Autosomal recessive lossoffunction mutations in STAT1 impair IFNγ receptor signaling and are also associated with increased susceptibility to infections by mycobacterial and other intracellular bacteria (see Fig. 13.7). However, due to its shared function in IFNα receptor signaling in response to IFNα and IFNβ (type I interferons), patients with STAT1 defects are also susceptible to viral infections. Interestingly, patients with partial loss of function of STAT1 have been identified who are susceptible to mycobacterial infections, but not viral infections, suggesting a more stringent requirement of STAT1 in protection against the former.
In addition to the TH17related defects described above for STAT3deficient HIES (see Section 139), other defects in cytokinemediated functions of this pathway have been identified that lack the hyperIgE component (Fig. 13.8). Whereas heightened susceptibility to intracellular bacteria is a feature common to immunodeficiencies that impair type 1 immunity, heightened susceptibility to infections by Candida spp. and pyogenic bacteria, particularly
C. albicans and S. aureus, respectively, is characteristic of these type 3 deficiencies. This reflects the specialized function of TH17 and ILC3 cells in barrier defense against fungi and extracellular bacteria. Inherited deficiencies in IL17F and IL17RA, the shared receptor component for homo and heterodimeric IL17F–IL17A ligands, confer susceptibility to these infectious agents and thus identify a key role for IL17 cytokines in host defense against them. A similar susceptibility to chronic mucocutaneous candidiasis and pyogenic bacteria has been found in patients with autosomal dominant, gainoffunction mutations in STAT1. Because TH17 cell development is impaired by STAT1 signaling downstream of several cytokine receptors (for example, type I and type II IFN receptors), individuals with these mutations have impaired type 3 defenses. Note that this is in contrast to patients with lossoffunction STAT1 mutations, who are predisposed to intracellular bacterial infections due to defective type 1 immunity.
In addition to inherited defects in effector cytokine genes, some forms of immunodeficiency result in the production of neutralizing autoantibodies against these cytokines. This results in infectious risks similar to those caused by primary cytokine deficiencies. Most patients with APECED syndrome (caused by defects in the AIRE gene; see Section 137) develop chronic mucocutaneous candidiasis that is due to the development of autoantibodies against IL17A, IL17F, and/or IL22. Patients with neutralizing autoantibodies against IFNγ who have impaired protection against atypical mycobacteria have also been reported, although the basis for this is unknown.
13-11 Inherited defects in the cytolytic pathway of lymphocytes can cause uncontrolled lymphoproliferation and inflammatory responses to viral infections.