Clinical,Genetic,and Immunological Characteristics Of Patients With X-Linked Hyper-IgM Syndrome

Background:X-linked hyper-IgM syndrome is a rare but life-threatening primary immunodeficiency caused by mutations in the CD40L gene.Due to its low incidence,the characteristics of this disease remain unfamiliar to the majority of clinicians in China.Delayed diagnosis and substandard treatment remain the key causes of death.Objective:To gather genetic,immunologic,and clinical information about Chinese patients with X-linked hyper-IgM syndrome,trying to provide more reliable information to clinicians in China.Methods:Performed an analysis of the clinical and genetic characteristics of a cohort of 22 genetically-diagnosed X-linked hyper-IgM syndrome patients from the Chinese mainland,followed their therapy and outcomes,and studied the lymphocyte subsets,CD40L expression,IL-17secretion,and natural killer cells'cytotoxic function by flow cytometry.Results:Opportunistic infections,including Pneumocystis carinii pneumonia and Talaromyces marneffei,were the most serious threats faced by X-linked hyper-IgM syndrome patients.Progressive multifocal leukoencephalopathy(PML)due to JC virus infection can be observed in elder patients with CD40L deficiency,which implies poor prognosis.In addition,neutropenia was the most common complication,and we noted an arrest of neutrophil development in the bone marrow.Moreover,we observed 22.7%of patients showed reduced IgM levels,while 4.5%of patients had elevated IgA levels.Twenty-one unique mutations were identified in the 22 patients;of these,9 were novel.missense mutations were the most common type,and all in exon 5.We observed a higher percentage of na?ve CD4~+T cells and terminally differentiated effector memory cytotoxic T lymphocytes(CD8~+TEMRA),and a lower percentage of natural killer cells(NK),central memory CD4~+T cells(CD4~+CM),na?ve CD8~+T cells,class-switched memory B,and T follicular helper cells(Tfh)in patients with CD40L deficiency.In addition,patients showed lower secretion of IL-17,while the one with Talaromyces marneffei infection barely expressed IL-17;poor NK cell cytotoxic function was also observed in CD40L-deficient patients,although no significant difference was found between patients with PML and those without PML.Conclusions:X-linked hyper-IgM syndrome is a complicated primary immunodeficiency.Affected patients presented various manifestations,in which infections remained the key problems.Recently,CD40L deficiency was reported in association with more and more opportunistic pathogenic microorganism infections,including Talaromyces marneffei and JC virus.In the present study,we found that patients with CD40L deficiency were defected both in adaptive immunity and innate immunity.Deficiency in IL-17 secretion may result in susceptibility to fungal diseases,especially to Talaromyces marneffei infections.The connection between the NK cell deficiency and JCV infections needs further studies.Neutropenia may be resulted from the arrest of neutrophil development in the bone marrow.Further investigations are required to identify the underlying mechanisms.