Inherited defects in TLR-dependent responses are rare and have been recognized only recently. The major signaling pathway downstream of most TLRs as well as of the interleukin-1 receptor (IL-1R) involves the MyD88 adaptor and the IRAK-4 and IRAK-1 kinases (see Chapter 4), and this pathway results in the nuclear factor kB (NF-KB)-dependent induction of proinflammatory cytokines. TLR 3, 7, 8, and 9 recognize nucleic acids, are located in endosomes, and require a protein called UNC93B for their function. UNC93B is an endoplasmic reticulum membrane protein that interacts with endosomal TLRs when they are synthesized in the endoplas-mic reticulum and helps deliver these TLRs to the endosomes. The UNC93B protein is also critical for signaling by nucleic acid-specific TLRS. Signaling downstream of the endosomal TLRs results in the synthesis and secretion of type I interferons. Defects in TLR signaling tend to have a fairly circumscribed clinical phenotype. Severe invasive bacterial infections early in life, especially pneumococcal disease, are observed in individuals with mutations in MYD88 and IRAK4. Later in life, infections tend to be less severe. Heterozygous mutations in TLR3 as well as homozygous mutations in UNC93B result in reduced type I interferon generation and susceptibility to herpes simplex encephalitis. Type I interferon receptors activate the STAT1 transcription factor. Loss-of-function STAT1 mutations (which interfere with interferon signaling) have also been linked to severe viral infections, notably herpes simplex encephalitis.
Some immune deficiencies are caused by defects in signaling pathways downstream of TLRs. Point mutations in the inhibitor of kB kinase y (IKKy), also known as nuclear factor kB essential modulator (NEMO), a component of the IkB kinase complex that is required for NF-kB activation, contribute to the X-linked recessive condition known as anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). In this disorder, differentiation of ectoderm-derived structures is abnormal, and immune function is impaired in a number of ways. Responses to TLR signals as well as CD40 signals are compromised. These patients suffer from infections with encapsulated pyogenic bacteria as well as with intracel-lular bacterial pathogens including mycobacteria, viruses, and fungi such as Pneumocystis jiroveci (see also discussion later in the section on hyper-IgM syndromes). An autosomal recessive form of EDA-ID has been described in which a hypermorphic point mutation in IkB a prevents the phosphorylation, ubiquitination, and degradation of IKBa, thus leading to impaired NF-kB activation.
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