Lessons learned from the study of human inborn errors of innate immunity

Abstract

Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors.

Keywords: Infection; Toll-like receptors; immunodeficiency; inborn error of immunity; innate immunity; interferon; nuclear factor κ light-chain enhancer of activated B cells; phagocytes; signaling pathway.

Figure 1:. A).Recognition of conserved bacterial/fungal patterns by cell surface and endosomal TLRs and/or cell surface CLRs.

Bacterial components are recognized by TLR1/2, TLR2/6 and TLR4, triggering recruitment of the TIR domain-containing adapter molecules TIRAP and MyD88, while TLR5 and IL-1R directly activate MyD88, followed by recruitment of IRAK family members. Upon sensing of fungal infections, CLRs signal through the CARD9-BCL10-MALT1 complex. Both signaling pathways eventually lead to activation of the IKK complex (IKKα, IKKβ, and NEMO/IKKγ) and to the phosphorylation of IκBα via TAK1 (the classic MyD88-dependent pathway). After IκBα degradation, NF-κB heterodimers (p50:RelA or p50:cRel) translocate to the nucleus (canonical NF-κB pathway). By contrast, the noncanonical NF-κB pathway is induced upon activation of some TNF-R super-family members, such as CD40, BAFF-R or LT-β receptor, and involves the IKKα-mediated phosphorylation of p100 associated with RelB, leading to the generation of transcriptionally active p52:RelB complexes. IKKα activation and the phosphorylation of p100 depend on NIK activation. NFκB activation and translocation results in the induction of inflammatory cytokine genes (such as IL-21, IL-23 and IL-6). Upon binding to their receptors (expressed on T and innate lymphoid cells), the pro-inflammatory cytokines activate T cells via the transcription factor STAT3 and upregulate RORγT expression, resulting in the differentiation of these cells into IL17-producing T cells. *gp130 is a ubiquitously expressed protein scaffolding many cytokine receptors, such as IL6R, IL-11R, IL-27R, oncostatin M and other. B) IFN-γ/IL-12 response to mycobacterial infection and Salmonella. Upon mycobacterial infection, the IFN-γ/IL-12 axis is induced in APCs and T/NK cells. IL-12, IL-23 and IFN-γ are secreted in a positive loop between them, and through their receptors (IL-12Rβ1/2, IL-12Rβ1/IL-23R and IFNGR1/2) activate downstream signaling via TYK2, JAK1–2 and STAT1, finally inducing the transcription of ISGs. For all proteins shadowed in grey mutations have been described.

Figure 2:. Recognition of viral nucleic acids by endosomal TLRs, cytosolic RLRs and DNA sensors.

The UNC-93B chaperone protein guides TLR7/8 and TLR9 trafficking from the ER to the endosome, where these receptors recognize viral ssRNA and CpG DNA, respectively. These TLRs recruit MyD88, IRAK4 and IRAK1, which activate TRAF3 and TRAF6. TRAF6, in turn, mediates the activation of NF-κB, leading to the induction of inflammatory cytokine genes, whereas TRAF3 activates IKKα, which catalyzes the phosphorylation of IRF7 and induces type I IFN genes (the classic MyD88-dependent pathway). After recognizing the viral dsRNA, UNC-93B-dependent endosomal TLR3 recruits the adapter molecule TRIF for the activation of TBK1 and IKKε, followed by the activation of IRF3 and upregulation of IFN production (the alternative TRIF-dependent pathway). IRF8 facilitates the activation of NF-κB and IRF7. RLRs, such as MDA5 and RIG-I recruit mitochondrial MAVS adapter molecules after the recognition of cytoplasmic viral dsRNA. Various cytoplasmic dsDNA sensors signal via the ER-located adapter molecule STING. The activation of these RNA and DNA signaling pathways results in the production of inflammatory cytokines via NF-κB activation, and IFN production via TBK1-IKKε-IRF activation. Secreted type I IFNs interact with their surfaceexpressed receptor IFNAR1/2, leading to the recruitment and activation of TYK2 and JAK1, which in turn phosphorylate and activate STAT1 and STAT2. STAT1/STAT2/IRF9 form complexes that interact with ISRE promoters for the induction of ISGs expression. Intracellular ISG15 is type I IFN-inducible and is involved in the USP18-dependent regulation 47 of type I IFN and the prevention of type I IFN-dependent auto-inflammation. For all proteins 48 shadowed in grey mutations have been described.