Impairment of Mycobacterial Immunity in Human Interleukin-12 Receptor Deficiency

Abstract

In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.

Genetic regulation of host responses to Salmonella infection in mice

“…The clinical manifestations of the disease are heterogenous and range from abdominal abscesses and adenitis to severe sepsis. Several Salmonella serotypes have been identified and include Salmonella Paratyphi 139,140 or non-typhoid Salmonella serotypes such as Salmonella Typhimurium, 140 Salmonella Enteritidis, 139,[141][142][143] Salmonella group B 139,140 or untyped Salmonella. 139,144,145 Host resistance loci identified using QTL analysis…”

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

“…49 In humans, mutations in the IL-12R cause severe immunodeficiency, associated with recurrent intracellular infections with Mycobacterium and Salmonella. 50,51 Introduction of a null allele at the IL-12 locus on a C57Bl/6J genetic background abrogates natural resistance to infection with M. tuberculosis, 52 and Leishmania major. 53 Finally, IL-6 and its receptor (IL-6R, one subunit of which maps on Chr.3) act synergistically with a number of other growth factors and cytokines to sustain normal proliferation and maturation of macrophages, T and B cells, and megakaryocytes.…”

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

“…The release of proinflammatory cytokines such as IL-1b, TNF, IL-12 or IL-18 from monocytes and monocyte-derived macrophages induces the production of T-cell-derived cytokines, most importantly IFN-g, which in turn will activate macrophages for the killing and elimination of the microorganisms [5,6]. Patients with defects in receptors for IL-12 and IFN have an increased susceptibility to mycobacterial infections [7][8][9], while the association between low CD4 counts and TB is well-known in HIV-infected patients [2].…”

“…The release of proinflammatory cytokines such as IL-1b, TNF, IL-12 or IL-18 from monocytes and monocyte-derived macrophages induces the production of T-cell-derived cytokines, most importantly IFN-g, which in turn will activate macrophages for the killing and elimination of the microorganisms [5,6]. Patients with defects in receptors for IL-12 and IFN have an increased susceptibility to mycobacterial infections [7][8][9], while the association between low CD4 counts and TB is well-known in HIV-infected patients [2].While most of the research has focused on the mechanisms responsible for the IFN-g induction, relatively little is known about the mechanisms leading to the production and release of the first wave of cytokines that are needed for the activation of T cells. While TNF-a is known to be important for the integrity of the granuloma, two of the cytokines of the IL-1 family, IL-1b and IL-18, are considered to be crucial for the induction of IFN-g. IL-1-mediated signals have been recently demonstrated to be an essential component of the MyD88-dependent innate response to M. tuberculosis infection, while IL-18-dependent pathways seemed to be dispensable [10].…”