Remarkably, of the ten TLRs found in humans, defects in only one—TLR3— have been linked to immunodeficiency. While defects in other TLRs have been identified (for example, TLR5), they have not been associated with an overt immunodeficiency phenotype, likely reflecting a substantial level of redundancy. On the other hand, patients with hemizygous (dominant) and homozygous (recessive) mutations in the gene encoding TLR3, which senses doublestranded RNA, typically have recurrent herpes simplex virus1 (HSV1) infections of the central nervous system (herpes simplex encephalitis) due to impaired production of type I interferons by cells of the nervous system. Those with inherited deficiencies in molecules involved in TLR3 signaling (for example, TRIF, TRAF3, or TBK1) are similarly susceptible to HSV1 encephalitis, as are patients with mutations in the TLRtransport protein UNC93B1, which is required for the transport of TLR3 from the endoplasmic reticulum to the endolysosome. Interestingly, leukocytes from these patients have no defect in their response to TLR3 ligands or HSV1, indicating redundancy of TLR3 function in these cells, but not those of the central nervous system. Similarly, these patients show only a limited predisposition to other viral infections, implying the existence of TLR3independent protection against most other types of viral infection.
Genetic defects that affect signaling by pattern recognition receptors (PRRs) other than TLRs have been described. CARD9 is an adaptor molecule involved in signaling downstream of Ctype lectin receptors expressed on myeloid cells. Dectin1, Dectin2, and macrophageinducible Ctype lectin (MINCLE) each recognize fungalassociated molecular patterns that signal through CARD9 to induce secretion of proinflammatory cytokines, including IL6 and IL23 (see Section 31). Autosomal recessive CARD9 deficiency results in impaired TH17 cell responses to fungi, with the result that patients with this deficiency, like patients with inborn errors of IL17 immunity (for example, IL17RA deficiency and IL17F deficiency; see Section 1310), suffer chronic mucocutaneous candidiasis. However, in addition, these patients can suffer infections by dermatophytes, which are ubiquitous filamentous fungi that normally cause common superficial skin and nail infections, such as tinea pedis (athlete’s foot).
Fig. 13.14 The autoinflammatory diseases.
Most of the other known defects in phagocytic cells affect their ability to ingest microbes and destroy them once ingested (see Fig. 13.13). Patients with chronic granulomatous disease (CGD) are highly susceptible to bacterial and fungal infections and form granulomas as a result of an inability to kill bacteria ingested by phagocytes (see Fig. 11.13). The defect in this case is in the production of reactive oxygen species (ROS) such as the superoxide anion (see Section 32). Discovery of the molecular defect in this disease gave weight to the idea that these agents killed bacteria directly; this notion has since been challenged by the finding that the generation of ROS is not itself sufficient to kill target microorganisms. It is now thought that ROS cause an influx of K+ ions into the phagocytic vacuole, increasing the pH to the optimal level for the action of microbicidal peptides and proteins, which are the key agents in killing the invading microorganism.