The innate immune system provides immediate protection against infection and serves an essential antigen-presenting role that allows the adaptive immune response to occur during the days and weeks that follow. The sensory apparatus that allows detection of infectious microbes has been deciphered in large part, and it is now known that Toll-like receptors, NOD-like receptors, RIG-I–like helicases, C-type lectin receptors, and cytosolic sensors of DNA, most notably cyclic guanosine monophosphate/adenosine monophosphate synthetase, permit recognition of specific molecules of microbial origin. Much has also been learned of the biochemical events that follow activation of these sensors. Susceptibility to infection in humans is strongly heritable, and among the many loci that influence it, those that encode proteins vital to the innate immune response are of central importance. Moreover, autoinflammatory and autoimmune diseases are dependent upon the activation of innate immune signaling pathways.
Acronyms and Abbreviations
BIR, baculovirus inhibitor of apoptosis repeat; CARD, caspase activating and recruitment domain; CD, cluster of differentiation; cGAS, cyclic AMP/GMP synthetase; CTLA, cytotoxic T-lymphocyte antigen; DAI, DNA-dependent activator of IRFs; ERK, extracellular signal-regulated kinase; FADD, Fas-associated death domain; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; IFN, interferon; IκB; inhibitor of κB; IKK, IκB kinase; IL, interleukin; IPAF, ice-protease activating factor; IPS-1, IFN-β promoter stimulator 1; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon response factor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; LRR, leucine-rich repeat; MAL, MyD88 adaptor-like; MDA5, melanoma differentiation-associated gene 5; MDP, muramyl dipeptide; MyD88, myeloid differentiation primary response 88; NACHT, a nucleotide-binding domain present in NAIP, CIITA, HET-E, and TP-1; NADPH, nicotinamide adenine dinucleotide phosphate; NBS, nucleotide binding sequence; NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; NK, natural killer; NLR, NOD-like receptor; NOD, nucleotide-binding oligomerization domain; PAR-2, proteinase-activated G-protein–coupled receptor; PRAT4A, protein associated with TLR4; PYD, pyrin domain; RIG-I, retinoic acid inducible gene I; RIP, receptor-interacting protein; RLH, RIG-I–like helicase; ROS, reactive oxygen species; SARM, sterile-α and armadillo motif; SOCS-1, suppressor of cytokine signaling 1; STAT, signal transducer and activator of transcription; STING, stimulator of interferon genes; TAK-1, transforming growth factor-β–activating kinase 1; TBK1, TANK-binding kinase 1; TIR, Toll/interleukin-1 receptor; TLR, Toll-like receptor; TNF, tumor necrosis factor; Tpl2, tumor progression locus 2; TRAF, TNF receptor–associated factor; TRAM, TRIF-related adaptor molecule; TRIF, Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing IFN-β; UCM, upregulation of costimulatory molecules.
INNATE IMMUNITY VERSUS ADAPTIVE IMMUNITY
In humans, as in all mammals, resistance to microbial infection is based partly upon lymphocytes, which yield highly specific responses to microbial antigens: either the production of antibodies or the expansion of T-cell cell clones that are directly cytotoxic to infected cells (Chaps. 75 and 76). This, the adaptive immune response, is a recent fixture in evolution, witnessed only in vertebrates and traceable to the development of a mechanism for recombination of genomic DNA that arose approximately 450 ...