DEFECTS IN INNATE IMMUNITY
Defects in the complement pathway resulting in immunodeficiency are sum-marized in the previous section. Recent work has identified defects in pathways involved in the recognition and response to pathogen-associated molecular patterns. Some of these defects are outlined next.
Defective NFκB activation caused by X-linked hypomorphic mutations of the essential modulator gene (NEMO) compromises signaling mechanisms downstream of Toll, IL-1, and TNF-α receptors. These pa-tients are susceptible to infections caused by a range of microorganisms, including mycobacteria, Gram-positive and Gram-negative bacteria, fungi, and viruses.
UNC93B is a protein of the endoplas-mic reticulum involved in Toll-receptor activation. Mutations in UNC93B impair the production of IFN-α and IFN-β in response to HSV and other viruses. Affected patients present with Herpes sim-plex viral encephalitis. Recently, heterozy-gous dominant-negative mutations in the gene encoding toll receptor 3 (TLR3) have been identified in patients with Herpes sim-plex encephalitis. TLR3 is expressed in the central nervous system where it helps to initiate IFN-α and IFN-β responses to viral duble-stranded DNA.
Interleukin-receptor-associated kinase-4 mediates signaling downstream of Toll receptors and members of the IL-1 receptor superfamily. IRAK-4-deficient individuals present during childhood with recurrent, severe, pyogenic sepsis. They are particu-larly susceptible to recurrent pneumococ-cal infections.
The signal-transducing molecule STAT-1 is required for signaling via recep-tors to IFN-γ as well as IFN-α and IFN-β. IFN-γ-receptor-mediated signaling involves the dimerization of phosphory-lated STAT-1 molecules. Signaling via IFN-α and IFN-β receptors involves the formation of a complex between STAT-1, STAT-2, and a third protein called inter-feron-stimulated-gene factor 3-γ. Com-plete (homozygous) defects of the signal-transducing molecules STAT-1 results in defective responses to IFN-γ, IFN-α, and IFN-β eater leading to the susceptibility to disseminated mycobacterial infections as well as fatal Herpes simplex viral infection. Partial STAT-1 deficiency, which interferes with STAT-1 dimerization required for sig-nal transduction via IFN-γ receptors, leads to increased susceptibility to mycobacte-rial infections. In these patients, the cellu-lar responses to IFN-α and INF-β is intact, thus preserving antiviral immunity.
The WHIM syndrome is a condition characterized by severe warts, hypogam-maglobulinemia, and neutropenia. This is the first example of an immunodeficiency caused by aberrant chemokine-recep-tor function. WHIM syndrome is caused by a mutation in the gene encoding the CXCR 4 chemokine receptor. The mutant form of this receptor shows enhanced responsiveness to its ligand.
The hyper-IgE syndrome (HIES) is a complex clinical entity characterized by recurrent bacterial (S. aureus, Gram-nega-tive bacteria) and fungal infections of skin, lymph nodes, lungs, bones, and joints. These patients have elevated serum IgE levels, eosinophilia, dermatitis, facial dysmorphic features, delayed shedding of primary dentition, osteopenia, and impaired acute-phase responses during infections.
Most patients have an autosomal dominant inheritance while others are sporadic cases. Patients with classical HIES have heterozy-gous mutations in the gene encoding the signal-tranducing protein STAT-3. These mutations mainly involve the DNA-bind-ing domain or the SRC homology 2 domain of the protein and are permissive of protein expression. These mutant proteins severely impair the DNA binding of the phosphory-lated STAT-3 dimer in response to IFN-α and responses to the cytokines IL-10 and IL-6. Reduced response to IL-6 would explain the defective acute-phase response, and the defective response to IL-10 explains the overproduction of IgE. STAT-3 is essen-tial for the generation of TH17 cells and for IL-12 signaling, which are required for the secretion of the bactericidal peptides called β-defensins by epithelial cells of the skin and lungs. This may in part explain the increased incidence of severe sepsis.