Rheumatoid Arthritis Patients Elaborate from Systemic Lupus Erythematosus and Immune Complex-Mediated Cell Activation

IL-1R–associated kinases (IRAKs) are important mediators of MyD88-dependent signaling by the TLR/IL-1R superfamily and facilitate inflammatory responses. IRAK4 and IRAK1 function as active kinases and as scaffolds for protein–protein interactions. We report that although IRAK1/4 kinase activity is essential for human plasmacytoid dendritic cell (pDC) activation, it is dis-pensable in B, T, dendritic, and monocytic cells, which is in contrast with an essential active kinase role in comparable mouse cell types. An IRAK1/4 kinase inhibitor abrogated TLR7/9-induced IFN-a responses in both mouse and human pDCs, but other human immune cell populations activated via TLR7/9 or IL-1R were refractory to IRAK4 kinase inhibition. Gene ablation experiments using small interfering RNA demonstrated an essential scaffolding role for IRAK1 and IRAK4 in MyD88-dependent signaling. Finally, we demonstrate that autoimmune patient (systemic lupus erythematosus and rheumatoid arthritis) serum activates both pDC and B cells, but IRAK1/4 kinase inhibition affects only the pDC response, underscoring the differential IRAK1/4 functional requirements in human immune cells. These data reveal important species differences and elaborate cell type requirements for IRAK1/4 kinase activity. I nterleukin-1R–associated kinase 1 (IRAK1) and IRAK4 are essential for transduction of MyD88-dependent TLR and IL-1R signals that underscore a majority of innate and some adap-tive immune responses (1). Recruitment of IRAK4 and IRAK1 to the MyD88-signaling complex elaborates NF-kB–dependent inflammation (2, 3). MyD88 is also coupled to IFN regulatory factors (IRFs) that mediate differential expression of specific cytokines, depending on the TLR/IL-1R signaling pathway (4, 5). Studies with cells derived from human patients with inherited IRAK4 deficiency have shown that, in the absence of IRAK4, cytokine responses to MyD88-dependent signaling are ablated (6, 7). IRAK4-deficient patients also have defects in B cell central and peripheral tolerance, suggesting a role for IRAK4 in directing B cell responses (8). How IRAKs facilitate TLR/IL-1R–mediated signaling across other human immune cell types is not well characterized. It is clear that although similarities in IRAK4 activity exist between human and mouse, there are important differences as well. Mice deficient for IRAK4 are severely impaired in their cellular responses to IL-1, IL-18, and most TLR ligands, sharing an overlapping phenotype with IRAK4-deficient human patients (3). However, although IRAK4-deficient mice display broad susceptibility to viral and bacterial infections, IRAK4-deficient human patients exhibit a narrow infectious phenotype, limited primarily to pyogenic bacterial infections at an early age (6, 7). IRAK1 deficiency in humans has not been described. Intriguingly, however , IRAK1 has recently …