Inherited disorders of cytokines

Cytokines are soluble mediators involved in the development or function of the immune system. This paper reviews the literature on childhood-onset inherited disorders associated with impaired cytokine-mediated immunity.

Cytokine-mediated immunity defects can be classified into seven different groups: defects in the interleukin (IL)-7 receptor (IL7RA), in the common cytokine receptor gamma chain (gammac) of the IL-2, -4, -7, -15, and -21, and in Jak3 (JAK3) downstream of the gamma chain; mutation in the IL-2 receptor alpha (IL-2RA) and defective expression of the IL-2Rbeta chain; mutations in the gene encoding for a chemokine receptor, CXCR4; mutations in five genes involved in the IL-12/23-interferon-gamma axis (IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1); mutations in three genes involved in the nuclear factor-kappaB signaling pathway (IRAK4, NEMO, IkappaBA); mutations in the tumor necrosis factor receptor signaling pathway (TNFRSF1A); and mutations in the transforming growth factor-1 gene (TGFB1).

Genetic cytokine-mediated immunity defects are associated with a highly heterogeneous group of clinical features, ranging from susceptibility to infections to developmental defects. This heterogeneity highlights the diversity and pleiotropy of cytokines. It is likely that many more cytokine defects and their responsive pathways will be discovered in the coming years, expanding further the heterogeneity associated with this group of childhood-onset illnesses.