The final immunodeficiency to be considered in this section is hyperIgE syndrome (HIES), also called Job’s syndrome. This disease is characterized by recurrent skin and pulmonary infections caused by pyogenic bacteria, chronic mucocutaneous candidiasis (noninvasive fungal infection of the skin and mucosal surfaces), very high serum concentrations of IgE, and chronic eczematous dermatitis or skin rash. HIES is inherited in an autosomal recessive or dominant pattern, with the latter manifesting skeletal and dental abnormalities not found in the recessive variant. The inherited defect in the autosomal dominant variant of HIES is in the transcription factor STAT3, which is activated downstream of several cytokine receptors, including those for IL6, IL22, and IL23, and which is central to the differentiation of TH17 cells and activation of ILC3 cells. STAT3 signaling activated by IL6 and IL22 is also important for enhanced antimicrobial resistance of epithelial cells of the skin and mucosal barriers. Because differentiation of TH17 cells is deficient in these patients, the recruitment of neutrophils normally orchestrated by the TH17 response is also defective, as is production of IL22, an important cytokine in activating epithelial cell production of antimicrobial peptides. This is thought to underlie the impaired defense against extracellular bacteria and fungi at barrier epithelia, such as the skin and mucosae. The cause of the elevated IgE is not understood, but it might be due to an abnormal accentuation of skin and mucosal TH2 responses as a result of TH17 deficiency. In an autosomal recessive variant of HIES, the mutation is in the gene that encodes the protein DOCK8 (dedicator of cytokinesis 8), the function of which in immune cells is poorly characterized. However, because DOCK8 is thought to play a broader role in Tcell function, as well as NKcell function, this variant of HIES is distinguished from that caused by STAT3 defects by the additional occurrence of opportunistic infections and recurrent cutaneous viral infections (for example, herpes simplex), as well as allergic and autoimmune manifestations.
agents are pinpointed by genetic deficiencies of cytokine pathways central to type 1/TH1 and type 3/TH17 responses.