Selective predisposition to bacterial infections in IRAK-4-deficient children:: IRAK-4-dependent TLRs are otherwise redundant in protective immunity

Human interleukin ( IL) 1 receptor - associated kinase 4 ( IRAK- 4) deficiency is a recently discovered primary immunodefi ciency that impairs Toll/ IL- 1R immunity, except for the Toll- like receptor ( TLR) 3 - and TLR4 - interferon ( IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK- 4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells ( PBMCs) did not induce the 11 non- IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly( I: C). The patients' individual cell subsets from both myeloid ( granulocytes, monocytes, monocyte- derived dendritic cells [ MDDCs], myeloid DCs [ MDCs], and plasmacytoid DCs) and lymphoid ( B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly( I: C) and lipopolysaccharide in MDCs and MDDCs. Most patients ( 22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent ( 13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease ( 9 out of 28; 32%). Almost half of the patients died ( 12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK- 4 - dependent TLRs and IL- 1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK- 4 - dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.