Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: A pilot study

Pathogenesis of autoimmune disorders, including multiple sclerosis (MS), has been linked to an alteration of the resident microbial commensal community and of the interplay between the microbiota and the immune system. Dietary components such as fiber, acting on microbiota composition, could, in principle, result in immune modulation and, thus, could be used to obtain beneficial outcomes for patients. We verified this hypothesis in a pilot study involving two groups of clinically similar relapsing-remitting (RR) MS patients who had undergone either a high-vegetable/low-protein diet (HV/LP diet group; N = 10) or a "Western Diet" (WD group; N = 10) for at least 12 months. Gut microbiota composition, analyzed by 16 S V4 rRNA gene sequencing and immunological profiles, was examined after a minimum of 12 months of diet. Results showed that, in the HV/LP diet group compared to the WD group: (1) Lachnospiraceae family was significantly more abundant; (2) IL-17-producing T CD4+ lymphocytes (p = 0.04) and PD-1 expressing T CD4+ lymphocytes (p = 0.0004) were significantly decreased; and (3) PD-L1 expressing monocytes (p = 0.009) were significantly increased. In the HV/LP diet group, positive correlations between Lachnospiraceae and both CD14+/IL-10+ and CD14+/TGF\uce\ub2+monocytes (RSp= 0.707, p = 0.05, and RSp= 0.73, p = 0.04, respectively), as well as between Lachnospiraceae and CD4+/CD25+/FoxP3+ T lymphocytes (RSp= 0.68, p = 0.02) were observed. Evaluation of clinical parameters showed that in the HV/LP diet group alone the relapse rate during the 12 months follow-up period and the Expanded Disability Status Scale score at the end of the study period were significantly reduced. Diet modulates dysbiosis and improves clinical parameters in MS patients by increasing anti-inflammatory circuits. Because Lachnospiraceae favor Treg differentiation as well as TGF\uce\ub2 and IL-10 production this effect could be associated with an increase of these bacteria in the microbiota

Monosodium urate crystals activate the inflammasome in primary progressive multiple sclerosis

Inflammasome-driven inflammation is postulated to play a role in multiple sclerosis (MS), but there is no direct evidence that the nod-like receptor protein 3 (NLRP3) inflammasome is involved in MS pathogenesis. Uric acid was shown to be one of the "danger" signals involved in the activation of NLRP3 inflammasome; notably, the concentration of uric acid is increased in the serum and in the cerebrospinal fluid of MS individuals. To better investigate the role of the NLRP3 inflammasome in MS-associated inflammation, we primed with lipopolysaccharide and stimulated with monosodium urate crystals PBMCs of 41 MS patients with different disease phenotypes. Eleven individuals with primary progressive MS (PPMS), 10 individuals with stable relapsing-remitting MS (SMS), 10 individuals with acute relapsing-remitting MS (AMS), 10 individuals with benign MS were analyzed; 10 healthy controls were enrolled as well in the study. The expression of the NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1, caspase-8, IL-1\u3b2, and IL-18 inflammasome genes was evaluated by RT-PCR. NLRP3 and ASC-speck protein expression was analyzed by FlowSight AMNIS, whereas production of the pro-inflammatory cytokines IL-1\u3b2 and IL-18 and of caspase-1 and caspase-8 was measured by ELISA in supernatants. Results showed that uric acid serum concentration was significantly increased in PPMS; in these and in AMS patients, mRNA for NLRP3, ASC, and IL-18 was upregulated as well, but caspase-8 mRNA was upregulated only in PPMS. Expression of NLRP3 and ASC-speck protein was significantly increased in PPMS, SMS, and AMS patients, but IL-18 and caspase-8 production was significantly increased only in PPMS, in whom a direct correlation between hyperuricemia and caspase-8 was detected. The NLRP3/caspase-8 inflammasome pathway is activated in PPMS, possibly as a consequence of hyperuricemia. Therapeutic strategies reducing NLRP3 activation and/or lowering hyperuricemia could be useful in the therapy of PPMS

Alterations of natural killer cells activatory molecules phenotype and function in mothers of ASD children: a pilot study

IntroductionAutism spectrum disorder (ASD) is accompanied by complex immune alterations and inflammation, and the possible role played by Natural Killer (NK) in such alterations is only barely understood.MethodsTo address this question we analysed activating and inhibitory NK receptors, as well as NK cells phenotype and function in a group of mothers of children who developed ASD (ASD-MO; N=24) comparing results to those obtained in mothers of healthy children who did not develop (HC-MO; N=25).ResultsResults showed that in ASD-MO compared to HC-MO: 1) NK cells expressing the inhibitory receptor ILT2 are significantly decreased; 2) the activating HLA-G14bp+ polymorphism is more frequently observed and is correlated with the decrease of ILT2-expressing cells; 3) the CD56bright and CD56dim NK subsets are increased; 4) IFNγ and TNF production is reduced; and 5) perforin- and granzymes-releasing NK cells are increased even in unstimulated conditions and could not be upregulated by mitogenic stimulation.DiscussionResults herein reinforce the hypothesis that ASD relatives present traits similar to, but not as severe as the defining features of ASD (Autism endophenotype) and identify a role for NK cells impairment in generating the inflammatory milieu that is observed in ASD

Determinants of Disability in Multiple Sclerosis: An Immunological and MRI Study

Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity

The Role of the Inflammasome in Neurodegenerative Diseases

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1β and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases

The Role of the Inflammasome in Neurodegenerative Diseases

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1β and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases

Increased Levels of Beta-Endorphin and Noradrenaline after a Brief High-Impact Multidimensional Rehabilitation Program in Multiple Sclerosis

Finding new solutions for the management of multiple sclerosis (MS) is crucial: further research is needed to study the effect of non-pharmacological interventions on the symptoms and the course of the disease, especially on lifestyle. Benefits from a proper lifestyle are evident not only on a clinical level but also on immune and neuro-endocrine systems. A brief high-impact multidimensional rehabilitation program (b-HIPE) was proposed for a sample of people with MS (pwMS) with a medium level of disease disability. We tested the change on clinical parameters and quality of life (QoL) after participation in B-HIPE. We furthermore decided to measure beta-endorphin and catecholamines concentrations pre- and post-participation in the b-HIPE program, due to the relationship between these hormones and the immune system in neurodegenerative diseases. Our results showed that after the b-HIPE program, an improvement of clinical parameters and QoL occurred. Moreover, we found higher levels of beta-endorphin and noradrenaline after participation in the program. These findings highlight the importance of implementing lifestyle interventions in the clinical management of MS. Furthermore, we hypothesize that the B-HIPE program increased beta-endorphin and noradrenaline levels, helping to reduce the inflammation related to MS disease

Leishmania infantum infection reduces the amyloid β42-stimulated NLRP3 inflammasome activation

Activation of the NLRP3 inflammasome has been shown to play a major role in the neuroinflammation that accompanies Alzheimer’s disease (AD); interventions that down regulate the NLRP3 inflammasome could thus be beneficial in AD. Parasite infections were recently shown to be associated with improved cognitive functions in Apolipoprotein E4 (ApoE4)-expressing members of an Amazonian tribe. We verified in an in vitro model whether Leishmania infantum infection could reduce NLRP3. Results obtained in an initial experimental model in which PBMC were LPS primed and nigericin-stimulated showed that L. infantum infection significantly reduced ASC-speck formation (i.e. intracellular inflammasome proteins assembly), as well as the production of activated caspase 5 and IL-1β, but increased that of activated caspase 1 and IL-18. Moreover, L. infantum infection induced the generation of an anti-inflammatory milieu by suppressing the production of TNFα and increasing that of IL-10. These results were replicated when cells that had been LPS-primed were stimulated with Aβ42 and infected with L. infantum.. Results herein indicate that Leishmania infection favors an anti-inflammatory milieu, which includes the down-regulation of NLRP3 inflammasome activation, possibly to facilitate its survival inside host cells. A side effect of Leishmaniasis would be the hampering of neuroinflammation; this could play a protective role against AD development