regression with the number of publications ten years after the index date (defined as the publication year of Christmas/"serious" article) as the outcome and adjusted models for sex and age. Results We found that first authors of Christmas-themed papers had a publication rate ratio (PRR) of 3.8 (95% confidence interval (CI): 1.4-12.4) in unadjusted analysis and last authors had a PRR of 0.6 (95% CI: 0.2-1.6). The associations weakened and were statistically insignificant in adjusted analyses. Conclusion Our results indicate that first authors publish more in the years following the publication of a Christmas article, although the association may be entirely driven by sex and age. Causality remains uncertain and further studies (such as RCTs) which randomize authors to produce Christmas-themed (preferably in a Santa's workshop setting) or serious articles are needed. Funding. None. Trial registration. None.

[Christmas article: Copenhagen Christmas Cognitive Examination].

Introduction Motivation is important when administering cognitive tests. Routine cognitive testing may become trivial both for the examiner and the test subject when using tests that only incorporate neutral items. We hypothesized that a Christmas themed cognitive test could improve motivation for cognitive testing and might elicit positive emotional reactions. Methods We devised the Copenhagen Christmas Cognitive Examination (CCCE), a quickly administered test with ten items, all with Christmas themed content. The CCCE evaluates various important areas of cognition including anterograde and retrograde memory, visuoconstruction, naming and executive function. In this cross-sectional pilot study, we tested feasibility and further explored the possible emotional and motivational effects by administering a questionnaire with a 5-point Likert scale indicating agreement with statements regarding mood and motivation after testing. Results A total of 14 cognitively healthy participants (mean age 42 years (SD 12.3)) underwent testing with the CCCE. A high level of positive mood and motivation was present for most subjects after testing. Being in a Christmas mood after testing was significantly associated with higher test scores (Spearman's correlation coefficient 0.53, p = 0.019). Conclusion It was feasible to administer a Christmas themed cognitive test, and test subjects experienced positive emotional reactions after testing. Further testing in a non-healthy population is warranted. Funding none. Trial registration none.

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.

Natalizumab differentially affects plasmablasts and B cells in multiple sclerosis.

BACKGROUND: Natalizumab treatment increases the frequencies of B cells in blood but reduces IgG in blood and CSF. Plasmablasts are important in the production of IgG, and the development of plasmablasts is CD49d dependent. OBJECTIVE: We hypothesized that natalizumab treatment affects the development of plasmablasts. METHODS: We retrospectively analyzed frequencies and absolute counts of B cell subsets by flow cytometry from a longitudinal cohort of 9 progressive multiple sclerosis (MS) patients treated with natalizumab for 60 weeks, and a cross-sectional relapsing-remitting MS (RRMS) cohort with 17 untreated and 37 treated with natalizumab (17 stable and 20 unstable patients with relapse activity). Additionally, CD49d expression on B cell subsets was examined in 10 healthy controls, and blood and cerebrospinal fluid (CSF) frequencies of B cell subsets were quantified in untreated and natalizumab treated RRMS patients. RESULTS: In progressive MS, levels of IgG decreased in plasma (p<0.001) from baseline to 60 weeks follow-up. In the progressive MS and RRMS cohorts we observed that natalizumab treatment significantly increased the frequency of B cells (p=0.004; p<0.0001) and several B cell subsets, most pronounced for memory B cell subsets (p=0.0001; p<0.0001), while there was a decrease in plasmablast frequency (p=0.008; p=0.008). In both progressive MS and RRMS the absolute cell counts of B cells increased (p=0.004; p<0.001), which was explained by a significant increase in all subsets, except for plasmablasts. Furthermore, we found decreased memory B cell counts in unstable compared to stable natalizumab-treated patients (p=0.02). The expression of CD49d was higher on plasmablasts compared to other B cell subsets (p<0.0001). In CSF, plasmablasts could not be detected in patients treated with natalizumab, in contrast to an increased frequency in untreated RRMS patients. CONCLUSION: We confirm previous studies showing that natalizumab increases circulating number of B cells, particularly memory cells, concomitant with a decrease in plasma IgG concentrations. Moreover, we demonstrate in two separate cohorts that natalizumab treatment markedly decreases frequencies of plasmablasts while the absolute number is stable. Additionally, plasmablasts have high expression of CD49d, and plasmablasts could not be detected in the CSF of natalizumab-treated patients. Finally, memory B cells were found to be reduced in unstable natalizumab-treated patients, which could possibly indicate increased recruitment to the CNS.

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.

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.