Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity.

In the context of autoimmunity, myeloid cells of the central nervous system (CNS) constitute an ontogenically heterogeneous population that includes yolk sac-derived microglia and infiltrating bone marrow-derived cells (BMC). We previously identified a myeloid cell subset in the brain and spinal cord that expresses the surface markers CD88 and CD317 and is associated with the onset and persistence of clinical disease in the murine model of the human CNS autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). We employed an experimental platform utilizing single-cell transcriptomic and epigenomic profiling of bone marrow-chimeric mice to categorically distinguish BMC from microglia during CNS autoimmunity. Analysis of gene expression and chromosomal accessibility identified CD88+CD317+ myeloid cells in the CNS of EAE mice as originating from BMC and microglia. Interestingly, each cell lineage exhibited overlapping and unique gene expression patterns and transcription factor motifs that allowed their segregation. Our observations will facilitate determining pathogenic contributions of BMC and microglia in CNS autoimmune disease. Ultimately, this agnostic characterization of myeloid cells will be required for devising disease stage-specific and tissue-specific interventions for CNS inflammatory and neurodegenerative disorders.

CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity.

Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the central nervous system (CNS) and ameliorate experimental autoimmune encephalomyelitis (EAE). We generated CD11c.Cre+/-ITGA4fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed and compared with WT controls. Multiparameter flow cytometry was utilized to immunophenotype leukocyte subsets. Single-cell RNA sequencing was used to profile individual cells. α4-Integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon clinical EAE onset, CD11c+CD88+ cells appeared in the CNS and expressed CD317+ In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c+CD88+CD317+ cells. In human cerebrospinal fluid from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice.

Comparative Efficacy of Transcutaneous Functional Electrical Stimulation With or Without Biofeedback Therapy on Functional Non-retentive Fecal Incontinence in Children: A Randomized Clinical Trial.

BACKGROUND: We compared the effects of transcutaneous functional electrical stimulation (TFES) and biofeedback therapy with TFES alone in a cohort of children with functional non-retentive fecal incontinence (FNRFI). METHODS: This prospective, single-center randomized clinical trial was performed on 40 children with FNRFI. Patients were randomly allocated into two equal treatment groups. Group A (n = 20) underwent TFES + biofeedback therapy, and group B (n = 20) received TFES alone. All patients were assessed with a pediatric fecal incontinence (FI) score questionnaire, a visual pain score, and a bowel habit diary both before and at the end of treatment sessions and also at 6 months of follow-up. In addition, a FI quality-of-life (QoL) questionnaire was recorded for all patients before and 6 months after the treatment. RESULTS: FI significantly improved in 13/20 (65%) patients in group A and 11/20 (55%) patients in group B (P < 0.05). A significant reduction in FI score was seen in each group at the end of treatment sessions and maintained at 6 months of follow-up (P < 0.05). A significant improvement in FI-QoL scores was seen in both groups at 6 months of follow-up in which there was no significant difference in terms of FI-QoL scores improvement between both groups after treatment. CONCLUSIONS: The use of electrical stimulation in combination with other treatment methods improves symptoms in patients with FNRFI who are refractory to conventional treatment.

Clinical trials in multiple sclerosis: past, present, and future.

For the past four decades, multiple sclerosis (MS) has been a focus for clinical trial development and execution. Advances in translational neuroimmunology have led to the development of effective disease-modifying therapies (DMTs) that greatly benefit patients with MS and mitigate their burden of disease. These achievements also stem from continued progress made in the definition and discovery of sensitive disease diagnostic criteria, objective disability assessment scales, precise imaging techniques, and disease-specific biomarkers. As a result, our knowledge of MS pathophysiology is more mature; the established clinical practice for the diagnosis and management of MS could serve as a roadmap to guide the development of more disease-specific interventions. In this article we briefly review the main achievements in the evolution of clinical trials for MS, and discuss opportunities for improvements.

The temporal and causal relationship between inflammation and neurodegeneration in multiple sclerosis.

It is currently incompletely understood whether inflammation and neurodegeneration are causally related in multiple sclerosis (MS). The sequence of a potential causal relationship is also unknown. Inflammation is present in rather all clinical stages of MS. Its role in the pathogenesis of MS is supported by histopathological analyses, genetic data, and numerous animal models of MS. All approved disease-modifying therapies that reduce clinical relapses and diminish the accumulation of lesions on neuroimaging are anti-inflammatory. Axonal loss and accelerated brain volume loss can also be detected from clinical disease onset throughout all stages. The expression of neurofilament light chain in cerebrospinal fluid and serum, a scaffolding protein in axons and dendrites, is a biomarker of neuronal injury associated with clinical relapses and reflects neuronal loss during episodes of acute inflammation. The recent association of human endogenous retrovirus (HERV) and its envelope proteins with MS illustrates a pathogenic pathway that causally links central nervous system (CNS)-intrinsic proinflammatory effects and inhibition of myelin repair and neuroregeneration. A review of current data on the causal relationship between inflammation and neurodegeneration in MS identified numerous plausible pathomechanisms that link the two events. Observations from most experimental models appear to favor a pathogenesis in which inflammation precedes neurodegeneration.

Evaluation of dual pathology among drug-resistant epileptic patients with hippocampal sclerosis.

PURPOSE: Dual pathology (DP) is defined as simultaneous presence of hippocampal sclerosis (HS) and any other pathology in the brain. Since this is a less probed concept, we aimed to evaluate the frequency and characteristics of DP among drug-resistant epileptic patients with HS. METHODS: This is a cross-sectional study conducted during 2007-2016 in Kashani Comprehensive Epilepsy Center, Isfahan, Iran. Patients with diagnosis of drug-resistant epilepsy and HS were enrolled in the study, and demographic data, seizure semiology, EEG findings, and MRI findings were collected. We compared these variables between three groups of DP, unilateral HS, and bilateral HS. RESULTS: Of the 200 enrolled cases, 29 patients (14.5%) had DP and 21 patients (10.5%) had bilateral HS; the remaining patients had unilateral HS. The average age of patients with DP was 30.03, and 65.5% of them were male. Patients with DP had more EEG discharges from regional and multi-focal sites compared to unilateral HS (P value < 0.001). Also, complex partial seizure (CPS) was more commonly presented in patients with unilateral HS (96.8%). Comparison of disease characteristics between DP and bilateral HS showed no difference in most categories (P > 0.05). CONCLUSIONS: We found DP among 14.5% of our drug-resistant epileptic patients with HS. DP patients mostly presented with CPS and had high proportion of ictal and interictal EEG discharges from regional and multi-focal areas. Gliosis and focal cortical dysplasia were the most common pathologies among DP patients. Patients with DP showed a similar behavior to bilateral HS in many features.

Effects of Interferential Electrical Stimulation Plus Pelvic Floor Muscles Exercises on Functional Constipation in Children: A Randomized Clinical Trial.

OBJECTIVES: Functional constipation is a common condition in children. We assessed the effectiveness of combined interferential (IF) electrical stimulation and pelvic floor muscle (PFM) exercises on functional constipation in children. METHODS: We conducted a single-center, double-blind randomized clinical trial study during 2014-2017 in Tehran, Iran. Ninety children, aged 5-13 years, who fulfilled Rome III criteria were enrolled and randomly assigned into two treatment groups. Case group (n=45) underwent IF electrical stimulation and PFM exercises, whereas the control group (n=45) received PFM exercises plus sham stimulation. A complete bowel habit diary (with concerning data on the frequency of defecation per week, stool form, and the number of fecal soiling episodes), a constipation score questionnaire, and a visual pain score were recorded before, after the treatment and 6 months later for all participants. In addition, children in both groups were assessed with a constipation-related quality-of-life questionnaire before, after the end of treatment sessions, and 6 months after the treatment. RESULTS: Treatment success was achieved for 88.4% of children in the case group compared with 43.2% of children in the control group after the treatment (P<0.003). The median constipation score was reduced in both groups, with the cases having significantly lower scores after the treatment (4 vs. 8, P<0.000). Stool form normalized in 75.6% of the cases and 45.5% of the controls after the treatment (P<0.01). CONCLUSIONS: Our results showed that using IF electrical stimulation as an adjuvant therapy to the medical and rehabilitation programs significantly boosts the effects of treatment among these patients.

Neuromyelitis optica spectrum disorder and menstruation.

BACKGROUND: Gender issues and the female preponderance in neuromyelitis optica spectrum disorder (NMOSD) have been investigated before, yet the interplay between NMOSD and menstrual characteristics has remained unknown. Thus, the aim was to compare menstrual cycle patterns and their symptoms in NMOSD patients and healthy women. METHODS: This cross-sectional study was conducted during 2015-2016 in Isfahan, Iran, and included female patients aged>14years with a diagnosis of NMOSD and healthy subjects as controls. Data regarding age at menarche, menstrual characteristics, history of premenstrual syndrome (PMS) and possible perimenstrual symptoms were collected. Also, NMOSD patients were asked to report changes in their menstrual cycles after onset of the disorder. RESULTS: The final study population included 32 NMOSD and 33 healthy controls. These groups did not differ regarding their demographics (P>0.05), and age at menarche in the NMOSD and control groups was 13.31±1.49 years and 13.48±1.44 years, respectively (P=0.637). The controls experienced PMS more frequently (78.8% vs. 40.6% in the NMOSD patients; P=0.03), with no significant differences in other menstrual features between groups (P>0.05). However, changes in menstruation after NMOSD onset were reported by 43.8% of patients, with an increase in menstrual irregularities from 15.6% to 43.7% (P=0.012); other menstrual characteristics did not differ after disease onset (P>0.05). CONCLUSION: Menstruation do not differ between healthy controls and NMOSD patients before the onset of disease whereas, after its onset, those affected experienced more irregularities in their menstrual cycles. This may be an effect of NMOSD and its underlying disorders on menstruation and suggests that further interventions may be required for affected women.

Attitudes Toward Cancer and Cancer Patients in an Urban Iranian Population.

BACKGROUND: Because of the significant incidence and mortality of cancer in Iran, a Comprehensive National Cancer Control Program for the prevention and early detection of cancer was launched in 2007. However, cancer awareness and screening rates in Iran did not improve. This study aimed to evaluate public attitudes toward cancer and cancer patients in Iran. MATERIALS AND METHODS: We conducted a cross-sectional survey among 953 non-institutionalized individuals in Isfahan, Iran, from November 2014 to February 2015. We collected data on attitudes toward cancer in three domains (impossibility of recovery, cancer stereotypes, and discrimination), as well as questions on willingness to disclose a cancer diagnosis. RESULTS: Among all participants, 33.9% agreed that it is very difficult to regain one's health after a cancer diagnosis, 17.4% felt uncomfortable with a cancer patient, and 26.9% said that they would avoid marrying people whose family members had cancer. While 88.9% of study participants said that cancer patients deserve to be protected in society, 53.3% and 48.4% of participants agreed that they would not disclose a cancer diagnosis to neighbors and coworkers, respectively. CONCLUSION: Negative attitudes with respect to impossibility of recovery and discrimination toward cancer and cancer patients were common among urban Iranians. Most people would not disclose a cancer diagnosis to others in spite of advancements in cancer diagnosis and treatment, reflecting unfavorable attitudes toward cancer and cancer patients in society. Successful implementation of cancer awareness and prevention programs in Iran may require social changes based on adequate information on cancer and cancer patients. IMPLICATIONS FOR PRACTICE: Public attitudes toward cancer and cancer patients are an important factor affecting cancer control programs as well as quality of life and recovery of cancer patients. The issue has not been studied in Iran and the surrounding countries in the Middle East. This is the first report presented on the subject. These findings can be used by health policy makers, health managers, and clinicians for better practice.

Reliability and Validity of the Persian HIT-6 Questionnaire in Migraine and Tension-type Headache.

OBJECTIVE: Headache Impact Test (HIT-6) measures the impact headaches in a 1-month period. We validated the Persian translation of HIT-6, compared the HIT-6 psychometric analysis between migraine and tension-type headache (TTH) patients, and evaluated the capability of HIT-6 to differentiate between TTH, chronic migraine, and episodic migraine. METHODS: Qualified participants, including 274 patients diagnosed with migraine or TTH, were required to complete HIT-6, SF-36v2, and a symptoms questionnaire on their first visit. At 3 and 8 weeks from first visit, participants completed HIT-6. Internal consistency (Cronbach's α) and test-retest reproducibility (Pearson's correlation coefficient) were used to assess reliability. Convergent validity was also assessed. RESULTS: Tension-type headache, episodic, and chronic migraines included 24.5%, 61.9%, and 13.6% of the participants, respectively. Internal consistency among all patients, TTH, and migraine in the first visit were 0.74, 0.77, and 0.73, respectively. Test-retest reliability for HIT-6 between visit 1 and 2 showed a moderate level of correlation (r = 0.50). Convergent validity and also item total correlation were acceptable. There was no significant difference in HIT-6 total score between TTH and migraine. CONCLUSION: Persian HIT-6 is a valid and reliable questionnaire for the evaluation of headache. However, it cannot differentiate between chronic migraine, episodic migraine, and TTH in Iranian population.

Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

The psychometric properties of the persian migraine-specific quality of life questionnaire version 2.1 in episodic and chronic migraines.

BACKGROUND: Migraine-specific quality of life (MSQ) is a valid and reliable questionnaire. Linguistic validation of Persian MSQ questionnaire, analysis of psychometric properties between chronic and episodic migraine patients, and capability of MSQ to differentiate between chronic and episodic migraines were the aims of this study. METHOD: Participants were selected from four different neurology clinics that were diagnosed as chronic or episodic migraine patients. Baseline data included information from MSQ v. 2.1, MIGSEV, SF-36, and symptoms questionnaire. At the third week from the baseline, participants filled out MSQ and MIGSEV. Internal consistency (Cronbach alpha) and test-retest reproducibility (intraclass correlation coefficients) were used to assess reliability. Convergent and discriminant validities were also assessed. RESULTS: A total of 106 participants were enrolled. Internal consistencies of MSQ among all patients, chronic and episodic migraines, were 0.92, 0.91, and 0.92, respectively. Test-retest correlation of MSQ dimensions between visits 1 and 2 varied from 0.41 to 0.50. Convergent, item discriminant, and discriminant validities were approved. In all visits MSQ scores were lower in chronic migraine than episodic migraine; however, the difference was not statistically significant. CONCLUSION: Persian translation of MSQ is consistent with original version of MSQ in terms of psychometric properties in both chronic and episodic migraine patients.

Glial cell transcriptome analyses in 3xTg-AD mice: Effects of aging, disease progression, and anti-Aß immunotherapy.

Background: To investigate how changes in expression of glial genes relate to a progression of Alzheimer's disease (AD) pathology, and how anti-Aß immunotherapy impact these changes, we conducted a transcriptomic analysis for brains from cohorts of 2-, 10-, and 20 month old 3xTg-AD mice, and a cross-sectional study in groups of 20 month-old mice treated with active DNA Aß42 immunization, passive immunotherapy, untreated, and wild-type (wt) controls. Methods: Twenty-four Formalin-Fixed Paraffin-Embedded (FFPE) mouse brain sections were used for the gene expression analyses (nanostring). Adjacent sections from these and additional mouse brains were stained for microglia using antibodies detecting IbaI and Gal3. For a semi-quantitative analysis of increased tau and amyloid pathology with aging and disease progression, a comparison of ELISA results from brains of 12 and 20 months old 3xTg-AD mice were shown. Results: Based on the different comparisons of transcript numbers found the 3xTg-AD age groups with the senescent 20 months old wt control mouse brains, and the 20 months old 3xTg-AD mouse brains with the 20 months old wt control mouse brains, genes were assigned as upregulated due to aging, or due to disease progression, or due to both. The immunohistochemistry of microglia markers revealed that Gal3 might be an important marker for phagocytosing microglia around amyloid plaques. The comparison of the two anti-Aß immunotherapy approaches showed a differential downregulation of inflammatory glial genes. Conclusion: These results are relevant for future clinical trials using active anti-amyloid immunotherapy.

Assessment of intelligence quotient in patients with neuromyelitis optica spectrum disease and multiple sclerosis.

BACKGROUND: Cognitive impairment is common in people living with neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS). However, there is little published data on intelligence quotient (IQ) in NMOSD patients. Therefore, we performed the present study to compare IQ scores across NMOSD, MS, and control groups. METHOD: In this cross-sectional study, 49 NMOSD (30 with positive aquaporin4 antibody), 41 MS, and 20 control individuals were recruited. The IQ score for each person was measured using Wechsler Adult Intelligence Scale-Revised (WAIS-R). Participants were reported on eleven scores of subsets, verbal IQ (VIQ), performance IQ (PIQ), and full score IQ (FSIQ). RESULT: The scores of FSIQ, VIQ, PIQ, vocabulary, similarities, and digit-symbol in NMOSD and MS individuals were lower than the control group. Relative to control, NMOSD patients reported a lower score of information. We found no difference between NMOSD and MS groups, except in vocabulary and similarities. No significant difference between seropositive and seronegative NMOSD groups was observed except for the information and block design. In NMOSD group, a greater EDSS score was associated with decreased scores of FSIQ, VIQ, and PIQ. Being employed and being married were associated with greater scores of VIQ and PIQ, respectively. In both NMOSD and MS groups, advanced education was associated with increased scores of FSIQ and VIQ. CONCLUSION: Our study showed decreased IQ scores in NMOSD and MS. Further studies are required to examine intellectual quotient in people with NMOSD and MS.

Application of the Intracranial Arterial Pulsatility Index for Determination of Prognosis after Lacunar Infarct.

Background: We aimed to investigate the usefulness of intracranial arterial pulsatility index to assess the prognosis of lacunar infarcts. Materials and Methods: Forty-nine patients with confirmed acute lacunar infarct were enrolled in the study. A transcranial color-coded sonography was performed to assess the pulsatility index of bilateral middle cerebral, posterior cerebral, vertebral, and proximal internal carotid arteries. Patients' clinical status was assessed using a modified Rankin scale. Spearman correlation was used for reporting the relation between quantitative data. Statistical significance was defined as a two-tail p-value of less than 0.05. Results: The mean age ± standard deviation was 64.1 ± 9.07 years old, and 57.1% of the patients were male. Upon discharge, only 8.2% of the patients were ranked as 0 on the modified Rankin scale; however, after a 6-month follow-up period, this number increased to 49%. There were no significant differences between the left and right pulsatility index measurements in any of the assessed arteries. Patients with vertebral artery pulsatility indexes >1 on their primary assessment had significantly worse outcomes during the first, third, and sixth months follow-up (all r > 0.3, p-values < 0.01). Pulsatility indexes from other arteries did not predict the prognosis. Conclusion: Sonography-assisted assessment of the vertebral artery blood flow during the early stage of lacunar infarct provides a reliable reference for prognosis estimation.

Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure.

The advent of disease modifying therapies (DMT) in the past two decades has been the cornerstone of successful clinical management of multiple sclerosis (MS). Despite the great strides made in reducing the relapse frequency and occurrence of new signal changes on neuroimaging in patients with relapsing remitting MS (RRMS) by approved DMT, it has been challenging to demonstrate their effectiveness in non-active secondary progressive MS (SPMS) and primary progressive MS (PPMS) disease phenotypes. The dichotomy of DMT effectiveness between RRMS and progressive MS informs on distinct pathogeneses of the different MS phenotypes. Conversely, factors that render patients with progressive MS resistant to therapy are not understood. Thus far, age has emerged as the main correlate of the transition from RRMS to SPMS. Whether it is aging and age-related factors or the underlying immune senescence that qualitatively alter immune responses as the disease transitions to SPMS, that diminish DMT effectiveness, or both, is currently not known. Here, we will discuss the role of immune senescence on different arms of the immune system, and how it may explain relative DMT resistance.

The sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS) trial - Part I: Rationale and objectives.

Background: Natalizumab is a recombinant humanized monoclonal antibody (mAb) against α4-integrin that is approved for relapsing forms of multiple sclerosis (MS). Natalizumab is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), and with disease reactivation after cessation of treatment that is likely mediated by an accumulation of pro-inflammatory lymphocytes in the blood during therapy. Alemtuzumab is a mAb against CD52 that reduces the number of peripheral lymphocytes. Rationale: To determine if treatment with alemtuzumab after natalizumab reduces disease activity in patients with relapsing forms of MS. This review article will outline the rationale and objectives of the sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS; ClinicalTrials.gov ID: NCT03135249) trial in greater detail than would be feasible in a manuscript that summarizes the study results. Methods: The SUPPRESS trial is single arm, open-label, multicenter, efficacy pilot study that aims to establish a disease-free state over a 24-months period in patients who received the natalizumab- alemtuzumab sequential therapy. Participants will be recruited from four different sites. The primary endpoint is the annualized relapse rate (ARR) from the time of cessation of natalizumab treatment. Key secondary endpoint is freedom of relapse at 12-months, the number of new/enlarging T2 lesions on magnetic resonance imaging (MRI), and the number of gadolinium (Gd)-enhancing lesions on MRI. An exploratory endpoint is the Expanded Disability Status Scale (EDSS), retinal nerve fiber layer (RNFL) thickness assessment by optic coherence tomography (OCT) and assessment of quality of life (QoL) measures by a pre-defined, self-administered testing battery. To evaluate immunological effects, blood leukocytes will be collected and immunophenotyped by multi-parameter flow cytometry. Conclusion: The SUPPRESS trial will provide clinical, imaging, and biological data to determine whether sequential natalizumab to alemtuzumab combination therapy establish a disease-free state in patients with relapsing forms of MS.

Biological Significance of Anti-SARS-CoV-2 Antibodies: Lessons Learned From Progressive Multifocal Leukoencephalopathy.

OBJECTIVE: To discuss the pathogenic and diagnostic relevance of cellular and humoral immune responses against severe acute respiratory syndrome novel coronavirus (SARS-COV-2) and pertinent observations made in progressive multifocal leukoencephalopathy (PML). METHODS: Review of pertinent literature. RESULTS: There is at least 1 precedent for an antibody response against a viral pathogen that fails to provide host protection in the absence of immune-competent CD4+ T cells. PML is an infection of the CNS caused by JC virus (JCV), which commonly occurs during treatment with the therapeutic monoclonal antibody natalizumab. In this context, the humoral immune response fails to prevent JCV reactivation, and elevated anti-JCV serum indices are associated with a higher PML incidence. The more relevant immune-competent cells in host defense against JCV appear to be T cells. T cell-mediated responses are also detectable in convalescing patients with SARS-COV-2 irrespective of the humoral immune response. CONCLUSION: Based on pathogenic lessons learned from PML under natalizumab therapy, we suggest the incorporation of functional assays that determine neutralizing properties of SARS-CoV-2-specific antibodies. In addition, we outline the potential role of T-cell detection assays in determining herd immunity in a given population or in studying therapeutic responses to vaccines.

The antioxidant MnTBAP does not effectively downregulate CD4 expression in T cells in vivo.

The antioxidant MnTBAP was previously shown to down-regulate the surface expression of CD4 molecule in T cells. This observation obviously holds great potential impact in a number of pathological human conditions, including autoimmunity. Three different single doses of MnTBAP reduced the frequency of CD4high cells. However, the median florescent intensity (MFI) was not different. Initiation of in vivo pharmacotherapy or vehicle control was performed inC57BL/6 mice that were actively immunized for experimental autoimmune encephalomyelitis (EAE). In contrast to published reports, the mean frequency of CD4high cells, and the median fluorescent intensity (MFI) of CD4 was similar in both treatment groups. 25-day survival following active immunization among the MnTBAP treated animals compared to vehicle controls was16.6 ± 6.9 days vs 23.6 ± 2.7 days; (P value <0.05). We conclude that MnTBAP (Sack and Herzog, 2009 (Sack and Herzog, 2009)) does not effectively downregulate CD4 expression in T cells in vivo, probably due to extensive mechanism that distinguishes it from an in vitro model (Harding, 1993 (Harding, 1993)) possesses toxic properties that may limit its clinic use in possible doses that could deliver the immunomodulation through down regulation of CD4 expression, and (Saizawa et al., 1987 (Saizawa et al., 1987)) has limited availability in specific tissues, including the CNS.