Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis

Altres ajuts: This work was supported by the EU FP7-MINECO Infect-ERA Program, and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness.Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNβ-treated RRMS patients but not in HCMV(−) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNβ. Considering the B cell functional profile, HCMV(−) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk : Original Data and Meta-Analysis

Altres ajuts: Junta de Andalucía (JA)- Fondos Europeos de Desarrollo Regional (FEDER) (grant number CTS2704 to FM).Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15 : 01 risk allele

Neuromyelitis optica spectrum disorders. Comparison according to the phenotype and serostatus

Objective: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO. Methods: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays. Results: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presentedmore often with longitudinally extensive transverse myelitis (LETM) (p<0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female: male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p<0.001). Conclusions: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful

Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men

BACKGROUND: Atrial fibrillation (AF) is considered a predictive factor of poor clinical outcome in patients with an ischemic stroke (IS). This study addressed whether the impact of AF on the in-hospital mortality after first ever IS is different according to the patient’s gender. METHODS: We prospectively studied 1678 patients with first ever IS consecutively admitted to two University Hospitals. We recorded demographic data, vascular risk factors, and the stroke severity (NIHSS) at admission analyzing their impact on the in-hospital mortality and on the combined mortality-dependency at discharge using a Cox proportional hazards model. Two variable interactions between those factors independently related to in-hospital mortality and combined mortality-dependency at discharge were tested. RESULTS: Overall in-hospital mortality was 11.3%. Cox proportional hazards model showed that NIHSS at admission (HR: 1.178 [95% CI 1.149–1.207]), age (HR: 1.044 [95% CI 1.026–1.061]), AF (HR: 1.416 [95% CI 1.048–1.913]), male gender (HR: 1.853 [95% CI 1.323–2.192) and ischemic heart disease (HR: 1.527 [95% CI 1.063–2.192]) were independent predictors of in-hospital mortality. A significant interaction between gender and AF was found (p = 0.017). Data were stratified by gender, showing that AF was an independent predictor of poor outcome just for woman (HR: 2.183 [95% CI 1.403–3.396]; p < 0.001). The independent predictors of combined mortality-disability at discharge were NIHSS at admission (HR: 1.052 [95% CI 1.041–1.063]), age (HR: 1.011 [95% CI 1.004–1.018]), AF (HR: 1.197 [95% CI 1.031–1.390]), ischemic heart disease (HR: 1.222 [95% CI 1.004–1.488]), and smoking (HR: 1.262 [95% CI 1.033–1.541]). CONCLUSIONS: The impact of AF is different in the twogenders and appears as a specific ischemic stroke predictor of in-hospital mortality just for women

Delayed B cell repopulation after rituximab treatment in multiple sclerosis patients with expanded adaptive natural killer cells

Background and purpose: The aim was to evaluate whether adaptive NKG2C+ natural killer (NK) cells, characterized by enhanced antibody-dependent cell cytotoxicity (ADCC), may influence time to B cell repopulation after rituximab treatment in multiple sclerosis (MS) patients. Methods: This was a prospective observational study of MS patients treated with rituximab monitoring peripheral B cells for repeated doses. B cell repopulation was defined as CD19+ cells above 2% of total lymphocytes, classifying cases according to the median time of B cell repopulation as early or late (≤9 months, >9 months, respectively). Basal NK cell immunophenotype and in vitro ADCC responses induced by rituximab were assessed by flow cytometry. Results: B cell repopulation in 38 patients (24 relapsing-remitting MS [RRMS]; 14 progressive MS) was classified as early (≤9 months, n = 19) or late (>9 months, n = 19). RRMS patients with late B cell repopulation had higher proportions of NKG2C+ NK cells compared to those with early repopulation (24.7% ± 16.2% vs. 11.3% ± 10.4%, p < 0.05), and a direct correlation between time to B cell repopulation and percentage of NKG2C+ NK cells (R 0.45, p < 0.05) was observed. RRMS cases with late repopulation compared with early repopulation had a higher secretion of tumor necrosis factor α and interferon γ by NK cells after rituximab-dependent NK cell activation. The NK cell immunophenotype appeared unrelated to B cell repopulation in progressive MS patients. Conclusions: Adaptive NKG2C+ NK cells in RRMS may be associated with delayed B cell repopulation after rituximab, a finding probably related to enhanced depletion of B cells exerted by NK-cell-mediated ADCC, pointing to the use of personalized regimens with anti-CD20 monoclonal antibody therapy in some patients

Adaptive features of natural killer cells in multiple sclerosis

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(-), and PLZF(-) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(-) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(-) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(-) CD56dim NK cells in HCMV(+) and increased PLZF(-) CD56bright NK cells in HCMV(-) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(-) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.This work was supported by grants FIS/PI17/00254, SAF 2016-80363-C2-1-R (Spanish Ministry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Program (PCIN-2015-191-C02-01), and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness

Adaptive Features of Natural Killer Cells in Multiple Sclerosis

Funding. This work was supported by the EU FP7-MINECO Infect-ERA Program (PCIN-2015-191-C02-01), and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness.Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(-), and PLZF(-) CD56 NK cells were found in HCMV(+) cases. However, PLZF(-) NK cells were detected uncoupled from other adaptive markers within the CD56 subset from HCMV(+) cases and among CD56 NK cells from HCMV(-) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(-) CD56 NK cells in HCMV(+) and increased PLZF(-) CD56 NK cells in HCMV(-) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(-) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS

Dynamics and Predictors of Cognitive Impairment along the Disease Course in Multiple Sclerosis

(1) Background: The evolution and predictors of cognitive impairment (CI) in multiple sclerosis (MS) are poorly understood. We aimed to define the temporal dynamics of cognition throughout the disease course and identify clinical and neuroimaging measures that predict CI. (2) Methods: This paper features a longitudinal study with 212 patients who underwent several cognitive examinations at different time points. Dynamics of cognition were assessed using mixed-effects linear spline models. Machine learning techniques were used to identify which baseline demographic, clinical, and neuroimaging measures best predicted CI. (3) Results: In the first 5 years of MS, we detected an increase in the z-scores of global cognition, verbal memory, and information processing speed, which was followed by a decline in global cognition and memory (p < 0.05) between years 5 and 15. From 15 to 30 years of disease onset, cognitive decline continued, affecting global cognition and verbal memory. The baseline measures that best predicted CI were education, disease severity, lesion burden, and hippocampus and anterior cingulate cortex volume. (4) Conclusions: In MS, cognition deteriorates 5 years after disease onset, declining steadily over the next 25 years and more markedly affecting verbal memory. Education, disease severity, lesion burden, and volume of limbic structures predict future CI and may be helpful when identifying at-risk patients

Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'?

BACKGROUND AND PURPOSE: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. METHODS: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. RESULTS: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. CONCLUSIONS: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.This work was supported by grants FIS/PI14/00177,FIS/PI17/00254 and SAF 2013-49063-C2-1-R (SpanishMinistry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Pro-gram (PCIN-2015-191-C02-01) and Red Española de Esclerosis Múltiple from the Instituto de Salud CarlosIII, European Regional Development Fund (grant RD16/0015/0011) and Spanish Ministry of Economyand Competitiveness

Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis

Altres ajuts: This work was supported by the EU FP7-MINECO Infect-ERA Program, and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness.Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNβ-treated RRMS patients but not in HCMV(−) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNβ. Considering the B cell functional profile, HCMV(−) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS