Association Of HLA-DRB1/DQB1 Polymorphisms With Non-HIV-infected Talaromycosis Marneffei Induced By IFN-gama Antibodies

Objective Guangxi Zhuang Autonomous Region（Guangxi）is the main endemic area of non-HIV-infected Talaromycosis marneffei（TSM）.Compared with HIV-infected patients,non-HIV patients have poorer treatment outcomes and higher mortality rates.In-depth exploration of its pathogenesis will help clinicians improve the clinical management and diagnosis of these patients.By collecting blood samples from non-HIV patients in Guangxi,using enzyme linked immunosorbent assay（ELISA）and flow cytometry,we identify IFN-γautoantibodies in patients’plasma and calculate antibody positive rates;To investigate the association between HLA allele polymorphism and IFN-γantibody positive patients infected with Talaromyces marneffei（T.marneffei）,the allele typing of HLA-DRB1 and DQB1 was performed on objects by direct sequencing typing method.Methods Indirect enzyme-linked immunosorbent assay（ELISA）was used to initially screen for IFN-γantibodies in all subjects.Combined with IFN-γinterference test and functional experiments,flow cytometry was used to verify the presence of IFN-γantibody and its effect on the expression of HLA-DR molecules on the surface of immune cells.Polymerase chain reaction sequence based typing（PCR-SBT）was used to detect HLA-DRB1 and DQB1 in36 patients and 107 healthy people.Then,we compared the allele carrier rates of IFN-γautoantibody-positive patient groups with those of healthy control and analyzed the association of acquired IFN-γantibody immunodeficiency syndrome with T.marneffei infection and HLA allele polymorphisms.Results Of the 36 patients,33（91.7%）had IFN-γantibodies in plasma.And it was confirmed that these autoantibodies can inhibit the expression of IFN-γ-dependent HLA-DR molecules on the surface of immune cells.In the HLA genotyping results,25 DRB1 alleles and 16 DQB1 alleles were detected.DRB1*16:02(OR=19.37,95%CI（6.75-55.59）,P=8.72×10^-11,Pc=2.18×10^-9)and DQB1*05:02(OR=9.26,95%CI（3.04-28.17）,P=9.0×10^-6,Pc=1.4×10^-4)was associated with IFN-γantibody positive patients infected with T.marneffei,the difference was statistically significant（Pc<0.01）.Conclusion IFN-γautoantibodies is the major cause of non-HIV-infected TSM in Guangxi.Clinically,healthy people who have no obvious immune deficiency factors before,but have T.marneffei or other opportunistic infections,it is necessary to investigate the possibility of IFN-γautoantibodies.HLA-DRB1*16:02 and DQB1*05:02 are strongly associated with IFN-γantibody positive patients infected with T.marneffei,suggesting that these alleles may be susceptibility genes and play an important role in the pathogenesis.The Guangxi region is not only an endemic area of T.marneffei,but also a distribution area of IFN-γantibody related genes.The combination of environmental and genetic factors contributed to the high incidence of non-HIV-infected TSM induced by IFN-γautoantibodies.