Volume 1356, Issue 1 p. 1-21
Original Article

Toll-like receptor signaling in primary immune deficiencies

Paul J. Maglione

Paul J. Maglione

Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York

These authors contributed equally.

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Noa Simchoni

Noa Simchoni

Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York

These authors contributed equally.

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Charlotte Cunningham-Rundles

Corresponding Author

Charlotte Cunningham-Rundles

Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York

Address for correspondence: Charlotte Cunningham-Rundles, M.D., Ph.D., Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029. [email protected]Search for more papers by this author
First published: 30 April 2015
Citations: 55

Abstract

Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency.