Tanuja Chitnis

International consensus diagnostic criteria for neuromyelitis optica spectrum disorders

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

Body size and risk of MS in two cohorts of US women

Objective: To examine whether obesity during childhood, adolescence, or adulthood is associated with an increased risk of multiple sclerosis (MS). Methods: Women in the Nurses’ Health Study (n = 121,700) and Nurses’ Health Study II (n = 116,671) provided information on weight at age 18 and weight and height at baseline, from which body mass index was derived. Women also selected silhouettes representing their body size at ages 5, 10, and 20. Over the total 40 years of follow-up in both cohorts combined, we confirmed 593 cases of MS. Cox proportional hazards models, adjusting for age, latitude of residence, ethnicity, and cigarette smoking, were used to estimate the rate ratios and 95% confidence intervals (CI). Results: Obesity at age 18 (body mass index ≥30 kg/m2) was associated with a greater than twofold increased risk of MS (multivariate relative riskpooled = 2.25, 95% CI: 1.50-3.37, p trend <0.001). After adjusting for body size at age 20, having a large body size at ages 5 or 10 was not associated with risk of MS, whereas a large body size at age 20 was associated with a 96% increased risk of MS (95% CI: 1.33-2.89, p trend = 0.009). No significant association was found between adult body mass and MS risk. Conclusions: Obese adolescents have an increased risk of developing multiple sclerosis (MS). Although the mechanisms of this association remain uncertain, this result suggests that prevention of adolescent obesity may contribute to reduced MS risk. 25(OH)D = 25-hydroxyvitamin D; BMI = body mass index; CI = confidence interval; MS = multiple sclerosis; NHS = Nurses’ Health Study; NHSII = Nurses’ Health Study II; RR = relative risk.

Regulatory functions of CD8+CD28– T cells in an autoimmune disease model

CD8+ T cell depletion renders CD28-deficient mice susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, CD8-/-CD28-/- double-knockout mice are susceptible to EAE. These findings suggest a role for CD8+ T cells in the resistance of CD28-deficient mice to disease. Adoptive transfer of CD8+CD28- T cells into CD8-/- mice results in significant suppression of disease, while CD8+CD28+ T cells demonstrate no similar effect on the clinical course of EAE in the same recipients. In vitro, CD8+CD28- but not CD8+CD28+ T cells suppress IFN-gamma production of myelin oligodendrocyte glycoprotein-specific CD4+ T cells. This suppression requires cell-to-cell contact and is dependent on the presence of APCs. APCs cocultured with CD8+CD28- T cells become less efficient in inducing a T cell-dependent immune response. Such interaction prevents upregulation of costimulatory molecules by APCs, hence decreasing the delivery of these signals to CD4+ T cells. These are the first data establishing that regulatory CD8+CD28- T cells occur in normal mice and play a critical role in disease resistance in CD28-/- animals.

Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.

Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is mediated by myelin-specific CD4(+) T cells secreting Th1 cytokines, while recovery from disease is associated with expression of Th2 cytokines. Investigations into the role of individual cytokines in disease induction have yielded contradictory results. Here we used animals with targeted deletion of the STAT4 or STAT6 genes to determine the role of these signaling molecules in EAE. The STAT4 pathway controls the differentiation of cells into a Th1 phenotype, while the STAT6 pathway controls the differentiation of cells into a Th2 phenotype. We found that mice deficient in STAT4 are resistant to the induction of EAE, with minimal inflammatory infiltrates in the central nervous system. In contrast, STAT6-deficient mice, which have a predominantly Th1 phenotype, experience a more severe clinical course of EAE as compared with wild-type or STAT4 knockout mice. In addition, adoptive transfer studies confirm the regulatory functions of a Th2 environment in vivo. These novel data indicate that STAT4 and STAT6 genes play a critical role in regulating the autoimmune response in EAE.

Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis.

OBJECTIVE To investigate whether or not the disparity in disease progression in those with pediatric-onset compared with adult-onset multiple sclerosis (MS) is due to differences in relapse rates. DESIGN Inception cohort. Mean follow-up times were 3.67 (standard deviation, 1.64) and 3.98 (standard deviation, 1.17) years in the pediatric and adult groups, respectively. SETTING Comprehensive MS centers. PATIENTS Patients with relapsing-remitting MS who were seen at the pediatric and adult MS centers at Massachusetts General and Brigham and Womens Hospitals, respectively, 12 months or less from onset of first symptom in July 2001 or later and were followed up for 12 months or longer. One hundred ten patients with adult-onset and 21 patients with pediatric-onset MS were included. Three eligible patients with adult-onset MS were excluded owing to incomplete records. MAIN OUTCOME MEASURE Annualized relapse rates were compared between pediatric-onset and adult-onset patients using the proportional means model. RESULTS The annualized relapse rate in the pediatric-onset group was significantly higher than that in the adult-onset group (1.13 vs 0.40; P < .001) with an adjusted rate ratio of 2.81 (95% confidence interval, 2.07-3.81). When we controlled for time spent undergoing disease-modifying treatment in the analysis, the difference between the groups remained highly significant (adjusted rate ratio, 2.82; 95% confidence interval, 2.08-3.83; P < .001). When age at disease onset was treated as a continuous variable, a highly significant association between age and relapse rate was observed (P < .001). CONCLUSIONS Relapses are more frequent in patients with pediatric-onset compared with adult-onset MS in the disease-modifying treatment era. This finding suggests that patients with pediatric-onset MS experience a more inflammatory disease course than patients with adult onset of the disease.

Alterations of the human gut microbiome in multiple sclerosis.

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.