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, 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.

Clinical and genetic features of IL12Rb1 deficiency: Single center experience of 18 patients

“…These patients are also susceptible to salmonella, candida and M. tuberculosis species 2,13,14 . Some other intracellular microorganisms have been reported in a small number of patients 13 .…”

“…These patients are also susceptible to Salmonella, Candida and M. tuberculosis species 2,3 . Nine disease-causing genes have been described, including three genes controlling the response to IFN-γ (IFNGR1, IFNGR2, STAT1), four involved in IFN-γ production (IL12B, IL12RB1, NEMO,ISG15), one involved in the IFN-γ dependent induction of IL-12 (IRF8) and another gene controlling the macrophage respiratory burst, which can be triggered by IFN-γ (CYBB) 2,[4][5][6][7][8] . The considerable allelic heterogeneity at some of these loci has resulted in the definition of up to 18 different inborn errors of immunity 2 .…”

“…IL-12Rb1 is a common receptor chain of the IL-12 and the IL-23 receptors and deficiency of IL-12Rb1 causes a profound defect in both IL-12 and IL-23 signaling 2,7,8,9 . IL-12 is an important cytokine for the development of IFN-γ producing T cells and also induces IFN-γ production by Natural killer (NK) and Natural Killer T (NKT) cells 9 .…”

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…In 1996, we jointly reported the first genetic etiology of MSMD: autosomal recessive complete IFN-γ receptor 1 (IFN-γR1) deficiency (17,18). Over the next 20 y, we and others pursued this forward genetic approach and discovered a group of 17 inborn errors of IFN-γ immunity involving nine genes (19)(20)(21)(22)(23). Some MSMD-causing genes control the production of IFN-γ; others govern its action.…”

Frequency of Mycobacterium bovis and mycobacteria in primary immunodeficiencies

“…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). In this group of patients, non-tuberculosis mycobacteriae are predominantly observed.…”