Defects in Killing of Intracellular Bacteria by Activated Macrophages
Some bacterial species (Mycobacteria, Lis-teria, Salmonella) are resistant to the killing mechanisms operating within phagocytic cells and therefore can survive and multi-ply within monocytes and macrophages. Effective immunity against these organ-isms depends on T-cell- (and NK-cell-) dependent macrophage activation. Studies in gene-disrupted mouse and human immunodeficiencies have identified that
IL-12- and IL-23-dependent interferon gamma (IFN-γ) production is critically important for immunity against intracel-lular bacterial pathogens. This process is initiated by the stimulation of Toll recep-tors on the surface of antigen-presenting cells by bacterial ligands such as mycobac-terial lipoarabinomannan. This results in the secretion of IL-12 and IL-23 and TNF-α by the antigen-presenting cells. Binding of IL-12 and IL-23 to their respective recep-tors, expressed on the surface of activated T cells and NK cells, induces these cells to secrete a further cytokine IFN-γ. IFN-γ acting in concert with TNF-α activates macrophages, which are then capable of killing intracellular pathogens (e.g., Myco-bacteria and Salmonella). Individuals with impaired T-cell-mediated immunity (e.g., SCID or HIV infection) are highly suscep-tible to mycobacterial infections, including infections caused by poorly pathogenic mycobacterial species (nontuberculous mycobacteria and BCG). However, dissem-inated life-threatening infections by these organisms may also occur in the absence of a recognized primary or secondary immu-nodeficiency. Genetic analysis of affected kindred to date have identified mutations in seven different genes that participate in the production or response to IFN-γ. These patients are classified under the heading Mendelian susceptibility to mycobacte-rial disease (MSMD) (OMIM 209950). The genetic lesions responsible for MSMD affect the integrity of the IL-12/23-depen-dent IFN-γ pathway.
Thus, mutations have been identified in
■ The P40 subunit shared by IL-12 and IL-23 (also called IL12B);
■ The β chain shared by the IL-12 and IL-23 receptors;
■ The TYK2 kinase required for signaling via the IL-12 receptor;
■ The α and β chains of the IFN-γ receptor (IFN-γ R1 and IFN-γ 2);
■ The STAT-1 signal transducing molecule, which is required for signaling through the IFN-γ receptor;
■ The seventh defect responsible for increased susceptibility to mycobacterial infection is that NFκB essential modulator gene, which is required for NFκB activation, which is critical for signal transduction via the Toll, IL-1, and TNF-α receptors.
The severity of the clinical phenotype of MSMD depends on the genotype. Com-plete IFN-γR1 or R2 deficiencies lead to the abrogation of responses to IFN-γ. Such patients present in early childhood with disseminated NTM or BCG infections, resulting in a high mortality, despite chemotherapy. Mycobacterial lesions in such patients are multibacillary and asso-ciated with poor granuloma formation. In contrast, partial IFN-γ R1 deficiency, complete IL-12B deficiency, and IL-12/23 receptor deficiency predispose to myco-bacterial infections, presenting at a later age and with a favorable outcome, fol-lowing chemotherapy. Lesions in these latter patients are paucibacillary and are associated with an intact granulomatous response. Patients with partial or com-plete STAT-1 deficiency, which impairs the signaling via the IFN-γ R results in susceptibility to mycobacteria of low-grade virulence. Complete STAT-1 defi-ciency also impairs signaling via type I interferon receptors, which predisposes to life-threatening herpes viral infections occurring in childhood. The commonestinfections that affect patients with defects in the IL-12/23 are extraintestinal or sep-ticemic, relapsing infections with non-typhoidal Salmonella species.
As could be predicted, patients with IL-12/23 defects or partial IFN-γR defects respond to treatment with IFN-γ but those with complete IFN-γ defects are refractory to this therapy.