Human IRAK-4 deficiency and invasive pneumococcal disease

par Cheng-Lung Ku

Thèse de doctorat en Immunologie

Sous la direction de Jean-Laurent Casanova.

Soutenue en 2007

à Paris 5 .

mots clés

• Récepteurs de type Toll -- immunologie -- Thèses et écrits académiques
• Interleukin-1 Receptor-Associated Kinases -- Dissertations universitaires comme sujet
• Infections à pneumocoques -- Dissertations universitaires comme sujet

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Résumé

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.