Fine Particulate Matter-Induced Exacerbation of Allergic Asthma via Activation of T-cell Immunoglobulin and Mucin Domain 1

Background： Fine particulate matter （PM2.5） exacerbates airway inflammation and hyperreactivity in patients with asthma, but the mechanism remains unclear. The aim of this study was to observe the effects of prolonged exposure to high concentrations of PM2.5 on the pathology and airway hyperresponsiveness （AHR） of BALB/c mice undergoing sensitization and challenge with ovalbumin （OVA） and to observe the effects of apoptosis and T-cell immunoglobulin and mucin domain 1 （TIM-1） in this process. Methods： Forty female BALB/c mice were divided into four groups： control group, OVA group, OVA/PM group, and PM group （n - 10 in each group）. Mice in the control group were exposed to filtered clean air. Mice in the OVA group were sensitized and challenged with OVA. Mice in the OVA/PM group were sensitized and challenged as in the OVA group and then exposed to PM2.5 for 4 h per day and 5 days per week for a total of 8 weeks using a nose-only ＂PM2.5 online enrichment system＂ in The Second Hospital of Hebei Medical University. Mice in the PM group were exposed to the PM2.5 online enrichment system only. AHR was detected. Bronchoalveolar lavage fluid （BALF） was collected for cell classification. The levels of interleukin-4 （IL-4）, IL-5, and IL-33 in BALF were measured using enzyme-linked immunosorbent assay. Changes in histological structures were examined by light microscopy, and changes in ultramicrostructures were detected by electron microscopy. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling （TUNEL） assay in the lung tissues. Western blotting and immunohistochemistry were utilized to analyze the expression of Bcl-2, Bax, and TIM-1 in the lungs. Results： The results showed that AHR in the OVA/PM group was significantly more severe than that in the OVA and PM groups （P 〈 0.05）. AHR in the PM group was also considerably more severe than that in the control group （P 〈 0.05）. The BALF of OVA/PM group （28.00± 6.08 vs. 12.33 ±4.51, t = 4.631, P = 0.002） and PM group （29.00 ± 3.00 vs. 12.33 ± 4.51, t = 4.927, P = 0.001） had more lymphocytes than the BALF of the control group. The number of neutrophils in the BALF of the OVA/PM group （6.67 ± 1.53 vs. 3.33 ± 1.53, t = 2.886, P = 0.020） and PM group （6.67 ± 1.53 vs. 3.33 ± 1.53, t = 2.886, P = 0.020） was much higher than those in the BALF of OVA group （P 〈 0.05）. TUNEL assays showed that the number of apoptotic cells in the OVA/PM group was significantly higher than that in the OVA group （Tunel immunohistochemical scores [IHS%], 1.20 ± 0.18 vs. 0.51 ± 0.03, t = 8.094, P 〈 0.001） and PM group （Tunel IHS%, 1.20 ± 0.18 vs. 0.51 ±0.09, t = 8.094, P〈 0.001）, and that the number of apoptotic cells in the PM group was significantly higher than that in the control group （Tunel IHS%, 0.51 ± 0.09 vs. 0.26 ± 0.03, t = 2.894, P = 0.020）. The concentrations of IL-4 （77.44 ± 11.19 vs. 48.02 ±10.02 pg/ml, t = 4.595, P= 0.002） and IL-5 （15.65 ± 1.19vs. 12.35±0.95pg/ml, t=3.806,P=0.005） and the Bax/Bcl-2 ratio （1.51 ± 0.18 vs. 0.48 ± 0.10, t = 9.654, P 〈 0.001） and TIM-1/β-actin ratio （0.78 ± 0.11 vs. 0.40 ±0.06, t = 6.818, P 〈 0.001） in the OVA/PM group were increased compared to those in the OVA group. The concentrations of IL-4 （77.44 ± 11.19 vs. 41.47 ± 3.40 pg/ml, t = 5.617, P= 0.001） and IL-5 （ 15.65±1. 19 vs. 10.99 ± 1.40 pg/ml, t = 5.374, P = 0.001 ） and the Bax/Bcl-2 ratio （1.51 ±0.18 vs. 0.97 ± 0.16, t = 5.000, P = 0.001） and TIM-1/β-actin ratio （0.78 ± 0.11 vs. 0.31 ± 0.06,t = 8.545, P 〈 0.001 ） in the OVA/PM group were increased compared to those in the PM group. The concentration oflL-4 （41.47 ±3.40 vs. 25.46 ± 2.98 pg/ml, t = 2.501, P = 0.037） and the Bax/Bcl-2 ratio （0.97 ± 0.16 vs. 0.18 ± 0.03, t = 7.439, P 〈 0.001） and TIM-1/β-actin ratio （0.31 ± 0.06 vs. 0.02 ± 0.01, t = 5.109, P = 0.001） in the PM group were also higher than those in the control group. Conclusions： Exacerbated AHR associated with allergic asthma caused by PMz5 is related to increased apoptosis and TIM-1 activation. These data might provide insights into therapeutic targets for the treatment of acute exacerbations of asthma induced by PM2.5.

Routinely detected indicators in plasma have a predictive effect on the identification of HIV-infected patients with non-tuberculous mycobacterial and tuberculous infections

Background:It is difficult to quickly distinguish non-tuberculous mycobacterial(NTM)infection from tuberculosis(TB)infection in human immunodeficiency virus(HIV)-infected patients because of many similarities between these diseases.A simple and effective way to determine the differences using routine blood tests is necessary in developing countries.Methods:A retrospective cohort study was conducted to recruit HIV-infected patients with either NTM infection or TB infection diagnosed for the first time according to mycobacterial culture and microscopic identification from May 2010 to March 2016.These data included the analysis of blood cells,liver function,renal function,C-reactive protein(CRP),and erythrocyte sedimentation rate(ESR),and were compared between the HIV/TB and HIV/NTM groups.Results:A total of 240 patients were enrolled.The number of HIV/TB and HIV/NTM patients was 113 and 127,respectively.There were no significant differences in the CD4 T-cell count,age,sex,percentage of patients initiating antiretroviral therapy(ART)before the explicit diagnosis of TB or NTM infection.NTM infection was more likely to be restricted in the pulmonary while TB infection also involves extra-pulmonary sites.Both the leukocyte count(5.60×109/L)and the proportion of neutrophils in the leukocyte count(76.70%)in the HIV/TB group were significantly higher than those in the HIV/NTM group(4.40×10^(9)/L[P=0.0014]and 69.30%[P<0.001].The analysis of liver function markers indicated that the concentration of albumin but not ALT and AST was significantly lower in the HIV/TB group than in the HIV/NTM group(P<0.001).The creatinine and urea levels were not significantly different between the two groups.The ESR(84.00 mm/h)and the concentration of CRP(59.60 mg/L)were significantly higher in the HIV/TB group than in the HIV/NTM group(52.00 mm/h and 19.60 mg/L,respectively)(P<0.001).To distinguish TB infection from NTM infection,the best cut-off value was 69.5 mm/h for ESR,with a positive predictive value(PPV)of 0.740 and negative predictive value(NPV)of 0.721,and 48.8 mg/L for CRP,with a PPV of 0.676 and NPV of 0.697.Conclusion:The dissemination character as well as stronger immune response characterized by higher inflammation markers(e.g.WBC,ESR,CRP)can help distinguish TB from NTM infection in HIV-infected patients who need empirical therapy or diagnostic therapy immediately in low-income areas.

Targeted inhibition of myeloid-derived suppressor cells in the tumor microenvironment by low-dose doxorubicin to improve immune efficacy in murine neuroblastoma

Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin(DOX)to enhance immune efficacy in NB.Methods:Bagg albino(BALB/c)mice were used as tumor-bearing mouse models by injecting Neuro-2a cells,and MDSCs were eliminated by DOX or dopamine(DA)administration.Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX,5.0 mg/kg DOX,50.0 mg/kg DA,and control groups(n=20).The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition.NB antigen-specific cytotoxic T cells(CTLs)were prepared.Tumor-bearing mice were randomly divided into DOX,CTL,anti-ganglioside(GD2),DOX+CTL,DOX+anti-GD2,and control groups.Following low-dose DOX administration,immunotherapy was applied.The levels of human leukocyte antigen(HLA)-I,CD8,interleukin(IL)-2 and interferon(IFN)-γin peripheral blood,CTLs,T-helper 1(Th1)/Th2 cytokines,perforin,granzyme and tumor growth were compared among the groups.The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.Results:The slowest tumor growth(F=6.095,P=0.018)and strongest MDSC inhibition(F=14.632,P=0.001)were observed in 2.5 mg/kg DOX group.Proliferation of T cells was increased(F=448.721,P<0.001)and then decreased(F=2.047,P=0.186).After low-dose DOX administration,HLA-I(F=222.489),CD8(F=271.686),Th1/Th2 cytokines,CD4^(+)and CD8^(+)lymphocytes,granzyme(F=2376.475)and perforin(F=488.531)in tumor,IL-2(F=62.951)and IFN-γ(F=240.709)in peripheral blood of each immunotherapy group were all higher compared with the control group(all ofP values<0.05).The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.Conclusions:Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression,thereby fostering immune efficacy in NB.

Correction to: Routinely detected indicatorsin plasma have a predictive effect on theidentification of HIV-infected patients withnon-tuberculous mycobacterial andtuberculous infections

Correction After publication of this article[1]it came to our attention that the affiliation of Jun Chen and Hong-zhou Lu were incorrectly shown.Jun Chen’s affiliation should have been given as Department of Infectious Diseases,Shanghai Public Health Clinical Center,Fudan University,Shanghai,China.Hong-zhou Lu should have been given as Department of Infectious Diseases,Shanghai Public Health Clinical Center,Fudan University,Shanghai,China.Huashan Hospital affiliated to Fudan University,Shanghai,China.Medical College of Fudan University,Shanghai,China.The original article has been updated to reflect this change.