The Clinical Significance Of Correlation Between Serum TL1A And DcR3 Levels Of Neuromyelitis Optica Spectrum Disorders

Background and objectiveNeuromyelitis Optica(NMO),also known as Devic’s disease,is an inflammatory demyelinating disease of the central nervous system that is dominated by humoral immunity and cellular immunity.It is different from multiple sclerosis(MS)cause of the Serum aquaporin-4 immunoglobulin G antibody(AQP4-IgG)is involved.In 2015,the International NMO Diagnostic Group(IPND)revised the diagnostic criteria to define the unified term optic neuromyelitis spectrum diseases(NMOSD).Its clinical features include optic neuritis,acute myelitis,Posterior medullary region syndrome,and acute brainstem syndrome,acute intercranial syndrome and cerebral syndrome.Common in Asian population;to the female is more common,younger onset age and higher recurrence.TL1A is a member of the tumor necrosis factor-like ligand 1 family,also known as vascular endothelial growth inhibitor(VEGI)-251,is a type II transmembrane protein.The expression of TL1A in humans is mainly produced by stimulation of Toll-like receptor(TLR)ligands and pro-inflammatory cytokines such as TNF-α,IL-1 and PMA.The receptor of TL1A is death receptor 3(DR3),mainly expressed on activated lymphocytes,it enhances the reactivity of TCR-stimulated T cells’ to IL-2 and IL-15,and interacts with IL-12 and IL-15.And synergistically acted with IL-12 and IL-18,hereby increasing the expression of IFN-γ in T cells and NK cells.In addition,the co-stimulation of TL1A/DR3 signals can enhance the differentiation and proliferation of B cells,Th1,Th2,Treg and Th17 cells,and the secretion of cytokines such as IL-17 and IL-23.Enhanced proinflammatory action and t-cell immune response in the target organs of autoimmune and inflammatory diseases in which T cells are involved.DcR3 is a soluble decoy receptor that neutralizes the biological functions of three members of the tumor necrosis factor superfamily(TNFSF):Fas ligand(FasL),LIGHT and TL1A.In addition to its "bait" function,recombinant DcR3 can also regulate the activation and differentiation of dendritic cells(DC)and macrophages through a "non-bait" effect.DcR3-treated DCs differentiated T cells into a Th2 phenotype,while DcR3-treated macrophages exhibited an M2 phenotype.DcR3 is upregulated in various cancer cells and several inflammatory tissues,considered as a potential biomarker that limits the progression of inflammatory diseases and cancer metastasis.At present,its role in NMOSD has not been studied.The biomarker potential of TL1A and DcR3 in a variety of autoimmune and inflammatory diseases such as asthma,multiple sclerosis,systemic lupus erythematosus,inflammatory bowel disease,rheumatoid arthritis(RA),and psoriasis has been extensively studied.This study investigated the role of two cytokines in the pathogenesis of NMOSD by measuring the serum concentrations of TL1A and DcR3 in patients with acute and remission phase of NMOSD,and analyzing the clinical indicators of the remaining patients with NMOSD.Treatment provides a theoretical basis.Materials and MethodsThirty-two serum specimens of patients with NMOSD who were hospitalized in the Department of Neurology,the First Affiliated Hospital of Zhengzhou University from September 2017 to January 2020 were collected.Among these 32 specimens,27 were female,5 were male,and the average age was(37.78±16.60)years old.Clinical symptoms at the time of the onset included 9 cases of optic neuritis,17 cases of acute myelitis,3 cases of posterior medullary region syndrome,1 case of myelitis with optic neuritis,and 3 cases of dizziness and headache.All selected patients with NMOSD collected 3ml of peripheral blood and serum samples during the acute phase and remission phase and reserved them.They were asked by our neurologist for detailed medical history and disease process,neurological examination,imaging examination,laboratory examination and Electrophysiological detection.And in line with the latest NMOSD diagnostic criteria developed by IPND in 2015.For the control group,26 healthy volunteers(Healthy Control,HC)who were inpatient and outpatient in our hospital at the same time were selected.There were 17 females and 9 males.None of the selected healthy volunteers had a recent history of surgery and immunotherapy,and all autoimmune diseases,allergic diseases and recent infectious diseases have been ruled out.All routine tests such as blood routine and liver and kidney function are within the normal range.All enrollees were fasted for more than ten hours before collection,and 3 ml of venous blood in the elbow was collected through an anticoagulant-free blood collection tube.After standing,they were centrifuged,and the supernatant was dispensed in EP tubes and placed in a-80℃ refrigerator for later use.NMOSD patients blood samples were collected at the acute phase(within 2 weeks of onset and not receiving large dose methylprednisolone or intravenous immunoglobulin treatment)and remission phase(2-6 months after initial remission).Expanded Disability Status Scale(EDSS)scores of selected NMOSD patients in the acute phase and remission phase are used to evaluate the severity and change of the disease,and corresponding laboratory tests(such as CBA method to detect AQP-4 antibodies and ELASA method to detect corresponding autoimmune antibodies)and inspection methods(including nuclear magnetic resonance,CT,etc.),the use of double antibody sandwich enzyme-linked immunosorbent assay(ELISA)to detect serum samples in each group TL1A and DcR3 levels,and analyze the changes in the levels of these two cytokines in each group and their correlation with disease severity,clinical indicators,etc.Statistical analysis was performed using SPSS24.0.The measurement data were expressed as mean±standard deviation,and single-factor analysis of variance or Kruskal-Wallis was used to compare multiple sets of quantitative data.LSD-t test or Bonferroni method was used for comparison between groups,and paired t test was used to compare paired data.Correlation analysis was performed using Pearson or Spearman correlation coefficients.Measurement data for non-normal distributions are expressed as median(P25,P75),and nonparametric tests are used for comparison between groups.Count data is expressed as the number of cases.Fisher exact probability test or chi-square test is used for comparison between groups.The test level is set to 0.05.Results1.Comparison of serum TL1A levels in NMOSD acute group,remission group and HC groupSerum TL1A levels in the NMOSD acute phase group,remission phase group,and healthy control group were(45.73 ±15.02)ng/L,(27.73 ±10.50)ng/L,and(23.77±11.74)ng/L.The acute phase group was significantly higher than the remission stage group and HC group,and the difference was statistically significant(P<0.001,P<0.001).2.Comparison of serum DcR3 levels in NMOSDs acute group,remission group and HC groupThe serum DcR3 levels of the NMOSD in the acute phase group,the remission phase group and the healthy control group were(974.77±592.66)pg/ml,(306.53 ±146.07)pg/ml,and(261.41±104.61)pg/ml.The acute phase group was significantly higher than the remission stage group and HC group,and the difference was statistically significant(p<0.001,p<0.001).3.Comparison of serum TL1A level,DcR3 level,and EDSS score in NMOSD acute group and remission groupCorrelation analysis between serum TL1A level and group serum DcR3 level in the acute phase of NMOSD and EDSS score,the results showed that there was a positive correlation,and the difference was statistically significant(r=0.730,p<0.001).There was no significant correlation between DcR3 level and EDSS score,and the difference was not statistically significant(r=0.231,p=0.203).4.Correlation analysis between serum TL1A level and serum DcR3 in NMOSD acute group and remission groupCorrelation analysis between serum TL1A level and serum DcR3 level in patients with NMOSD in acute phase and remission phase showed that there was a positive correlation between serum TL1A level and serum DcR3 level in the acute phase group,with a significant difference(r=0.804,p<0.001).And there was no significant correlation between serum TL1A level and serum DcR3 level in the NMOSD remission group(r=0.286,p=0.113).Conclusion1.The level of TL1A in patients with NMOSD in the acute phase is higher than that in the remission phase and the control group.The EDSS score is positively correlated,and there is no significant difference with the patients in the NMOSD remission phase compared with the control group.Therefore,TL1A is expected to be a biomarker for observing the severity of patients in the acute stage.2.The DcR3 level in patients with NMOSD in the acute phase was significantly higher than those in the remission phase and the control group.However,there was no significant correlation between serum DcR3 levels and EDSS scores in patients with NMOSD.On the contrary,it may play a role in limiting the reactions and protecting the body.3.Serum DcR3 and TL1A in patients with acute phase showed a significant positive correlation,suggesting that the inflammatory response of patients with NMOSD in the acute phase may inhibit the inflammatory response through the TL1A/DcR3 signalling pathway,which inhibits the expansion of local inflammatory response.Therefore,DcR3 is expected to become a new targeted therapeutic drug for reducing nerve damage in patients with acute stage.