Jaine Ls Soares1, Enedina Ml Oliveira2, Alessandra Pontillo3. 1. Laboratorio de Imunogenetica, Departamento de Imunologia, Instituto de Ciencias Biomédicas (ICB), Universidade de Sao Paulo (USP). Avenida Professor Lineu Prestes 1730, Sao Paulo, Brazil. 2. Ambulatório de Doenças Desmielinizantes, Departamento de Neurologia e Neurocirurgia, Universidade Federal de Sao Paulo (UNIFESP). Rua Pedro de Toledo 650, Sao Paulo, Brazil. 3. Laboratorio de Imunogenetica, Departamento de Imunologia, Instituto de Ciencias Biomédicas (ICB), Universidade de Sao Paulo (USP). Avenida Professor Lineu Prestes 1730, Sao Paulo, Brazil. Electronic address: alepontillo@usp.br.
Abstract
BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease of central nervous system (CNS) with autoimmune and inflammatory characteristics, and a still uncertain pathogenesis. Early events as well as evolution of MS are heterogeneous (three main clinical forms) and multifactorial. Genome-wide association studies indicate that MS pathogenesis shares features with both autoimmune and inflammatory diseases. Innate immunity has been recently proved to be an important factor in MS. Genetic variants in inflammasome components have been associated with both autoimmune and neurodegenerative diseases, letting us hypothesize that inflammasome, and related cytokines IL-1ß and IL-18, could represent important contributors in MS pathogenesis, and eventually explain, at least in part, the heterogeneity observed in MS patients. AIM: To evaluate the contribution of inflammasome in MS, in term of (a) genetic effect on development, severity and/or prognosis, and (b) complex activation in peripheral blood as a measure of systemic inflammation. METHODS: Functional genetic variants in inflammasome components were analyzed in a cohort of MS patients, by the use of allele-specific assays and qPCR. Multivariate analysis was performed based on clinical form (recurrent remittent/RR, primary progressive/PP or secondary progressive/SP), severity index (EDSS) and progression index (PI), response to IFN-ß treatment. Peripheral blood monocytes (PBM) of patients were examined for inflammasome activation and expression profile. RESULTS AND DISCUSSION: Variants associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls, suggesting a protective role of diminished IL-18-mediate inflammation in MS development. On the other hands, gain-of-function variants in NLRP3 (Q705K) and IL1B (-511 C >T) associated with severity and progression of MS, suggesting that a constitutive activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation. Accordingly, -511C >T SNP resulted more frequent in progressive forms than in RR MS, reinforcing the idea that increased inflammasome activation characterized bad prognosis of MS. Altogether these findings corroborate previous data about the harmful role of NLRP3 inflammasome in experimental autoimmune encephalitis (EAE). Moreover, we reported for the first time the beneficial effect of NLRC4 rs479333 G >C variant in MS progression and in the response to IFN-ß treatment. This intronic polymorphism have been previously associated to decreased NLRC4 transcription and low IL-18 serum level, indicated once more that less activation of inflammasome and IL-18 production are beneficial for MS patients. PBM analysis showed that MS cells express higher level of inflammasome genes than HD ones, and are more prone to respond to a classical NLRP3 stimulus than HD.
BACKGROUND:Multiple sclerosis (MS) is a neurodegenerative disease of central nervous system (CNS) with autoimmune and inflammatory characteristics, and a still uncertain pathogenesis. Early events as well as evolution of MS are heterogeneous (three main clinical forms) and multifactorial. Genome-wide association studies indicate that MS pathogenesis shares features with both autoimmune and inflammatory diseases. Innate immunity has been recently proved to be an important factor in MS. Genetic variants in inflammasome components have been associated with both autoimmune and neurodegenerative diseases, letting us hypothesize that inflammasome, and related cytokines IL-1ß and IL-18, could represent important contributors in MS pathogenesis, and eventually explain, at least in part, the heterogeneity observed in MS patients. AIM: To evaluate the contribution of inflammasome in MS, in term of (a) genetic effect on development, severity and/or prognosis, and (b) complex activation in peripheral blood as a measure of systemic inflammation. METHODS: Functional genetic variants in inflammasome components were analyzed in a cohort of MS patients, by the use of allele-specific assays and qPCR. Multivariate analysis was performed based on clinical form (recurrent remittent/RR, primary progressive/PP or secondary progressive/SP), severity index (EDSS) and progression index (PI), response to IFN-ß treatment. Peripheral blood monocytes (PBM) of patients were examined for inflammasome activation and expression profile. RESULTS AND DISCUSSION: Variants associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls, suggesting a protective role of diminished IL-18-mediate inflammation in MS development. On the other hands, gain-of-function variants in NLRP3 (Q705K) and IL1B (-511 C >T) associated with severity and progression of MS, suggesting that a constitutive activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation. Accordingly, -511C >T SNP resulted more frequent in progressive forms than in RR MS, reinforcing the idea that increased inflammasome activation characterized bad prognosis of MS. Altogether these findings corroborate previous data about the harmful role of NLRP3 inflammasome in experimental autoimmune encephalitis (EAE). Moreover, we reported for the first time the beneficial effect of NLRC4rs479333 G >C variant in MS progression and in the response to IFN-ß treatment. This intronic polymorphism have been previously associated to decreased NLRC4 transcription and low IL-18 serum level, indicated once more that less activation of inflammasome and IL-18 production are beneficial for MS patients. PBM analysis showed that MS cells express higher level of inflammasome genes than HD ones, and are more prone to respond to a classical NLRP3 stimulus than HD.
Authors: Enrique González-Madrid; Ma Andreina Rangel-Ramírez; María José Mendoza-León; Oscar Álvarez-Mardones; Pablo A González; Alexis M Kalergis; Ma Cecilia Opazo; Claudia A Riedel Journal: Int J Mol Sci Date: 2022-06-25 Impact factor: 6.208
Authors: Haritha L Desu; Melanie Plastini; Placido Illiano; Helen M Bramlett; W Dalton Dietrich; Juan Pablo de Rivero Vaccari; Roberta Brambilla; Robert W Keane Journal: J Neuroinflammation Date: 2020-05-04 Impact factor: 8.322