The Genetic Immunodeficiency Of BCG Infection

ObjectiveAccording to the World Health Organization, one-third of the global population infected with Mycobacterium tuberculosis,9.15million new cases suffered and over1.65million deaths per year. Tuberculosis incidence in China is ranked second in the world, BCG vaccination as an important means to prevent serious TB infection. Most infants do not occurred BCG infection after inoculated, but there is still a few patients suffered, even disseminated and death. BCG infection only occured in the part of children, suggesting that these children may be reduced their own limitations and resist to host immune defense of BCG. Several primary immunodeficiency diseases were susceptive to mycobacteria, such as severe combined immunodeficiency, chronic granulomatous disease, hyper-IgM syndrome, hyper-IgE syndrome, as well as Mendelian Susceptibility to Mycobacteria Disease. We tried to find potential underlying immunogenetic mechanisms of BCG infection through the analysis of clinical features, phenotype, functional assays and gene mutation in patients with chronic granulomatous disease and suspected Mendelian susceptibility to mycobacterial disease.Methods1. We collected BCG-infected patients diagnosed in Shanghai Children’s hospital of Fudan University from January2007to January2012. The investigation included evaluation of the patient’s immune function, including analysis of lymphocyte subsets, serum immunoglobulin and DHR assay. And analysis of clinical and follow-up data on patients confirmed with chronic granulomatous disease.2. Analysis the clinical features of the patients who exclude common primary immunodeficiency. Then whole-blood cells were cultured and IFN-y levels in supernatant were analyzed by ELISA. The IL12RB1and IFNGR1mutations in these patients were detected using PCR and direct sequencing. Results were analyzed and blasted with data in the IDbase.Results1. There were23patients diagnosed chronic granulomatous disease, at about31%for all BCG infection patients. CGD patients with BCG infection mostly occured within1year after BCG vaccination, but do not rule out elder ones. There was no patient who presented the local infection at BCG vaccination site only, and9patients occurred in regional,11cases of patients with distant infection,3cases of patients with disseminated infection, involving lung, intestine, liver, skin and bone. It is hard to cure out of the mycobacterial infection in CGD patients, rhIFN-γ plus regular antituberculosis is more effective than antituberculosis alone.2.47cases exclude common primary immunodeficiency patients and2of them were detected with abnormalities of IFN-γ level and presented BCG disseminated infection. P2was found to have G219R homozygous mutation (655G> A) in IFNGR1gene, his father and mother are the abnormal gene carriers (heterozygous). P37was found to have L467P heterozygous mutation (1400T> C) in IFNGR1gene, and this site was reported as single nucleotide polymorphisms (SNP:rs1887415).ConclusionsBCG infection was often with several primary immunodeficiency diseases, such as chronic granulomatous disease, Mendelian susceptibility to mycobacterial diseases as well as severe combined immunodeficiency. CGD patients were susceptible to have BCG infection and prone to disseminated. And it is hard to cure out of the mycobacterial infection in CGD patients yet. CGD patients with BCG infection mostly occured within1year after BCG vaccination, but do not rule out elder ones. rhIFN-γ plus regular antituberculosis is more effective than antituberculosis alone. Patient who had mutation in IFNGR1gene prone to present BCG disseminated infection. For many patients who had recurrent serious BCG infections, the exact cause was still unknown and further research will be needed.