Inherited defects in cytokines that are involved in the development and function of different effector Tcell subsets have been defined, as have defects in the receptors or the signaling pathways through which they act. In contrast to the Tcell immunodeficiencies considered above, here we consider those deficiencies that do not have major defects in antibody production. A small number of families have been discovered with individuals who suffer from persistent and sometimes fatal attacks by intracellular pathogens normally restrained by type 1 immunity, especially Mycobacterium, Salmonella, and Listeria species. These microbes are specialized for survival within macrophages, and their eradication requires enhanced microbicidal activities induced by IFNγ produced by type 1 cells: NK cells, ILC1 cells, and TH1 cells (see Section 112). Accordingly, susceptibility to these infections is conferred by a variety of inherited mutations that impair or abolish the function of IL12 or IFNγ, key cytokines in the development and functions of type 1 cells (Fig. 13.7). Patients with mutations in the genes encoding the p40 subunit of IL12 (IL12B), the IL12 receptor β1 chain (IL12RB1), and the two subunits (R1 and R2) of the IFNγ receptor (IFNGR1 and IFNGR2) have been identified. Although affected individuals have heightened susceptibility to the more virulent M. tuberculosis, they suffer more frequently from the nontuberculous, or atypical, strains of mycobacteria, such as Mycobacterium avium, likely due to the greater prevalence of atypical strains in the environment. They may also develop disseminated infection after vaccination with Mycobacterium bovis bacillus Calmette–Guérin (BCG), the strain of M. bovis that is used as a live vaccine against M. tuberculosis. Because the IL12 p40 subunit is shared by IL12 and IL23, IL12 p40 deficiency results in a broader infectious disease risk due to defective type 1 and type 3 (TH17) functions (see Fig. 13.7).
Fig. 13.7 Inherited defects in effector cytokine pathways also, because Stat1 is activated is by the receptors of type ii that impair type 1/TH1 and type 3/TH17 immunity. Shown are interferon (iFn-γ) and type i interferon (iFn-α and iFn-β, not shown), pathways in il-12, il-23, and iFn-γ signaling for which inherited defects in Stat1 result in impaired antibacterial and antiviral immune defects have been described. note that defects in il-12p40 defense, whereas deficiency in either of the iFn-γ receptor subunits (p40) and il-12Rβ1 result in impaired function of both ilC1 cells/ (iFn-γR1 or iFn-γR2) primarily results in impaired defense against nK cells/tH1 cells and ilC3/tH17 cells because these subunits intracellular bacteria. are shared, respectively, by il-12 and il-23 and their receptors.
Similarly, deficiency of the IL12Rβ1 chain, which is shared by the IL12 and IL23 receptors, results in broader susceptibilities than the deficiencies of IFNγ or its receptor.