Nrf2 through Aryl Hydrocarbon Receptor Regulates IL-22 Response in CD4+ T Cells.

IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-ß and IL-6 promote Th17 differentiation; however, these cytokines have multiple targets. The identification and screening of additional molecules that regulate IL-17A and IL-22 responses in certain inflammatory conditions is of great clinical significance. In this study, we show that CDDO-Im, a specific Nrf2 activator, promotes IL-17A and IL-22 responses in murine Th17 cells. In contrast, CDDO-Im inhibits IL-17A response in multiple sclerosis patient-derived PBMCs. However, Nrf2 specifically regulates IL-22 response in vivo. Nrf2 acts through the regulation of antioxidant response element (ARE) binding motifs in target genes to induce or repress transcription. Promoter analysis revealed that Il17a, Rorc, and Ahr genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of Rorc and inhibited Rorc-dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity. Chromatin immunoprecipitation quantitative PCR data showed that Nrf2 bound to ARE of AhR. Finally, we confirmed that the CDDO-Im-mediated induction of IL-22 production in CD4+ T cells was abrogated in CD4-specific Ahr knockout mice (AhrCD4 ). CH-223191, a specific AhR antagonist, inhibits CDDO-Im-induced IL-22 production in CD4+ T cells, which further confirmed the AhR-dependent regulation. Collectively, our data showed that Nrf2 via AhR pathways regulated IL-22 response in CD4+ T cells.

Fluid Intake and Urinary Symptoms in Patients with Multiple Sclerosis.

PURPOSE: The relationship between fluid intake and lower urinary tract symptoms in individuals with neurogenic bladder is unknown. We investigated the association between fluid intake and urinary symptoms in patients with multiple sclerosis. MATERIALS AND METHODS: A prospective cross-sectional study of patients with multiple sclerosis presenting to the neurology office was conducted. Fluid intake and lower urinary tract symptoms were assessed by the questionnaire based voiding diary and the American Urological Association Symptom Score, respectively. The relationship between fluid intake and lower urinary tract symptoms was assessed using univariate and multivariate analyses. RESULTS: Among 200 individuals with multiple sclerosis the mean total daily fluid intake was 2,489 ml (SD 1,883) and did not differ according to severity (ie mild, moderate, severe) of lower urinary tract symptoms (F=0.30, p=0.74). Fluid restricting behavior to control urinary symptoms was reported by 47% of subjects. Subjects who reported fluid restricting were more likely to have worse urinary symptoms (OR 1.95, 95% CI 1.53-2.47, p <0.01). After accounting for fluid restricting behavior on multivariate analysis, there was a minimal relationship between caffeinated fluid intake and lower urinary tract symptom severity (OR 1.00, 95% CI 1.00-1.01, p=0.01), and there was no relationship between total fluid intake and lower urinary tract symptom severity (OR 1.00, 95% CI 1.00-1.00, p=0.07). CONCLUSIONS: Caffeinated fluid intake has a minimal effect on lower urinary tract symptoms in patients with multiple sclerosis. On average, patients with multiple sclerosis do not hydrate excessively and a considerable proportion restrict fluid intake to control urinary symptoms. Fluid intake may not contribute considerably to lower urinary tract symptoms in patients with multiple sclerosis.

Unemployment in multiple sclerosis: the contribution of personality and disease.

BACKGROUND: Multiple sclerosis (MS) is the leading cause of neurological disability among young and middle-aged adults. One of the most devastating consequences of MS in this relatively young population group is unemployment. Although certain demographic and disease factors have been associated with employment, few studies have examined the contribution of person-specific factors, such as personality. OBJECTIVE: The goal of this study was to determine the extent to which personality, demographics, and clinical measures contribute to unemployment in MS. METHOD: A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS). RESULTS: Employment status was related with disease duration, MS subtype, level of neurological impairment, fatigue, performance on measures assessing information processing speed (Symbol Digit Modalities Test (SDMT)), learning and memory (Selective Reminding Test), and the personality characteristic of persistence. Based on a forward logistic regression analysis, EDSS, SDMT, and persistence were the strongest predictors of employment status. CONCLUSIONS: These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis: 2-year follow-up (investigational new drug No. 65863).

High-dose cyclophosphamide (HDC) is a chemotherapy treatment designed to eradicate autoreative B- and T-cells responsible for lymphocyte-mediated autoimmune illness while sparing the pluripotent blood stem cell of any ill effects. Multiple sclerosis (MS) is the most common inflammatory and demyelinating immune-mediated disorder of the central nervous system in young adults. Patients with moderate to severe, refractory MS, defined as an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after two or more Food and Drug Administration-approved disease-modifying agents, received 200 mg/kg of cyclophosphamide over 4 days. For the next 2 years, quarterly EDSS score evaluations and biannual brain magnetic resonance imaging and neuro-ophthalmologic evaluations were obtained. Fifteen patients were evaluated for clinical response. During follow-up, one patient increased their baseline EDSS score by 1.0. EDSS score stability of decrease was realized in five of seven (71%) patients with relapsing-remitting MS and six of eight (75%) patients with secondary progressive MS. Four patients required additional immunomodulatory treatment after treatment. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. HDC can effectively decrease symptoms, stop disease progression, and allow for disability regression in relapsing-remitting MS and secondary progressive MS patients. The most appropriate candidates for HDC, its duration of benefit, and the potential need for prophylactic preventative immune manipulation after HDC all require further investigation.

Negative affect predicts subsequent cognitive change in multiple sclerosis.

Baseline predictors of cognitive change were explored in a sample of persons with multiple sclerosis (MS). Potential predictors included demographic features, baseline clinical characteristics, and psychological state. Participants were 38 individuals diagnosed with either relapsing remitting or secondary progressive MS who did not meet criteria for a current major depressive episode. Subjects were tested at baseline and approximately 1 year in an ongoing longitudinal study of cognition in MS. Participants completed neuropsychological tests sensitive to impairment in MS. They also completed self-report measures of depression, anxiety, fatigue, apathy, and positive and negative affect. Baseline measures of negative affect (e.g., depressed mood, state anxiety, and negative affective state) consistently predicted cognitive change over the course of the study. Higher baseline levels of negative affect were associated with greater relative declines in cognitive performance. This longitudinal relation occurred in the absence of a cross-sectional relation between negative affect and overall cognition. High baseline negative affect particularly predicted a relative decline in episodic memory for newly learned verbal and visuospatial information. The negative affect measures were unique in their predictive value among all the baseline measures assessed. (JINS, 2009, 15, 53-61.).

Effects of donepezil on memory and cognition in multiple sclerosis.

Acetylcholinesterase inhibitors are used to treat dementia associated with Alzheimer's disease, but their cognitive benefits may extend to additional disorders such as multiple sclerosis (MS). A single-center double-blind placebo-controlled randomized clinical trial evaluated the effectiveness of donepezil in a sample of 69 MS persons selected for initial memory difficulties. Subjects received neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in total recall on the Selective Reminding Test, a measure of verbal learning and memory. Secondary outcomes included other neuropsychological tests from the Brief Repeatable Battery, patient-reported change in memory, and physician-reported impression of cognitive change. Donepezil improved memory performance on the SRT compared to placebo. This benefit remained significant after controlling for various covariates including Expanded Disability Status Scale (EDSS), MS subtype, interferon beta use, treatment group beliefs, gender, baseline selected reminding test (SRT) score, and reading ability. Subjects on donepezil were more likely to report memory improvement (65.7%) than those on placebo (32.4%). The clinician also reported cognitive improvement in more donepezil (54.3%) than placebo (29.4%) subjects. No serious adverse events related to study medication occurred. However, more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams. Donepezil improved learning and memory in MS patients with initial cognitive difficulties in a single-center clinical trial. Replication of results in a larger multi-center investigation is warranted in order to more definitively assess the efficacy of this intervention.

Perceived cognitive dysfunction and observed neuropsychological performance: longitudinal relation in persons with multiple sclerosis.

The relation between self-reported cognitive dysfunction and neuropsychological performance over 24 weeks was assessed in a sample of 53 multiple sclerosis patients. Subjects were assessed at Weeks Zero and 24 as part of a clinical trial to enhance cognition. At baseline, subjects had at least mild cognitive impairment on the Rey Auditory Verbal Learning Test and an absence of depression. Neuropsychological performance was assessed with a modification of the well standardized Brief Repeatable Battery. The 5-item Perceived Deficits Questionnaire and a 2-item memory and attention/concentration questionnaire assessed self-perceived cognitive impairment. Self-assessed cognition did not correlate with neuropsychological performance at either baseline or 24 weeks. However, changes in the self-assessment measures did correlate with changes in neuropsychological performance. Patients accurately perceived some changes in their level of cognitive dysfunction, though they were insensitive to the degree of their current dysfunction. Possible explanations of this pattern of results are discussed.