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.

Clinical Immunology and Multiplex Biomarkers of Human Tuberculosis

“…Affected patients with partial IFNgR1 deficiency display less severe clinical disease phenotypes than patients completely deficient for IFNgR1 (Ottenhoff et al 2002;reviewed in Al-Muhsen and Casanova 2008). NEMO and STAT1 mutations are associated with several infectious diseases, with a spectrum extending beyond mycobacteria, including fungal, bacterial, and viral infections (reviewed in Al-Muhsen and Casanova 2008; Lee et al 2011). Monocytes from patients with X-linked recessive NEMO deficiency have an intrinsic defect in T-cell-dependent IL-12 production, which leads to impaired IFN-g production by T cells.…”

“…Other PID diseases enhancing susceptibility to severe mycobacterial infections can be caused by autosomal dominant mutations in the interferon regulatory factor 8 (IRF8) as well as the excessive production of neutralizing autoantibodies to IFN-g. These disorders result in the depletion of circulating monocytes and dendritic cells and block downstream mediators of IFN-g, respectively, highlighting the importance of these cells and mediators in antimycobacterial immunity (Lee et al 2011).…”

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

“…Because of the burden of tuberculosis (TB) in Taiwan, all newborns receive Bacillus Calmette-Guérin (BCG) vaccination at birth to avoid TB meningitis [11]. However, this policy has also put newborns with primary immunodeficiencies, such as SCID, at a higher risk for disseminated BCGitis [12][13][14].…”

Frequency of Mycobacterium bovis and mycobacteria in primary immunodeficiencies

“…Innate immunity against Mycobacterium tuberculosis, non-tuberculosis mycobacteriae, and the mycobacterial group including the Bacille Calmette-Guerin (BCG) vaccine strain is related with operation of the interleukin 12-23/interferon gamma (IL-12/23-IFN-γ) pathway (1,2). Mycobacterial infections are observed commonly in patients with severe forms of primary immunodeficiency, including severe combined immune deficiency (SCID), complete Di George syndrome, X-linked hyper immunoglobulin (Ig)-M syndrome (HIGM type 1, CD154 deficiency), CD40 deficiency, immune deficiencies accompanying ectodermal dysplasia (nuclear factor kappa-beta essential modulator (NEMO), IKBA), chronic granulomatous disease (CGD), interleukin 12-interferon gamma (IL-12/IFN-γ) receptor disorders, and hyper IgE syndrome, and these diseases have been examined under the title of Mendelian Susceptibility to Mycobacterial Diseases (MSMD) (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”