Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.

Keywords: BCG; IFN-γ; IL-12; ISG15; Mycobacteriosis; Primary immunodeficiency; Tuberculosis.

Figure 1. MSMD-causing mutations of IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB.

The exons of each gene are shown, designated by roman numerals. Red: recessive loss-of-function mutations associated with complete defects. Purple: recessive mutations associated with partial deficiency. Green: dominant mutations causing partial deficiency.

Figure 1. MSMD-causing mutations of IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB.

The exons of each gene are shown, designated by roman numerals. Red: recessive loss-of-function mutations associated with complete defects. Purple: recessive mutations associated with partial deficiency. Green: dominant mutations causing partial deficiency.

Figure 2. Cells producing and responding to IFN-γ

Proteins for which mutations in the corresponding genes have been identified and associated with Mendelian susceptibility to mycobacterial diseases (MSMD) are indicated in blue. The allelic heterogeneity of nine genes results in the definition of 18 genetic disorders. MSMD-causing mutations of IFNGR1, IFNGR2, STAT1, IRF8 and CYBB impair the action of IFN-γ. MSMD-causing mutations of IL12B, IL12RB1, ISG15, IRF8 and NEMO impair the production of IFN-γ.

Figure 3. Distribution of genetic disorders in MSMD patients with known etiologies

The genetic defects observed in 406 MSMD patients with known mutations are shown. The proportions of complete recessive (CR), partial recessive (PR), and partial dominant (PD) defects of autosomal genes (IFNGR1, IFNGR2, STAT1, IRF8, IL12B, IL12RB1 and ISG15), and X-linked recessive (XR) genes (NEMO and CYBB) are indicated.

Figure 4. Infections in patients with deficiencies of IFN-γR and STAT1

Infections in 115 patients with IFN-γR1 deficiencies (complete and partial), 21 patients with IFN-γR2 deficiencies (complete and partial) and 17 reported patients with partial dominant STAT1 deficiency. Some patients had multiple episodes of infectious diseases. BCG: bacillus Calmette-Guerin, EM: environmental mycobacteria.

Figure 5. Infections in patients with IL-12Rβ1 and IL-12p40 deficiencies

Infections in 180 patients with complete IL-12Rβ1 deficiency and in 50 reported patients with complete IL-12p40 deficiency. Some patients had multiple episodes of infectious diseases. BCG: bacillus Calmette-Guerin, EM: environmental mycobacteria.