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.