ABSTRACT
Objective:To investigate the clinical characteristics and prognosis of cryptococcal meningitis patients with anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies.Methods:A total of 216 non-acquired immunodeficiency syndrome (AIDS) related cryptococcal meningitis cases with positive cultures of Cryptococcus, hospitalized at Huashan Hospital, Fudan University during January 2014 and December 2021, were retrospectively included. The serum anti-GM-CSF autoantibodies were detected by enzyme linked immunosorbent assay, and the clinical characteristics and prognosis were compared between patients with and without anti-GM-CSF autoantibodies. Statistical comparisons were mainly performed using the chi-square test or Fisher′s exact test. Cox proportional-hazards model was used to analyze the risk factors associated with prognosis. Results:Among 216 enrolled patients, 23 patients were positive of anti-GM-CSF autoantibodies, with a positive rate of 10.6%. Among 23 patients, seven cases were infected with Cryptococcus gattii, and 16 cases were infected with Cryptococcus neoformans. In the group with positive anti-GM-CSF autoantibodies, 30.4%(7/23) of the patients were infected with Cryptococcus gattii, which was higher than that of 1.6%(3/193) in the group with negative anti-GM-CSF autoantibodies, and the difference was statistically significant ( χ2=38.82, P<0.001). In the group with positive anti-GM-CSF autoantibodies, 30.0% (6/20) had mass lesions with a diameter greater than three centimeters in the lungs, and the one-year all-cause mortality rate was 50.0% (10/20), which were both higher than those of 3.4%(5/145) and 16.1% (29/180) in the negative group, respectively. The differences were both statistically significant (both Fisher′s exact test, P<0.01). Age≥60 years (hazard ratio ( HR)=4.146, P=0.002), predisposing factors ( HR=3.160, P=0.021), epilepsy ( HR=6.129, P=0.002), positive anti-GM-CSF autoantibodies ( HR=2.675, P=0.034), white blood cell count of cerebrospinal fluid (CSF)<100 ×10 6/L ( HR=2.736, P=0.039), the titers of cryptococcal capsular polysaccharide antigen of CSF≥1∶1 280 ( HR=4.361, P=0.009) were independent risk factors for one-year all-cause mortality in patients with cryptococcal meningitis. Conclusions:In non-AIDS related cryptococcal meningitis patients, the positive rate of serum anti-GM-CSF autoantibodies is as high as 10.6%. Patients with anti-GM-CSF autoantibodies could be infected with both Cryptococcus neoformans and Cryptococcus gattii, and they have higher proportion of lung mass lesions than patients with negative anti-GM-CSF autoantibodies. The one-year survival rate decreases significantly in patients with anti-GM-CSF autoantibodies, which is an independent risk factor for the prognosis of cryptococcal meningitis.
ABSTRACT
Purpose@#Caspase recruitment domain containing protein 9 (CARD9) has been demonstrated to be a pro-tumor factor in various cancers. However, our previous study found a significant decrease of CARD9 in malignant pleural effusion compared with benign pleural effusion. So we investigated the role of CARD9 in non-small cell lung cancer (NSCLC) and its working mechanism. @*Materials and Methods@#Immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were used to detect the expression of CARD9 in specimens of NSCLC patients. The Cancer Genome Atlas (TCGA) databasewas also used to analyze the expression of CARD9 in NSCLC and its predicting value for prognosis. Immunofluorescence was used for CARD9 cellular location. Cell growth assay, clonal formation assay, wound healing assay, matrigel invasion assay, and flow cytometry were used to test cell proliferation, migration, invasion, apoptosis, and cycle progression of NSCLC cells with CARD9 knockdown or CARD9 overexpression. Co-immunoprecipitation was used to identify the interaction between CARD9 and B-cell lymphoma 10 (BCL10). SB203580 was used to inhibit p38 activation. @*Results@#CARD9 was decreased in NSCLC tissues compared with normal tissues; low CARD9 expression was associated with poor survival. CARD9 was expressed both in tumor cells and macrophages. Downregulation of CARD9 in NSCLC cells enhanced the abilities of proliferation, invasion and migration via activated MAPK/p38 signaling, while overexpression of CARD9 presented antitumor effects. BCL10 was identified to interact with CARD9. @*Conclusion@#We demonstrate that CARD9 is an independent prognostic factor in NSCLC patients and inhibits proliferation, migration, and invasion by suppressing MAPK/p38 pathway in NSCLC cells.