| Background and Objectives:Neuromyelitis optica(NMO)is an autoimmune inflammatory demyelinating disease in the central nervous system(CNS),mostly involving optic nerve and spinal cord,mainly mediated by humoral immunity and also involving cellular immunity.With the development of research,NMO has been found to have more clinical features.In 2007,Wingerchuk et al put forward the concept of neuromyelitis optica spectrum disorder(NMOSD).In 2015,the International panel for NMO diagnosis(IPND)formally formulated a new diagnostic standard for NMOSD,integrating NMO into the broader category of NMOSD.Cytokines are a a group of small proteins involved in immune regulation,and often play important roles in the initiation,propagation,or regulation of autoimmune injury.In recent years,there have been more and more researches on the relationships between cytokines and NMOSD.A large number of studies have shown that various cytokines play important roles in the immune pathogenesis and immunomodulation of NMOSD.Some of these cytokines have the potential to be an effective way to find new therapeutic targets for NMOSD and useful biomarkers to predict the changes of NMOSD.Interleukin-38(IL-38)is a newly discovered cytokine member of IL-1 family inrecent years.It can be expressed in a variety of tissues and cells,such as skin,thymus,spleen,brain and in proliferating B cells of the tonsil.IL-38 can bind to IL-36 R and inhibit the pro-inflammatory function of the three agonist ligands IL-36α,IL-36β,and IL-36γ.In addition,it has been demonstrated that IL-38 can also affect the function of Th17 and reduce the expression of Th17 related cytokines such as IL-17 and IL-22,thus playing an anti-inflammatory effect to some extent.Recent studies have shown that IL-38 is associated with systemic lupus erythematosus(SLE),rheumatoid arthritis(RA),psoriasis and other autoimmune diseases.However,the role of IL-38 in NMOSD is still not very clear.Interleukin-39(IL-39)is the most recently discovered member of the IL-12 cytokine family and is composed of the IL-23p19 alpha subunit and EBi3 beta subunit.In 2016,Wang et al.found that IL-39 can be secreted by LPS-stimulated B cells and GL7(+)-activated B cells of lupus-like mice and might contribute to the immunopathogenic mechanisms of systemic lupus erythaematosus(SLE).At present,there is no data on the role of IL-39 in NMOSD.In this study,we measured the levels of serum IL-39 and IL-38 during the different stages of NMOSD patients and healthy controls,and analysed the correlations between these two newly recognized cytokines and clinical parameters of NMOSD to explore the possible roles of these two cytokines in the pathogenesis of NMOSD,thus providing further theoretical bases for the immunotherapy and disease prediction of NMOSD.Materials and Methods:Thirty-two patients with NMOSD were enrolled in the study in the neurology department of our hospital from October in 2016 to October in 2018,with their serum samples in different stages collected.There are 27 females and 5 males in these patients.The average age is(39.56±13.83)years,ranging from 18 to 69 years.All of these NMOSD patients were selected by two or more neurologists in our hospital,receiving detailed medical history enquiries and illness evaluation.All of them received specialized examination of nervous system,imaging examination of nervous system,laboratory examination and electrophysiological examination.All thediagnoses were in accordance with the diagnostic criteria of NMOSD developed by the International NMO Diagnostic Group(IPND)in 2015.Twenty-two healthy volunteers constituted the control group,including 18 females and 4 males,with an average age of(39.86 ±13.76)years,All of these volunteers in the control group were excluded from autoimmune disease history,allergic disease history and recent infection history,and their blood routine examination,liver and kidney function and other routine tests were all in the normal range.There were no statistically significant differences in age and sex between the experimental group and the control group.All patients and healthy volunteers need to be fasting before blood drawing more than 10 hours.All the subjects are drawn venous blood 3 ml from elbow by using vacuum blood vessel without anticoagulant the next morning.After staying in the room 1 to 2 hours,the supernatant was centrifuged and packed in EP tube,then placed in the refrigerator at-80 ℃.NMOSD patients’ venous blood samples were collected in the acute phase(onset 1 to 14 days,before using hormone or gamma globulin)and in the remission phase(30-60 days after initial remission).Healthy volunteers were collected blood samples only once.All NMOSD patients enrolled in the acute and remission phase were evaluated the severity and degree of disability by using Expanded Disability Status Scale(EDSS)scores.The involved lesions in the central nervous system of NMOSD patients were assessed by the magnetic resonance imaging(MRI).The serum AQP-4 antibody titres were detected by Cell-based immunofluorescence assay(CBA).The serum levels of IL-38 and IL-39 were measured using double-antibody sandwich enzyme-linked immunosorbent assay(ELISA).The relationships between the levels of these two cytokines and the severity of the disease,the recurrence rate of the disease and other clinical indicators were analyzed.All data was statistically analyzed by using SPSS 24.0.The results were expressed as mean ±standard deviation or median(P25 / P75).According to the specific applicable conditions,analysis of variance,Student’s t-test,paired t-test,Kruskal-Wallis or Mann-Whitney U test were used to analyze the differences in different sample groups.Values were considered statistically significant at P < 0.05.Results:1.Comparison of serum IL-38 levels among NMOSD group in acute phase,remission phase and healthy control group: The serum levels of IL-38 in the acute phase(17.60 ±9.57)pg/ml were higher than those in the healthy control group(7.56 ±1.59)pg/ml,P < 0.001.The serum levels of IL-38 in the remission phase(19.61 ±10.35)pg/ml were slightly higher than those in the acute phase,P = 0.002.2.Comparison of serum IL-39 levels among NMOSD group in acute phase,remission phase and healthy control group: The serum levels of IL-39 in the acute phase(36.25 ±16.90)pg/ml were significantly higher than those in the healthy control group(8.70 ±2.04)pg/ml,P < 0.001.The serum levels of IL-39 in the remission phase(25.36 ±12.02)pg/ml were significantly decreased compared with these in the acute phase,while still higher than these in the healthy control group.3.Correlation analyses between serum IL-39 or IL-38 levels and clinical features in NMOSD,including corresponding EDSS scores,annual relapse rate(ARR),total length of spinal cord lesions and AQP4 antibody titers:(1)Serum IL-39 levels were positively correlated with corresponding EDSS scores in acute phase and remission phage,the differences were statistically significant(r = 0.785,P < 0.01;r = 0.853,P < 0.01);serum IL-38 levels in acute and remission phage were negatively correlated with the corresponding EDSS scores,the differences were statistically significant(r =-0.887,P < 0.01;r =-0.630,P < 0.01);serum IL-39 levels and the corresponding EDSS scores in the patients with first attack of NMOSD were further analyzed,the results were still positively correlated(r = 0.755,P < 0.01;r = 0.741,P < 0.01);serum IL-38 levels and the corresponding EDSS scores in the patients with first attack of NMOSD were also further analyzed,the results were negatively correlated(r =-0.935,P < 0.01;r =-0.824,P < 0.01).(2)There were no significant correlations between serum IL-39 levels and ARR in the acute and remission phase(r = 0.308,P = 0.086;r = 0.350,P = 0.050);the serum IL-38 levels were negatively correlated with the ARR in the acute and remission phase,the differences were statistically significant(r =-0.725,P < 0.01;r =-0.647,P < 0.01);serum IL-39 levels were positively correlated with the total length of newly identified spinal cord lesions at sampling(r = 0.722,P < 0.01),while there was no significant correlation between serum IL-39 levels and AQP4 antibodytitres(r = 0.165,P = 0.367);there were no significant correlations between serum IL-38 levels and total length of newly identified spinal cord lesions or AQP4 antibody titres in the NMOSD patients(r = 0.325,P = 0.069;r = 0.106,P = 0.565). |
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