Rodriguez, Moses

OBJECTIVES: To describe the demographic and clinical characteristics of pediatric multiple sclerosis (MS) in the United States. METHODS: This prospective observational study included children and adolescents with MS. Cases were evaluated across 9 geographically diverse sites as part of the US Network of Pediatric MS Centers. RESULTS: A total of 490 children and adolescents (324 girls, 166 boys) were enrolled; 28% developed symptoms before 12 years of age. The proportion of girls increased with age from 58% (<12 years) to 70% (≥12 years). Race and ethnicity as self-identified were: white, 67%; African American, 21%; and non-Hispanic, 70%. Most (94%) of the cases were born in the United States, and 39% had 1 or both foreign-born parents. Fifty-five percent of cases had a monofocal presentation; 31% had a prodrome (most frequently infectious), most often among those aged <12 years (P < .001). Children aged <12 years presented more commonly with encephalopathy and coordination problems (P < .001). Sensory symptoms were more frequently reported by older children (ie, those aged ≥12 years) (P < .001); 78% of girls had MS onset postmenarche. The initial Expanded Disability Status Scale score for the group was <3.0, and the annualized relapse rate was 0.647 for the first 2 years. Interval from symptom onset to diagnosis and from diagnosis to initiation of disease-modifying therapy was longer among those <12 years of age. CONCLUSIONS: Pediatric MS in the United States is characterized by racial and ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features and timing of treatment among those <12 years of age compared with older children.

Abstract The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood–brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1β/IL-6high), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35–55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35–55–primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4+ T cells were due to an autocrine effect of IL-1β/IL-23–mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype–Th17 axis in an animal model of multiple sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurologic disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurologic deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurologic function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurologic disease, we propose the IgM may act late in the cascade of neuronal stress and/or death by a broad mechanism.

AbstractCNSregeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long‐term prognosis in patients. Approachable molecular targets that stimulateCNSrepair are not part of the clinical praxis or have not been identified yet. The purpose of this study was to identify the molecular target of the human monoclonal antibodyHIgM12.HIgM12 reverses motor deficits in chronically demyelinated mice, a model ofMS. Here, we identified polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) as the antigen forHIgM12 by using differentNCAMknockout strains and throughPSAremoval from theNCAMprotein core. Antibody binding toCNStissue and primary cells, antibody‐mediated cell adhesion, and neurite outgrowth onHIgM12‐coated nitrocellulose was detected only in the presence ofPSAas assessed by western blotting, immunoprecipitation, immunocytochemistry, and histochemistry. We conclude thatHIgM12 mediates it'sin vivoandin vitroeffects through binding toPSAand has the potential to be an effective therapy forMSand neurodegenerative diseases.imageThe human antibody HIgM12 stimulates neurite outgrowthin vitroand promotes function in chronically demyelinated mice, a model of multiple sclerosis. The cellular antigen for HIgM12 was undetermined. Here, we identified polysialic acid attached to NCAM (neural cell adhesion molecule) as the cellular target for HIgM12. This includes glial fibrillary acidic protein (GFAP)‐positive mouse astrocytes (GFAP, red; HIgM12, green; DAPI, blue) among other cell types of the central nervous system. These findings indicate a new strategy for the treatment of neuro‐motor disorders including multiple sclerosis.

There is currently an urgent need for a viable, cheap, and readily available treatment for the Ebola virus outbreak in West Africa. Here, it is proposed that melatonin may have significant utility in helping the management of this outbreak. Optimizing natural killer (NK) cell responses seems crucial to surviving Ebola virus infection. Melatonin increases NK cell cytotoxicity significantly, suggesting efficacy in managing the Ebola virus. Under conditions of challenge, melatonin increases heme oxygenase‐1 (HO‐1), which inhibits Ebola virus replication. Melatonin also has protective effects in cases of septic shock, which, although bacterial, has similar end‐point presentations involving blood vessel leakage. Melatonin's effects on haemorrhage are mediated primarily by a decrease in pro‐inflammatory cytokines. By optimizing the appropriate immune response, melatonin is likely to afford protection to those at high risk of Ebola viral infection, as well as having direct impacts on the course of infection per se. Although no direct data pertain to the utility of melatonin in the management of the Ebola virus, convergent bodies of data suggest its utility, which is reviewed in this article. J. Med. Virol. 87:537–543, 2015. © 2015 Wiley Periodicals, Inc.