Immunological aspects of immunodeficiency diseases part 115

The hyper-IgE syndrome (HIES) is a complex clinical entity characterized by recurrent bacterial (S.aureus, Gram-negative bacteria) and fungal infections of skin, lymphonodes, lung, 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. Patient with classical HIES have heterozygous mutations in the gene encoding the signal-transducing protein STAT-3. These mutations mainly involve the DNA-binding 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 phosphorylated STAT-3 dimer in response to IFN-α and responses to the cytokines IL-10 and IL-6. Reduced responses 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 essential 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.