Toll-like receptor signaling in primary immune deficiencies.
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.
Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York.
Paul J
PJ
Maglione
Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York.
Noa
N
Simchoni
Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York.
Charlotte
C
Cunningham-Rundles
D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology*; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
C491731:IKBKG protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase; D000243:Adenosine Deaminase
Toll-like receptors; human immunology; infection; primary immune deficiency