Only mutations in NEMO have been identified as the main genetic basis for several devastating human diseases, including immunodeficiency. A large number of patients have deficient antibody production, and other compartments of the immune systems can also show abnormality. Not surprisingly, those patients are susceptible to various bacterial, viral, and fungal infections.
Please review the following
Based on what these innate pathogen recognistion post recepotors signaling pathwatys have evolved to recongize.
IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. J Immunol. 2000 Apr 15;164(8):4301-6.
Swantek JL(1), Tsen MF, Cobb MH, Thomas JA.
Author information:
(1)Departments of Pharmacology, Pediatrics, and Molecular Biology, University of
Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Endotoxin triggers many of the inflammatory, hemodynamic, and hematological derangements of Gram-negative septic shock. Recent genetic studies in mice have identified the Toll-like receptor 4 as the transmembrane endotoxin signal transducer. The IL-1 intracellular signaling pathway has been implicated in Toll-like receptor signal transduction. LPS-induced activation of the IL-1 receptor-associated kinase (IRAK), and the influence of IRAK on intracellular signaling and cellular responses to endotoxin has not been explored in relevant innate immune cells. We demonstrate that LPS activates IRAK in murine macrophages. IRAK-deficient macrophages, in contrast, are resistant to LPS. Deletion of IRAK disrupts several endotoxin-triggered signaling cascades.Furthermore, macrophages lacking IRAK exhibit impaired LPS-stimulated TNF-alpha production, and IRAK-deficient mice withstand the lethal effects of LPS. These findings, coupled with the critical role for IRAK in IL-1 and IL-18 signal transduction, demonstrate the importance of this kinase and the IL-1/Toll signaling cassette in sensing and responding to Gram-negative infection.
K. Takeda, S. Akira, TLR in innate immunity, Int. Immunol. 17 (2005) 1–14.
Roles of Toll-like receptors in innate immune responses. Genes Cells. 2001 Sep;6(9):733-42.
Takeda K(1), Akira S.
Author information:
(1)Department of Host Defense, Research Institute for Microbial Diseases, Osaka
University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.
NFKB (as you can see in http://lsi.zju.edu.cn/wescms/sys/filebrowser/file.php?cmd=download&id=5327) is in the pathway of innate and adaptative immunity cascades (i.e. BCR and TCR). NFKB1 & 2 are considered causing genes of CVID. IRAK4/MyD88 pathway exclusively precludes NFKB activation throughout innate immunity (particularly against S. pneumoniae, S. aureus and -rarely- gramnegative bacilli)
NEMO of IKK complex is the main regulator of concentration of NFKB in the host immune cells. NFKB concentration in the cell increases by any foreign antigen. Please go through the detailed mechanism of NFKB Signalling pathway.
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