Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Myeloid-derived cells play important modulatory and effector roles in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, composed of monocytic (MO) and polymorphonuclear (PMN) fractions, which can suppress T cell activities in EAE. Their role in MS remains poorly characterized. We found decreased numbers of circulating MDSCs, driven by lower frequencies of the MO-MDSCs, and higher MDSC expression of microRNA miR-223 in MS versus healthy subjects. To gain mechanistic insights, we interrogated the EAE model. MiR-223 knock out (miR-223 12/ 12) mice developed less severe EAE with increased MDSC numbers in the spleen and spinal cord compared to littermate controls. MiR-223 12/ 12 MO-MDSCs suppressed T cell proliferation and cytokine production in vitro and EAE in vivo more than wild-type MO-MDSCs. They also displayed an increased expression of critical mediators of MDSC suppressive function, Arginase-1(Arg1), and the signal transducer and activator of transcription 3 (Stat3), which herein, we demonstrate being an miR-223 target gene. Consistently, MDSCs from MS patients displayed decreased STAT3 and ARG1 expression compared with healthy controls, suggesting that circulating MDSCs in MS are not only reduced in numbers but also less suppressive. These results support a critical role for miR-223 in modulating MDSC biology in EAE and in MS and suggest potential novel therapeutic applications

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

Background: Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients. Objective: To phenotypically characterize circulating leukocytes in DMF-treated MS patients. Methods: Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients (n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MS patients (n = 17) and healthy controls (n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients. Results: Lymphopenic DMF-treated patients had significantly fewer circulating CD8+ and CD4+ T cells, CD56dim natural killer (NK) cells, CD19+ B cells and plasmacytoid dendritic cells when compared to controls. CXCR3+ and CCR6+ expression was disproportionately reduced among CD4+ T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56hi NKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of na\uefve T cells compared to the controls. Conclusions: DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of na\uefve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had a disproportionate loss of CD8+ T-cells, which may affect their immunocompetence

Rituximab in refractory Vogt–Koyanagi–Harada disease

IntroductionVogt–Koyanagi–Harada (VKH) prognosis depends on early recognition and treatment; chronic disease may be developed when either delayed or inadequate treatment is performed, whereas other cases despite correct treatment are refractory to different drugs and also become chronic. We report a case of refractory VKH controlled with rituximab treatment.Case reportA 41-year-old female with painful visual loss and headache was examined. (VA 0.4 in RE and hand movements (HM) in LE). Retinal examination demonstrated multiple serous retinal detachments in both eyes. High-dose oral steroids were started, followed by progressive tapering of prednisone. New acute anterior and posterior relapses were achieved, and other immunommodulators were progressively added—new high-dose steroid treatment, adalimumab, cyclosporine, and methotrexate—but patient had new anterior and posterior recurrences associated with tinnitus and headache. Thus, an infusion of 1 g of rituximab was administered after 15 months follow-up; the VA was 0.2 in RE and counting fingers in LE. Three additional doses of 1 g each were administered 1, 6, and 16 months later. We have achieved a final VA after 34 months follow-up of 0.2 in RE and HM in LE, with definitive control of inflammation, without acute relapses since rituximab was administered.ConclusionAfter searching PubMed/Medline, this is the first report of VKH disease treated with rituximab. Additional studies are warranted to confirm the efficacy of this new approach for inflammatory control in refractory cases of VKH disease

Interactive Exhibits for Geophysical Education: Uncovering the Secrets of the Earth

The Educational & Outreach Group of the Istituto Nazionale di Geofisica e Vulcanologia (INGV, Rome, Italy) designed a portable museum to bring on the road educational activities focused on the understanding of geomagnetism, plate tectonics, seismology and seismic hazard. Here the main experiments, models and exhibits which have been successfully installed in Genoa for the Science Festival (2003, 2004) and in Rome (2005) with enthusiastic audience participation are shown.Published375-3815.8. TTC - Formazione e informazioneN/A or not JCRope

The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis

The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Genomic Regions Associated with Multiple Sclerosis Are Active in B Cells

More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis

Interactive Exhibits for Geophysical Education: Uncovering the Secrets of the Earth

The Educational & Outreach Group of the Istituto Nazionale di Geofisica e Vulcanologia (INGV, Rome, Italy) designed a portable museum to bring on the road educational activities focused on the understanding of geomagnetism, plate tectonics, seismology and seismic hazard. Here the main experiments, models and exhibits which have been successfully installed in Genoa for the Science Festival (2003, 2004) and in Rome (2005) with enthusiastic audience participation are shown

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses