688 www.thelancet.com/infection Vol 9 November 2009 Review Genetic deficiencies of innate immune signalling in human infectious disease Esther van de Vosse, Jaap T van Dissel, Tom H M Ottenhoff The type-1 cytokine (interleukin 12, interleukin 23, interferon γ, interleukin 17) signalling pathway is triggered during infection by activation of phagocyte-expressed pattern-recognition receptors that recognise specific pathogen- associated molecular patterns. Triggering of this pathway results, among other things, in activation of microbicidal mechanisms in phagocytic cells. Individuals with a deficiency in one of the proteins in the pathway are unusually susceptible to otherwise poorly pathogenic, mostly environmental, mycobacteria and salmonellae. Individuals with deficiencies in other innate immune signalling proteins show unusual susceptibility to pathogens other than mycobacteria or salmonellae. We discuss recent insights into key molecules involved in type-1 cytokine signalling pathways and provide an update on the molecular genetic defects underlying mendelian susceptibility to mycobacterial disease. We also discuss deficiencies in the innate immune signalling proteins that lead to susceptibility to other pathogens. Knowledge of innate immune signalling has allowed the identification of defects in such patients. However, some patients have enhanced susceptibility to pathogens even though no mutations have been found in the candidate genes identified thus far. Whereas a few patients might have autoantibodies against type-1 cytokines, others might harbour mutations in new genes and pathways that still need to be identified. Introduction The type-1 cytokine (interleukin 12, interleukin 23, interferon γ, interleukin 17) pathway is important in the innate and adaptive immune system for fighting infections by intracellular pathogens. Individuals with defects in type-1 cytokine pathway genes have unusually enhanced susceptibilities to infections with otherwise poorly pathogenic, mostly environmental, mycobacteria or vaccine-associated Mycobacterium bovis BCG. To a lesser degree, these patients can also have infections with salmonellae and other intracellular bacteria and viruses. Collectively, the genetic defects underlying this increased susceptibility are referred to as mendelian susceptibility to mycobacterial disease (MSMD). In individuals with MSMD, mutations have been identified in the genes encoding interleukin-12/23 subunit p40 (IL12B), interleukin-12/23 receptor β1 (IL12RB1), interferon-γ receptor 1 (IFNGR1), interferon-γ receptor 2 (IFNGR2), and signal transducer and activator of transcription (STAT) 1 (STAT1). Mutations in other pathways of the innate immune system also result in enhanced susceptibility to infections, but interestingly with a different clinical range of infections and causative pathogens. Defects have been described thus far in the genes encoding interleukin-1 receptor-associated kinase 4 (IRAK4), the UNC93 homologue B (UNC93B1), Toll-like receptor (TLR) 3 (TLR3), myeloid differentiation primary response protein (MYD88), nuclear-factor κB (NFκB) essential modulator (NEMO; IKBKG), NFκB inhibitor α (NFKBIA, formerly IκBα), STAT3 (STAT3), and tyrosine kinase 2 (TYK2). Type-1 cytokine pathway Activation of phagocyte-expressed pattern-recognition receptors (PRRs) by pathogen-associated molecular patterns associated with mycobacterial or salmonella infection results in the production of interleukins 23 and 18, among other cytokines. Interleukin 23 binds to the interleukin-23 receptor, which is present on natural-killer or natural-killer-like T cells, thereby inducing early production of interferon γ, in synergy with interleukin 18 or interleukin 1β. 1 This early interferon γ in turn activates the interferon-γ receptor on macrophages and monocytes, inducing the production of interleukin 12 and further enhancing interleukin-18 production. In addition, interferon γ in synergy with tumour necrosis factor (TNF) initiates various microbicidal mechanisms in infected macrophages, typically leading to control of bacterial infection. In parallel, interleukin 12 binds to the interleukin-12 receptor on T cells from where, in synergy with interleukin 18, it drives activation, differentiation, and proliferation of T cells along the T-helper-1 pathway, characterised by production of interferon γ. T-helper-1 cells are the main source of interferon γ during the ensuing adaptive immune response, and are necessary for controlling the chronic phase of infection. Interleukin 12 can also drive, in synergy with interleukin 18, interferon-γ production in natural-killer and natural-killer-like T cells. 1 Thus, the type-1 cytokine pathway forms an innate immune signalling loop with interleukin 23, interleukin 12, and interferon γ as key cytokines (figure 1), whereas T-helper-1 cell activity provides a link to adaptive immune responses. The two main cytokines in the pathway, interleukins 23 and 12, are closely related: interleukin 23 is composed of interleukin-12 subunit p40 (IL12p40) and interleukin-23 subunit p19 (IL23p19), whereas interleukin 12 is composed of IL12p40 and interleukin-12 subunit p35 (IL12p35). Their receptors, interleukin-23 receptor (composed of IL12p40-binding IL12Rβ1 and IL23p19- binding IL23R subunit) and interleukin-12 receptor (composed of IL12Rβ1 and IL12p35-binding IL12Rβ2), Lancet Infect Dis 2009; 9: 688–98 Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands (E van de Vosse PhD, J T van Dissel MD, T H M Ottenhoff MD) Correspondence to: Dr Esther van de Vosse, Department of Infectious Diseases, C5 room 42, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands e.van_de_vosse@lumc.nl