Page 318 - Williams Hematology ( PDFDrive )

293

CHAPTER 20 INNATE IMMUNITY VERSUS

ADAPTIVE IMMUNITY
INNATE IMMUNITY In humans, as in all mammals, resistance to microbial infection is based

partly upon lymphocytes, which yield highly specific responses to
Bruce Beutler 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 develop-
SUMMARY ment of a mechanism for recombination of genomic DNA that arose
approximately 450 to 500 million years ago, operating on genes encod-
The innate immune system provides immediate protection against infection ing proteins with immunoglobulin domains in some lineages and on
1,2
and serves an essential antigen-presenting role that allows the adaptive genes encoding proteins with leucine-rich repeats in other lineages. A
more fundamental type of immunity, known as innate immunity, is rep-
immune response to occur during the days and weeks that follow. The sensory resented in one form or another in all multicellular organisms. For this
apparatus that allows detection of infectious microbes has been deciphered reason, a great deal of progress in the innate immunity field has come
in large part, and it is now known that Toll-like receptors, NOD-like receptors, from the study of model animals such as Drosophila melanogaster, and
RIG-I–like helicases, C-type lectin receptors, and cytosolic sensors of DNA, model plants such as Arabidopsis thaliana. Despite the vast evolution-
most notably cyclic guanosine monophosphate/adenosine monophosphate ary divergence of these organisms from Homo sapiens, these species use
synthetase, permit recognition of specific molecules of microbial origin. Much defensive proteins and signaling pathways that are ancestrally related to
has also been learned of the biochemical events that follow activation of these those represented in humans.
sensors. Susceptibility to infection in humans is strongly heritable, and among Like the adaptive immune system, the innate immune system is
the many loci that influence it, those that encode proteins vital to the innate endowed with a means of detecting microbes, destroying them, and at
immune response are of central importance. Moreover, autoinflammatory and the same time, exercising self-tolerance. These mechanisms are far older
autoimmune diseases are dependent upon the activation of innate immune than the analogous adaptive mechanisms and as a consequence are more
refined. Although it is sometimes termed the “primitive” immune sys-
signaling pathways.
tem, the innate immune system is both sophisticated and highly effec-
tive. Moreover, adaptive immunity is largely dependent upon innate
immunity in the sense that antigen presentation and adaptive immune
activation depend upon innate immune cells.
Innate immunity, which acts immediately to protect the host in
the event of microbial inoculation, fills a temporal gap that would oth-
erwise exist in the global immune response. Days or weeks are required
Acronyms and Abbreviations: BIR, baculovirus inhibitor of apoptosis repeat; for an effective adaptive immune response to develop when the naïve
CARD, caspase activating and recruitment domain; CD, cluster of differentiation; host encounters a new pathogen. During this time, innate immunity
cGAS, cyclic AMP/GMP synthetase; CTLA, cytotoxic T-lymphocyte antigen; DAI, alone protects the host. Indeed, innate immunity is objectively more
DNA-dependent activator of IRFs; ERK, extracellular signal-regulated kinase; FADD, important than adaptive immunity. In a nonsterile environment, sur-
Fas-associated death domain; G-CSF, granulocyte colony-stimulating factor; GM-CSF, vival would be impossible without it (Table 20–1).
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 TYPES OF INNATE IMMUNITY
response factor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysac- Innate immunity embraces a large number of host resistance mecha-
charide; LRR, leucine-rich repeat; MAL, MyD88 adaptor-like; MDA5, melanoma nisms, which may be divided into cellular and noncellular components,
differentiation-associated gene 5; MDP, muramyl dipeptide; MyD88, myeloid differ- and also into afferent and effector components. Noncellular compo-
entiation primary response 88; NACHT, a nucleotide-binding domain present in NAIP, nents of innate immunity include antimicrobial peptides, which selec-
CIITA, HET-E, and TP-1; NADPH, nicotinamide adenine dinucleotide phosphate; NBS, tively disrupt microbial cell membranes, complement, components of
nucleotide binding sequence; NEMO, NF-κB essential modulator; NF-κB, nuclear fac- which also disrupt cell membranes, and the proteins hemopexin and
tor-κB; NK, natural killer; NLR, NOD-like receptor; NOD, nucleotide-binding oligomer- haptoglobin, which deny iron to invasive microbes. Cellular compo-
ization domain; PAR-2, proteinase-activated G-protein–coupled receptor; PRAT4A, nents include myeloid cells (granulocytes, monocyte/macrophages,
protein associated with TLR4; PYD, pyrin domain; RIG-I, retinoic acid inducible gene I; mast cells, and dendritic cells) and lymphoid cells (natural killer [NK]
RIP, receptor-interacting protein; RLH, RIG-I–like helicase; ROS, reactive oxygen spe- cells and NKT cells). As such, it can be seen that despite their recent
cies; SARM, sterile-α and armadillo motif; SOCS-1, suppressor of cytokine signaling evolutionary origin, some lymphoid cells have been coopted to serve
1; STAT, signal transducer and activator of transcription; STING, stimulator of inter- in the innate immune system rather than the adaptive immune system.
feron genes; TAK-1, transforming growth factor-β–activating kinase 1; TBK1, TANK- Many other cells are also endowed with some degree of innate (often
binding kinase 1; TIR, Toll/interleukin-1 receptor; TLR, Toll-like receptor; TNF, “cell-autonomous”) immune function. For example, fibroblasts can
tumor necrosis factor; Tpl2, tumor progression locus 2; TRAF, TNF receptor– sense viral infection and respond with interferon (IFN) production.
associated factor; TRAM, TRIF-related adaptor molecule; TRIF, Toll/interleukin-1 Once initiated, the innate immune response runs its course in a
receptor (TIR) domain-containing adaptor inducing IFN-β; UCM, upregulation of preprogrammed fashion, proceeding from microbe sensing all the
costimulatory molecules.
way through to microbial killing, making division into “afferent” and
“effector” functions somewhat arbitrary. Nonetheless, the proteins

Kaushansky_chapter 20_p0293-0306.indd 293 9/17/15 5:51 PM