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Anti-inflammatory therapies of amyotrophic lateral sclerosis guided by immune pathways.

ABSTRACT: Sporadic ALS patients display heterogeneous immune pathways in peripheral blood mononuclear cells (PBMCs). We tested nine sALS patients and one unaffected identical twin of an index case by RNA-Seq of PBMCs. The inflammatory patients (n = 3) clustered into a subset with an inflammatory Th1/Th17 signature and the non-inflammatory patients (n = 7) into another subset with a B cell signature. The inflammatory subset was remarkable for granulocyte and agranulocyte diapedesis, hepatic fibrosis, roles of cytokines and metalloproteases. The non-inflammatory subset was highlighted by degradation of vitamin E, serotonin and nucleotides, altered T cell and B cell signaling, agranulocyte diapedesis, and up regulation of B cell genes. Identification of these differentially regulated pathways in sALS patients may guide the choice of anti-inflammatory therapies.

SUBMITTER: Lam L

PROVIDER: S-EPMC4700124 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Anti-inflammatory therapies of amyotrophic lateral sclerosis guided by immune pathways.

Lam Larry L Halder Ramesh C RC Montoya Dennis J DJ Rubbi Liudmilla L Rinaldi Arturo A Sagong Bien B Weitzman Sarah S Rubattino Rachel R Singh Ram Raj RR Pellegrini Matteo M Fiala Milan M

American journal of neurodegenerative disease 20151228 2

Sporadic ALS patients display heterogeneous immune pathways in peripheral blood mononuclear cells (PBMCs). We tested nine sALS patients and one unaffected identical twin of an index case by RNA-Seq of PBMCs. The inflammatory patients (n = 3) clustered into a subset with an inflammatory Th1/Th17 signature and the non-inflammatory patients (n = 7) into another subset with a B cell signature. The inflammatory subset was remarkable for granulocyte and agranulocyte diapedesis, hepatic fibrosis, roles ...[more]

PMID: 26807342

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Project description:Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder with typical onset in the 5th- 6th decade of life. The hypothesis of an autoimmune origin of ALS receives less attention today, but immunological phenomena still seem to be involved and mechanisms such as protective autoimmunity may be important. Detection of antibodies against a variety of gangliosides has been repeatedly described in ALS-patients by several authors, but widely differing frequencies and titres have been reported. Therefore, we investigated the presence of six common antibodies with a commercially available test panel for GA1, GM1, GM2, GD1a, GD1b and GQ1b in a large group of clinically well-characterized ALS patients and compared them to a collective of 200 healthy blood donors.IgG and IgM antibodies to the six gangliosides asialoGM1 (GA1), GM1, GM2, GD1a, GD1b, GQ1b were determined by GanglioCombi ELISA in sera of 84 ALS patients. Results were expressed as a %-ratio of a highly positive control and categorized as negative (<30%), borderline (30-50%), moderately (50-100%) and strongly positive (>100%). The values obtained from 200 Swiss blood donors served as a reference group.In twenty-two (26.2%) ALS-patients elevated anti-ganglioside antibodies could be detected: Taking all subspecific antibodies together, IgG antibodies were found in 9/84 (10.7%) and IgM in 15/84 (17.9%) patients. There was no correlation between age, gender, site of onset or survival and anti-ganglioside-positive/-negative titres in ALS-patients. No statistically significant difference in the frequency of anti-ganglioside antibodies compared to the group of healthy blood donors was found.Even with this more comprehensive approach, anti-ganglioside antibody frequencies and patterns in our ALS cohort closely resembled the values measured in healthy controls. In accordance with other studies, we did not observe any association of a distinct ALS phenotype with elevated anti-ganglioside antibodies or an impact on survival.

Project description:BackgroundAmyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND.ObjectivesTo assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment.Search methodsOn 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies.Selection criteriaWe planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally.Data collection and analysisWe followed standard Cochrane methodology.Main resultsNo studies were eligible for inclusion in the review. We identified four ongoing trials.Authors' conclusionsCurrently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.

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Anti-inflammatory therapies of amyotrophic lateral sclerosis guided by immune pathways.

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Anti-inflammatory therapies of amyotrophic lateral sclerosis guided by immune pathways.

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