title: Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs).
abstract: Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guérin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-γ integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-γ pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-γR1, IFN-γR2, IL-12p40, IL-12R-β1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN-γ (autoAbs-IFN-γ), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent MSMD phenotype lacking BCG-induced diseases.
authors.affiliation: Primary Immunodeficiency Care And Research (PICAR) Institute, Chang Gung Medical Hospital and Children's Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan. wen2707@hotmail.com
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Lee
authors.forename: Jing-Long
authors.initials: JL
authors.lastname: Huang
authors.forename: Kuo-Wei
authors.initials: KW
authors.lastname: Yeh
authors.forename: Tang-Her
authors.initials: TH
authors.lastname: Jaing
authors.forename: Tzou-Yien
authors.initials: TY
authors.lastname: Lin
authors.forename: Yhu-Chering
authors.initials: YC
authors.lastname: Huang
authors.forename: Cheng-Hsun
authors.initials: CH
authors.lastname: Chiu
mesh_terms: D004198:Disease Susceptibility; D004476:Ectodermal Dysplasia / Q000276:immunology; D006105:Granulomatous Disease, Chronic / Q000276:immunology; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007589:Job Syndrome / Q000276:immunology; D009164:Mycobacterium Infections / Q000276:immunology*; D016511:Severe Combined Immunodeficiency / Q000276:immunology
chemical_list: D007371:Interferon-gamma