Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs)

J Formos Med Assoc. 2011 Dec;110(12):750-8. doi: 10.1016/j.jfma.2011.11.004. Epub 2011 Dec 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Disease Susceptibility
  • Ectodermal Dysplasia / immunology
  • Granulomatous Disease, Chronic / immunology
  • Humans
  • Hyper-IgM Immunodeficiency Syndrome / immunology
  • Immunologic Deficiency Syndromes / immunology*
  • Interferon-gamma / immunology
  • Job Syndrome / immunology
  • Mycobacterium Infections / immunology*
  • Severe Combined Immunodeficiency / immunology

Substances

  • Interferon-gamma