Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria, such as Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccines and nontuberculous, environmental mycobacteria (EM). Since 1996, MSMD-causing mutations have been found in six autosomal genes involved in IL-12/23-dependent, IFN-γ-mediated immunity. The aim of this review is to provide the description of the two described forms of X-linked recessive (XR) MSMD. Germline mutations in two genes, NEMO and CYBB, have long been known to cause other human diseases-incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (NEMO/IKKG), and X-linked chronic granulomatous disease (CGD) (CYBB)-but specific mutations in either of these two genes have recently been shown to cause XR-MSMD. NEMO is an essential component of several NF-κB-dependent signaling pathways. The MSMD-causing mutations in NEMO selectively affect the CD40-dependent induction of IL-12 in mononuclear cells. CYBB encodes gp91(phox) , which is an essential component of the NADPH oxidase in phagocytes. The MSMD-causing mutation in CYBB selectively affects the respiratory burst in macrophages. Mutations in NEMO and CYBB may therefore cause MSMD by selectively exerting their deleterious impact on a single signaling pathway (CD40-IL-12, NEMO) or a single cell type (macrophages, CYBB). These experiments of Nature illustrate how specific germline mutations in pleiotropic genes can dissociate signaling pathways or cell lineages, thereby resulting in surprisingly narrow clinical phenotypes.

Figure 1

MSMD-causing gene products in the IL-12/23–IFN-γ circuit. Schematic representation of cytokine production and cooperation between monocytes-macrophages-dendritic cells and NKT cells. Mutant molecules in patients with MSMD are indicated in gray. Allelic heterogeneity of the eight genes results in the definition of 15 genetic disorders. The IL-12–IFN-γ loop and the CD40L-activated CD40 pathway, mediating cooperation between T cells and monocyte/cells, are crucial for protective immunity to mycobacterial infection in humans. IRF8 is an IFN-γ–inducible transcription factor required for the induction of various target genes, including IL-12. The NEMO mutations in the LZ domain mostly impair CD40-NEMO–dependent pathways. The Q231P and T178P gp91^phox mutations specifically abolish the respiratory burst in monocyte-derived macrophages; gp91^phox induction might led to release of IL-12 (for which, any evidence have been demonstrated).