Expression Level Of OX40/OX40L Co-stimulatory Molecule In The Peripheral Blood Of Asthma Patients And Its Clinical Implications

Bronchial asthma has been one of the most common chronic airway diseases atpresent. With the development of industrialization, the incidence of asthma showed arising trend and it has become a serious social health problem globally. It has beenconfirmed that the T cell is the hub of the immunoregulatory cells and play a key role inimmunological pathogenesis of bronchial asthma. Excessively activated T cells andimbalanced number and function of T helper (Th) cell subsets (Thl/Th2subsets) wereamong the most important abnormalities. A variety of T cell surface molecules wereinvolved in this complicated process.In recent years, more and more attentions have beenfocused on the OX40/OX40L co-stimulatory molecules, which are expressed on activatedCD4+Tand CD8+T cells. Studies have confirmed that CD4+T cell was central in thedevelopment and progression of bronchial asthma, and OX40/OX40L co-stimulatorysignals could promote T cell division and proliferation, as well as regulate cytokineproduction of CD4+T cells. OX40/OX40L interactions were found to play an importantrole in the development of multiple inflammatory and autoimmune diseases of the host.Recently, elevated expression of OX40/OX40L on the lymphocytes in peripheralblood of bronchial asthma patients were noticed. However, how the excessive expressionof OX40/OX40L and the increased concentration of serum sOX40L in the peripheral bloodof asthma patients participate in the promotion of immune imbalance, systemicinflammation and the exacerbation of the disease are not clear. Also their correlations withairway inflammation and clinical symptoms and severity of asthma remains to be clarified.This research project studied the expression level OX40/OX40L in the peripheral bloodand analyzed the concentration of serum sOX40L in bronchial asthma patients. We foundthat the expressions of OX40/OX40L and the serum concentrations of sOX40L weresignificantly increased in the acute exacerbation asthmatic patients and closely related with clinical indexes such as FeNO、EOS and Total IgE. The concentrations of sOX40L wasassociated with the severity of bronchial asthma, indicating that the co-stimulatory signalOX40/OX40L maybe a meaningful biomarker that reflecting the status of activation ofinflammatory cells and determining the severity of bronchial asthma. Therefore, theOX40/OX40L co-stimulatory molecules maybe play a key role in the development ofasthma and it will be a new molecular target for immunotherapeutics in bronchial asthma.Objective To detect the expression level of co-stimulatory molecules OX40/OX40Lin peripheral blood lymphocytes and the serum concentrations of sOX40L in bronchialasthma patients and explore their clinical implications.Methods Thirty-one male and thirty-four female bronchial asthma patients in theacute exacerbation aged16-70(mean age44.1±14.38years),who were newly diagnosed orin his/her first visit to hospital without previous regular treatment,were selected fromoutpatients at the Department of Respiratory Diseases in the Second Affiliated Hospital ofSoochow University from November2011to June2012(acute exacerbation group).Twentycases were complicated with allergic rhinitis and fifteen cases who had a long-term historyof smoking. All the asthma patients met the diagnostic criteria established by the Chinesemedical association in2008and the Global initiative for Asthma (GINA) asthma(2010).The asthma patients in acute exacerbation group were divided into four subgroupsaccording to the clinical symptoms and sign,as follows:mild (15cases), moderate (33cases), severe (17cases), extemely severe (0case).Thirty healthy volunteers fromHealthcare Center of the hospital including11male and19female, aged20-60(40.50±10.84years), were enrolled as control(control group).There was no statistical difference (P>0.05) in age and gender between the three groups.Expressions of OX40/OX40L on T lymphocytes, B lymphocytes and monocytes inperipheral mononuclear cells (PBMCs) before and after treatment were measured by flowcytometry in sixty-five acute exacerbation asthmatic patients group(all with positivebronchial dilation test(BDT),and30healthy controls. Pulmonary function test,asthmacontrol test (ACT score) score, eosinophil(EOS), total IgE and level of fractionatedexhaled nitric oxide(FeNO)of acute asthmatic patients were measured as well at the sametime.The serum concentration of sOX40L of all the participator was determined by enzymelinked immunosorbent assay(ELISA). The expression level of OX40/OX40L,serumconcentrations of sOX40L, the change of FEV1%, EOS, FeNO, IgE and ACT score were retested during the follow-up when the aboved-mentioned patients have resumed to theirstable stage(remission group)and the data were compared to those in acute exacerbation.Results1.The expressions of CD4+OX40+、CD14+OX40L+、CD19+OX40L+onlymphocytes in peripheral blood of acute exacerbation asthmatic patients were higher thanthose in the remission group(all P<0.05) and healthy control group(all P<0.01).In theremission group their expression level could descend to some extent,but still higher thanthe level of control group on average.The expression of CD8+OX40+on CD8+T cells of theacute exacerbation asthmatic patients had no obvious statistical difference compared withthe remission group and the control group(all P>0.05). And the expressions ofCD4+OX40L+on CD4+T cells of asthmatic patients in acute exacerbation were obviouslyhigher than the control group (P<0.05). Also, the serum concentrations of sOX40L in acuteexacerbation bronchial asthma patients were higher than those in the remission group(P<0.05) and healthy control group (P<0.01), In addition, the level of sOX40L in severesubgroup was also found to be significantly higher than the moderate subgroup and mildsubgroup in asthma patients in acute exacerbation (P<0.05).2.Correlation analysis showed that the expression of CD4+OX40+on CD4+T cells inacute exacerbation asthmatic patients was positively correlated with the FeNO, the countof eosinophil (EOS) and total IgE(r=0.78,P<0.01, r=0.76,P<0.01, r=0.38,P<0.05).However, it had no significantly correlation with the patients’ FEV1%and the ACT(r=-0.13,P>0.05, r=0.10,P>0.05), as well as with the smoking status, the gender andexistence of allergic rhinitis. But the FeNO had an obviously positively correlation with theEOS count(r=0.719,P<0.05). The expression level of CD14+OX40L+/CD14+and inperipheral blood of acute exacerbation asthmatic patients also had significant positivelycorrelation with the level of FeNO (r=0.39,P<0.01). The expression level ofCD19+OX40L+/CD19+on B lymphocytes of acute exacerbation asthmatic patients hadsignificant positively correlation with the level of EOS、 FeNO、 IgE as well (r=0.377,P<0.05;r=0.379,P<0.05; r=0.372,P<0.05),but negatively correlate with ACT scoreand FEV1%(r=-0.32,P<0.05;r=0.10,P<0.01).The concentrations of sOX40L of acuteexacerbation asthmatic patients had a significantly negative correlation with the FEV1%,but a positively correlation with the level of EOS and FeNO(r=0.431, P<0.05, r=0.395,P<0.05,r=-0.48,P<0.01).The overexpression level of CD4+OX40+and CD4+OX40L+onCD4+T cells had no correction with each other (r=0.03,P>0.05). Conclusion Overexpression of costimulatory molecules OX40/OX40L exist on thelymphocytes in peripheral blood of acute exacerbation bronchial asthma patients,accompanied by increased serum concentrations of sOX40L in peripheral blood at thesame time,all had significant correlation with index such as EOS, FeNO, FEV1%,etal.Their expression level can reflect the severity of acute attack of bronchial asthma,especially for the serum concentrations of sOX40L, prompting that this costimulatorymolecule can be regarded as a meaningful biomarker that reflecting the status ofinflammatory cell activation and the severity of the disease.Thus, we conclude that theOX40/OX40L co-stimulatory molecules maybe play a vital role in the process of thedevelopment of bronchial asthma, which may become a new immunotherapeutical targetfor bronchial asthma in the future.