Human IRAK-4 deficiency and invasive pneumococcal disease

The susceptibility to severe Streptococcus pneumoniae is associated with a variety of human primary immunodeficiencies. Previous studies in human inherited defects showed several immune responses that were critical for this protection: antibody- and complement-mediated opsonization, the spleen and NF-KB-mediated immune responses. Recently, human Interleukin-l-receptor-associated-kinase-4 (IRAK-4) deficiency which presented a complete impairment in most Toll-like receptors' (TLRs) signaling was found and patients suffered from mostly pyogenic bacterial infections, especially caused by S. Pneumoniae. To provide a global view, we diagnosed up to 28 patients with IRAK-4 deficiency and assessed blood TLRs responses and the production of multiple cytokines in individual leukocyte subsets, which revealed a multi-cytokines and —leukocytes impairment upon TLRs activation. Most patients (22/28, 79%) suffered from invasive pneumococcal disease, often recurrent (13/22, 59%). Other infections were rare, with the exception of severe staphylococcal disease. Almost half the patients died (12/28, 43%). No death or invasive infection occurred in patients over 8 and 14 years of age, respectively. The TIR-1RAK-4 pathway is therefore vital for childhood immunity to pyogenic bacteria and plays a non-redundant role in the immunity against S. Pneumoniae. LRAK-4-dependent human TLRs appear to be less important in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.