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Title: Impaired Toll-like receptor 8-mediated IL-6 and TNF-α production in antigen presenting cells from patients with X-linked agammaglobulinaemia Running title: Defective TLR-8 signaling in XLA

Abstract The critical role of Bruton’s tyrosine kinase (Btk) in B-cells has been documented by the block of B-cell development in X-linked agammaglobulinemia (XLA). Less is known about Btk function in myeloid cells. Several pieces of evidence indicate that Btk is a component of Toll-like receptors (TLRs) signaling. We analyzed whether Btk deficiency in XLA is associated with an impaired dendritic cells (DCs) compartment or defective TLR signaling. We analyzed the expression of TLRs 1-9 on myeloid DCs generated from XLA patients, and evaluated their response to activation by specific TLRs agonists. We show that XLA patients have normal numbers of circulating DCs. Btk deficient DCs have no defect in response to stimulation of TLRs 1/2, 2/6, 3, 4 and 5, but display a profound impairment of IL-6 and TNF-α production in response to stimulation by TLR-8 cognate agonist, ssRNA. These findings may provide an explanation for the susceptibility to enteroviral infections in XLA patients. From bloodjournal.hematologylibrary.org by guest on June 7, 2013. For personal use only.