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Objective: To investigate the effects of leptin on different T-cell populations, in order to gain more insight into the link between leptin and obesity., Methods: Three hundred and nine RRMS patients and 322 controls participated in a cross-sectional survey, to confirm whether excess weight/obesity in adolescence or early adulthood increased the risk of MS. Serum leptin levels were determined by ELISA. MBP 83-102 , and MOG 63-87 peptide-specific T cells lines were expanded from peripheral blood mononuclear cells. Leptin receptor expression was measured by RT-PCR and flow cytometry. Bcl-2, p-STAT3, pERK1/2, and p27 kip1 expression were assayed using ELISA, and apoptosis induction was determined by Annexin V detection. Cytokines were assessed by ELISPOT and ELISA, and regulatory T cells (Tregs) by flow cytometry., Results: Logistic regression analysis, showed excess weight at age 15, and obesity at 20 years of age increased MS risk (OR = 2.16, P = 0.01 and OR = 3.9, P = 0.01). Leptin levels correlated with BMI in both groups. The addition of Leptin increased autoreactive T-cell proliferation, reduced apoptosis induction, and promoted proinflammatory cytokine secretion. Obese patients produced more proinflammatory cytokines compared to overweight/normal/underweight subjects. Inverse correlation was found between leptin levels and circulating Treg cells (r = -0.97, P < 0.0001). Leptin inhibited Treg proliferation. Effects of leptin on CD4 + CD25 - effector T cells were mediated by increased STAT3 and ERK1/2 phosphorylation, and down modulation of the cell cycle inhibitor P27 kip1 . In contrast, leptin effects on Tregs resulted from decreased phosphorylation of ERK1/2 and upregulation of p27 kip1 ., Interpretation: Leptin promotes autoreactive T-cell proliferation and proinflammatory cytokine secretion, but inhibits Treg-cell proliferation., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: To investigate the diagnostic performance of an Artificial Intelligence (AI) system for detection of COVID-19 in chest radiographs (CXR), and compare results to those of physicians working alone, or with AI support., Materials and Methods: An AI system was fine-tuned to discriminate confirmed COVID-19 pneumonia, from other viral and bacterial pneumonia and non-pneumonia patients and used to review 302 CXR images from adult patients retrospectively sourced from nine different databases. Fifty-four physicians blind to diagnosis, were invited to interpret images under identical conditions in a test set, and randomly assigned either to receive or not receive support from the AI system. Comparisons were then made between diagnostic performance of physicians working with and without AI support. AI system performance was evaluated using the area under the receiver operating characteristic (AUROC), and sensitivity and specificity of physician performance compared to that of the AI system., Results: Discrimination by the AI system of COVID-19 pneumonia showed an AUROC curve of 0.96 in the validation and 0.83 in the external test set, respectively. The AI system outperformed physicians in the AUROC overall (70% increase in sensitivity and 1% increase in specificity, p < 0.0001). When working with AI support, physicians increased their diagnostic sensitivity from 47% to 61% (p < 0.001), although specificity decreased from 79% to 75% (p = 0.007)., Conclusions: Our results suggest interpreting chest radiographs (CXR) supported by AI, increases physician diagnostic sensitivity for COVID-19 detection. This approach involving a human-machine partnership may help expedite triaging efforts and improve resource allocation in the current crisis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mauricio F. Farez has received professional travel/accommodations stipends from Merck-Serono Argentina, Teva Argentina and Novartis Argentina. The rest of the authors declare no competing interests., (© 2020 Elsevier B.V.)

Objective: To investigate the frequency, phenotype, function, and longitudinal repertoire of mucosal-associated invariant T (MAIT) cells in relapsing remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) patients. Methods: Forty-five RRMS patients in remission, 20 RRMS patients experiencing exacerbations, 15 PPMS patients, and 30 healthy controls (HCs) were included in the study. MAIT cells were identified phenotypically as CD3 + TCRγδ - Vα7.2 + CD161 high . In 15 patients, MAIT cell number and MRI lesions were evaluated every 6 months, for 36 months. MAIT cell TCRVβ repertoire was defined using single-cell cloning and mRNA sequencing. Results: Circulating MAIT cells were significantly reduced in both RRMS and PPMS patients, particularly during exacerbations, compared to healthy subjects. This decrease was accompanied by pro-inflammatory cytokine production (TNF-α, IFN-γ, IL-17, and GM-CSF). Three months post-exacerbation, peripheral blood MAIT cell percentages increased significantly along with clinical recovery. Likewise, we observed inverse correlation between MRI lesions and peripheral blood MAIT cell numbers. In paired samples, MAIT cell percentage was significantly higher in CSF than in peripheral blood, suggesting MAIT cell migration through the blood-brain barrier. Finally, MAIT cells showed limited TCRVβ repertoires, in both CSF and peripheral blood, which remained stable over time. Conclusions: MAIT cell levels correlated with MS course both clinically and radiologically, showing marked and sustained oligoclonality. These findings may contribute to a better understanding of pathophysiological phenomena underlying the course of MS, and discovery of MAIT cell inhibitors could pave the way for the development of new therapeutic strategies., (Copyright © 2019 Carnero Contentti, Farez and Correale.)

As life expectancy increases, there is a marked increase in the elderly population eager to continue driving. A large proportion of these elderly drive safely, however, patients with mild dementia are high-risk drivers., Objective: to identify the cognitive tests that best predict driving ability in subjects with mild dementia., Methods: 28 drivers with mild dementia and 28 healthy elderly subjects underwent an extensive cognitive assessment (NACC Uniform Data Set Neuropsychological Battery), completed an adapted On Road Driving Test (ORDT) and a Driving Simulator assessment., Results: drivers with mild dementia made more mistakes on the ORDT and had slower responses in the simulator tasks. Cognitive tests correlated strongly with on road and simulator driving performance. Age, the Digit Symbol Modalities Test and Boston Naming Test scores were the variables that best predicted performance on the ORDT and were included in a logistic regression model., Conclusion: the strong correlation between driving performance and performance on specific cognitive tests supports the importance of cognitive assessment as a useful tool for deciding whether patients with mild dementia can drive safely. The algorithm including these three variables could be used as a screening tool for the detection of unsafe driving in elderly subjects with cognitive decline., Competing Interests: Disclosure: The authors report no conflicts of interest

Objective: The risk of recurrence of new amnesia events in patients having previously experienced transient global amnesia (TGA) ranges between 2.9-23.8%. Our objective was to search for recurrence predictors in TGA patients., Methods: Retrospective analysis to identify recurrence predictors in a cohort of 203 TGA patients from a single center in Buenos Aires, Argentina, diagnosed between January 2011 and March 2017 Clinical features and complementary studies (laboratory results, jugular vein Doppler ultrasound and brain MRI) were analyzed. Comparison between patients with recurrent versus single episode TGA was performed, applying a multivariate logistic regression model., Results: Mean age at presentation was 65 years (20-84); 52% were female. Median time elapsed between symptom onset and ER visit was two hours, with the average episode duration lasting four hours. Mean follow-up was 22 months. Sixty-six percent of patients referred to an identifiable trigger. Jugular reflux was present in 66% of patients; and 22% showed images with hippocampus restriction on diffusion-weighted MRI. Eight percent of patients had TGA recurrence. Patients with recurrent TGA had a more frequent history of migraine than patients without recurrence (37.5% vs. 14%; p = 0.03). None of the other clinical characteristics and complementary studies were predictors of increased risk of recurrence., Conclusions: Patients with migraine may have a higher risk of recurrent TGA. None of the other clinical characteristics evaluated allowed us to predict an increased risk of recurrence. Although the complementary studies allowed us to guide the diagnosis, they did not appear to have a significant impact on the prediction of recurrence risk.

Background and Purpose: Although incidence rates vary, infectious, autoimmune, and neoplastic diseases can all cause chronic and subacute meningitis (CSM). We report a Latin-American, single center, CSM case series, analyzing the main clinical characteristics as well as ancillary diagnostic methods differentiating neoplastic from non-neoplastic etiologies., Methods: Retrospective review of CSM cases from a single center in Buenos Aires, Argentina., Results: Seventy patients with CSM diagnosis were identified, 49 with neoplastic and 21 with non-neoplastic meningitis. A history of previous cancer was significantly higher in neoplastic cases, whereas prevalence of autoimmune disease and fever was more common in non-neoplastic meningitis. C-reactive protein values were higher in non-neoplastic CSM, as was pleocytosis in cerebrospinal fluid analysis. The most frequent etiologies were breast and lung cancer for neoplastic meningitis cases; and idiopathic, tuberculous, and fungal infection for non-neoplastic cases., Conclusions: Chronic and subacute meningitis diagnosis is challenging in daily neurological practice. The results we report contribute information from Latin America regarding etiologies of CSM, which can be identified after a comprehensive evaluation in a majority of cases., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In MS patients, hypertension is associated with a delayed diagnosis and an increased risk of progression. Understanding the mechanisms of this association could potentially lead to improved prevention of disease progression. We aimed to establish whether high blood pressure contributes to white-matter injury and brain atrophy in MS. Methods: Cross-sectional study of 95 patients with RRMS. Estimates of fractional anisotropy, gray-matter volume and lesion load were obtained from 3T MRI. We used fractional anisotropy voxel-based statistics to establish the effect of blood pressure on white matter tracts. Additionally, we used voxel-based morphometry (VBM) to study the effect on gray matter integrity. Results: Only 29.5% had normal blood pressure levels, with 52.6% suffering from prehypertension and 17.9% with hypertension. Increasing systolic blood pressure was associated with damage to posterior white-matter tracts as well as greater levels of gray matter atrophy, in particular in the frontal cortex. Age-adjusted linear regression indicated that neither lesion volume (β = 0.002, 95%CI: 0.02-0.02; p = 0.85) or lesion number (β = -0.004, 95%CI: 0.03-0.02; p = 0.74) were associated with systolic blood pressure. Conclusions: Prehypertension and hypertension are frequent in MS. Increased blood pressure is related to white- and gray-matter integrity, both related to MS disability outcomes. These findings suggest attention to the control of blood pressure in MS patients.

Background Primary central nervous system lymphomas (PCNSL) are infrequent. The traditional treatment of choice is chemotherapy. Complete resections have generally not been recommended, because of the risk of permanent central nervous system deficits with no proven improvement in survival. The aim of the current study was to compare survival among patients with PCNSL who underwent biopsy versus surgical resection. Methods A retrospective study was conducted on 50 patients with a confirmed diagnosis of PCNSL treated at our center from January 1994 to July 2015. Results Patients in the resection group exhibited significantly longer median survival time, relative to the biopsy group, surviving a median 31 months versus 14.5 months; p = 0.016. Conclusions In our series, patients who had surgical resection of their tumor survived a median 16.5 months longer than patients who underwent biopsy alone.

Intravenous thrombolysis improves outcomes in acute ischemic stroke in a time-dependent fashion. As in teaching hospitals, clinical outcomes may worsen due to the arrival of new inexperienced house staff early in the academic year (July effect, JE), we evaluated the impact of the "JE" on the door-to-needle time for intravenous thrombolysis and other stroke outcomes. In this retrospective cohort study, we assessed all acute ischemic strokes treated with intravenous thrombolysis between July 2003 and June 2016. Among 101 patients, there was no detrimental July effect on the door-to-needle time, rate of thrombolysis within 60 minutes of arrival, thrombolysis of stroke mimics, post-thrombolysis intracranial hemorrhages, National Institutes of Health Stroke Scale, and modified Rankin Scale outcomes., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

It is generally accepted that autoimmune diseases like multiple sclerosis (MS) arise from complex interactions between genetic susceptibility and environmental factors. Genetic variants confer predisposition to develop MS, but cannot be therapeutically modified. On the other hand, several studies have shown that different lifestyle and environmental factors influence disease development, as well as activity levels and progression. Unlike genetic risk factors, these can be modified, with potential for prevention, particularly in high-risk populations. Most studies identifying particular lifestyle and environmental factors have been carried out in Caucasian patients with MS. Little or no data is available on the behavior of these factors in Latin American populations. Ethnic and geographic differences between Latin America and other world regions suggest potential regional variations in MS, at least with respect to some of these factors. Furthermore, particular environmental characteristics observed more frequently in Latin America could explain regional differences in MS prevalence. Site-specific studies exploring influences of local environmental factors are warranted.

Methods: Review of hospital records and structured telephone interviews of 100 consecutive stroke patients. Forward stepwise logistic regression was used for the statistical analysis., Results: Seventy patients (75%) arrived at the hospital 4.5 hours after stroke symptoms onset. The use of EMS did not improve arrival times. Most patients who recognized their symptoms did not use EMS (p < 0.02). Nineteen patients (20%) were initially misdiagnosed. Eighteen of them were first assessed by non-neurologist physicians (p < 0.001)., Conclusions: Our population showed a low level of stroke awareness. The use of EMS did not improve arrival times at the hospital and the non-utilization of the EMS was associated with the recognition of stroke symptoms. There was a concerning rate of misdiagnosis, mostly by non-neurologist medical providers.

Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory disorder causing central nervous system (CNS) demyelination and axonal injury. Although its etiology remains elusive, several lines of evidence support the concept that autoimmunity plays a major role in disease pathogenesis. The course of MS is highly variable; nevertheless, the majority of patients initially present a relapsing-remitting clinical course. After 10-15 years of disease, this pattern becomes progressive in up to 50% of untreated patients, during which time clinical symptoms slowly cause constant deterioration over a period of many years. In about 15% of MS patients, however, disease progression is relentless from disease onset. Published evidence supports the concept that progressive MS reflects a poorly understood mechanism of insidious axonal degeneration and neuronal loss. Recently, the type of microglial cell and of astrocyte activation and proliferation observed has suggested contribution of resident CNS cells may play a critical role in disease progression. Astrocytes could contribute to this process through several mechanisms: (a) as part of the innate immune system, (b) as a source of cytotoxic factors, (c) inhibiting remyelination and axonal regeneration by forming a glial scar, and (d) contributing to axonal mitochondrial dysfunction. Furthermore, regulatory mechanisms mediated by astrocytes can be affected by aging. Notably, astrocytes might also limit the detrimental effects of pro-inflammatory factors, while providing support and protection for oligodendrocytes and neurons. Because of the dichotomy observed in astrocytic effects, the design of therapeutic strategies targeting astrocytes becomes a challenging endeavor. Better knowledge of molecular and functional properties of astrocytes, therefore, should promote understanding of their specific role in MS pathophysiology, and consequently lead to development of novel and more successful therapeutic approaches.

Objectives: To assess decision-making under explicit risk conditions in relapsing-remitting multiple sclerosis patients and its relationship to decisions made under conditions of ambiguity. To assess cognitive functions related to decision-making performance in patients with multiple sclerosis (MS)., Setting: MS center in Buenos Aires, Argentina., Participants: 27 patients with relapsing-remitting multiple sclerosis and 27 sex-matched, age-matched and education-matched healthy controls., Intervention: Neuropsychological assessment and decision-making evaluation using the Game of Dice Task and the Iowa Gambling Task., Outcomes: Game of Dice Task and the Iowa Gambling Task scores., Results: Patients with MS showed significantly poorer performance on the Game of Dice Task, choosing disadvantageous dice more often (p=0.019), as well as significantly lower overall scores in the Iowa Gambling Task (p=0.007). Block analysis showed that patients with MS and controls had scores that were comparable for blocks 1 and 2 (p=0.15 and p=0.24, respectively). Conversely, patients with MS scored poorly on blocks 4 (p=0.003) and 5 (p=0.023), the last two of the test, corresponding to decision-making under conditions of risk. Finally, the Game of Dice Task performance together with the last three blocks of the Iowa Gambling Task were correlated with visuospatial learning, processing speed and working memory but not with executive functioning., Conclusions: Patients with MS showed deficits in decision-making under risk conditions, which might be related to deficits in visuospatial learning, processing speed and working memory., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background. Comorbid autoimmune diseases in MS patients have been studied extensively with controversial results. Moreover, no such data exists for Latin-American MS patients. Methods. We conducted a case-control study aimed to establish the prevalence of autoimmune disorders in a cohort of Argentinean MS patients. Results. There were no significant differences in autoimmune disease prevalence in MS patients with respect to controls. The presence of one or more autoimmune disorders did not increase risk of MS (OR 0.85, 95% CI 0.6-1.3). Discussion. Our results indicate absence of increased comorbid autoimmune disease prevalence in MS patients, as well as of increased risk of MS in patients suffering from other autoimmune disorders.

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease affecting the Central Nervous System (CNS), in which Th1 and Th17 cells appear to recognize and react against certain myelin sheath components. Epidemiological evidence has accumulated indicating steady increase in autoimmune disease incidence in developed countries. Reduced infectious disease prevalence in particular has been proposed as the cause. In agreement with this hypothesis, we recently demonstrated significantly better clinical and radiological outcome in helminth-infected MS patients, compared to uninfected ones. Parasite-driven protection was associated with regulatory T cell induction and anti-inflammatory cytokine secretion, including increased TGF-β and IL-10 levels. Interestingly, surface expression of TLR2, on both B cells and dendritic cells (DC) was significantly higher in infected MS patients. Moreover, stimulation of myelin-specific T cell lines with a TLR2 agonist induced inhibition of T cell proliferation, suppression of IFN-γ, IL-12, and IL-17 secretion, as well as increase in IL-10 production, suggesting the functional responses observed correlate with TLR2 expression patterns. Furthermore, parasite antigens were able to induce TLR2 expression on both B cells and DCs. All functional effects mediated by TLR2 were abrogated when MyD88 gene expression was silenced; indicating helminth-mediated signaling induced changes in cytokine secretion in a MyD88-dependent manner. In addition, helminth antigens significantly enhanced co-stimulatory molecule expression, effects not mediated by MyD88. Parasite antigens acting on MyD88 induced significant ERK kinase phosphorylation in DC. Addition of the ERK inhibitor U0126 was associated with dose-dependent IL-10 inhibition and reciprocal enhancement in IL-12, both correlating with ERK inhibition. Finally, cytokine effects and changes observed in co-stimulatory DC molecules after helminth antigen exposure were lost when TLR2 was silenced. Overall, the data described indicate that helminth molecules exert potent regulatory effects on both DCs and B cells from MS patients through TLR2 regulation.

Many studies have addressed the question of whether intensive insulin therapy (IIT) provides better outcomes for brain-injured patients than does conventional insulin therapy (CIT), with conflicting results. We performed a systematic review and meta-analysis of the literature to estimate the effect of IIT on patients with brain injury. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and citations of key articles and selected "all randomized controlled trials" (RCTs) comparing the effect of IIT to CIT among adult patients with acute brain injury (traumatic brain injury, stroke, subarachnoid hemorrhage, and encephalitis). Of the 2807 studies, we identified 9 RCTs with a total of 1160 patients for analysis. IIT did not appear to decrease the risk of in-hospital or late mortality (RR=1.04, 95% CI=0.75, 1.43 and RR=1.07, 95%CI=0.91, 1.27 respectively). No significant heterogeneity was found (I(2)=0.0%). IIT also did not have a protective effect on long-term neurological outcomes (LTNO) (RR=1.10, 95% CI=0.96, 1.27). IIT, however, did decrease the rate of infections (RR=0.76, 95% CI=0.58, 0.98). Heterogeneity was present (I(2)=64%), which was eliminated upon sensitivity analysis bringing the RR to 0.66 (95% CI=0.55, 0.80, I(2)=0%). IIT increased the rate of hypoglycemic episodes (RR=1.72, 95% CI=1.20, 2.46) however there was intractable heterogeneity present (I(2)=89%), which did not resolve upon sensitivity analysis. We found no evidence of publication bias by Egger's test (p=0.50). To conclude, IIT has no mortality or LTNO benefit to patients with brain injury, but is beneficial at decreasing infection rates.

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) participates in the differentiation of FoxP3(+) T(reg), Tr1 cells, and IL-17-producing T cells (Th17). Most of our understanding on the role of AHR on the FoxP3(+) T(reg) compartment results from studies using the toxic synthetic chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin. Thus, the physiological relevance of AHR signaling on FoxP3(+) T(reg) in vivo is unclear. We studied mice that carry a GFP reporter in the endogenous foxp3 locus and a mutated AHR protein with reduced affinity for its ligands, and found that AHR signaling participates in the differentiation of FoxP3(+) T(reg) in vivo. Moreover, we found that treatment with the endogenous AHR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) given parenterally or orally induces FoxP3(+) T(reg) that suppress experimental autoimmune encephalomyelitis. ITE acts not only on T cells, but also directly on dendritic cells to induce tolerogenic dendritic cells that support FoxP3(+) T(reg) differentiation in a retinoic acid-dependent manner. Thus, our work demonstrates that the endogenous AHR ligand ITE promotes the induction of active immunologic tolerance by direct effects on dendritic and T cells, and identifies nontoxic endogenous AHR ligands as potential unique compounds for the treatment of autoimmune disorders.

Background: Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3(+) regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage., Methods/principal Findings: Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos., Conclusions/significance: Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity.

Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.

Multiple sclerosis (MS) is a progressive neurological disease caused by an autoimmune attack to the central nervous system (CNS). MS is thought to result from a complex interaction between genetic and environmental factors. In this review we analyze the contribution of genomics, trancriptomics and proteomics in delineating these factors, as well as their utility for the monitoring of disease progression, the identification of new targets for therapeutic intervention and the early detection of individuals at risk.

Regulatory T cells (T(reg)) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T(reg) cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T(H)17). Although T(reg) cell dysfunction and/or T(H)17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T(reg) and T(H)17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T(reg) cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T(reg) cell development, boosted T(H)17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.