Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency

Abstract

Autosomal recessive IRAK-4 and MyD88 deficiencies predispose affected patients to recurrent invasive pyogenic bacterial infection. Both defects result in the selective impairment of cellular responses to Toll-like receptors (TLRs) other than TLR3 and of cellular responses to most interleukin-1 receptors (IL-1Rs), including IL-1R, IL-18R, and IL-33R. Hypomorphic mutations in the X-linked NEMO gene and hypermorphic mutations in the autosomal IKBA gene cause X-linked recessive and autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) syndromes. Both of these defects impair NF-κB-mediated cellular responses to multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor receptors (TNF-Rs). They therefore confer a much broader predisposition to infections than that for IRAK-4 and MyD88 deficiencies. These disorders were initially thought to be rare but have now been diagnosed in over 170 patients worldwide. We review here the infectious diseases affecting patients with inborn errors of NF-κB-dependent TLR and IL-1R immunity.

Fig. 1.

TIR and NF-κB signaling pathways. Immune receptor signaling pathways leading to NF-κB activation can be grouped into four categories on the basis of the surface receptors involved: members of the TIR superfamily (IL-1Rs/TLRs), antigen receptors (TCR and BCR), members of the TNF-R superfamily (TNF-Rs), and RANK, VEGFR3, and EDAR. The two proteins of the TIR signaling pathway (MyD88 and IRAK-4) and the two proteins of the NF-κB signaling pathway (NEMO and IκBα) responsible for primary immunodeficiencies are shown.