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302 Part IV: Molecular and Cellular Hematology Chapter 20: Innate Immunity 303

penta-spanning ER membrane protein that undergoes a conformational which stimulates platelet production, often consumed in the course of
change leading to the activation of TBK1 to phosphorylate IRF3, which a serious infection.
dimerizes and translocates to the nucleus to induce type I IFNs. STING
also activates the IKK complex, leading to degradation of IκB and release Interleukin-12
of NF-κB to enter the nucleus and induce other cytokines. A putative A cytokine made in abundance by dendritic and other cells in response
cytosolic DNA sensor DAI (for DNA-dependent activator of IRFs) has to TLR stimulation, IL-12 activates the production of IFN-γ by lym-
also been described. DAI contains DNA binding domains and enhances phoid cells, which, in turn, increases the microbicidal activity of mono-
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DNA-mediated induction of type I IFNs in vitro. However, the role of nuclear phagocytes. Unlike most cytokines, IL-12 is a heterodimeric
DAI as a sensor of cytoplasmic DNA appears to be redundant. 105 protein, and the IL-12 p40 subunit is subject to induction, whereas the
Both the RLH-MAVS pathway and the cGAS-STING pathway p35 subunit is synthesized constitutively. Mutations of the genes encod-
become activated in B cells when they are stimulated by type 2 T-cell– ing IL-12 or its receptor, or IFN-γ or its receptor, are known to cause
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independent antigens, such as pneumococcal vaccine (PPSV23). relatively severe susceptibility to infection by mycobacteria and other
These pathways sense the induction of endogenous retroviruses, leading intracellular infections. Hence the IL-12/IFN-γ feedback loop is consid-
to sustained B-cell activation and an immunoglobulin (Ig) M response. ered one of the most important innate/adaptive immune interactions.
Chemokines
KEY EFFECTOR CYTOKINES IN THE INNATE A family of small proteins, highly redundant in receptor specificity and
IMMUNE RESPONSE organized into CC and CXC subfamilies, the chemokines are induced
by primary microbial stimuli and by TNF and IL-1. Binding to G-
Cells of the innate immune system exhibit a measure of autonomy (e.g., protein–coupled receptors, they exhibit phagocyte chemotactic activity
neutrophils directly engulf and destroy pathogens), but also initiate the (Chaps. 61 and 68), and are believed to contribute to the egress of neu-
adaptive immune response to microbes and summon “reinforcements” trophils from blood into infected tissue.
to the site of infection. These functions depend upon the production of
cytokines, too numerous to describe in this chapter. However, a few of Granulocyte Colony-Stimulating Factor and Granulocyte-
the key mediators are listed here. Macrophage Colony-Stimulating Factor
The central hematopoietic response is attuned to events in the periph-
Tumor Necrosis Factor-α eral tissues, and granulocyte colony-stimulating factor (G-CSF) and
A homotrimeric cytokine that is made by many cells, TNF is synthesized granulocyte-macrophage colony-stimulating factor (GM-CSF) promote
in greatest amounts by mononuclear phagocytes that have been exposed the production and release of granulocytes and monocytes to cope with
to LPS or other TLR-activating stimuli. It was recognized as a key an infectious challenge. These cytokines are produced by macrophages,
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endogenous mediator of endotoxicity, and later, as a mediator of other endothelial cells and fibroblasts in direct response to TLR signaling
forms of inflammation (including sterile inflammation, as observed in (Chap. 61), and also in response to secondary cytokines such as TNF.
rheumatoid arthritis and cancer, Crohn disease, ankylosing spondylitis, They signal via JAK/STAT-coupled receptors.
and psoriasis). The TNF signaling pathway depends upon two receptors,
involves NF-κB activation, and is ancestrally related to the Drosophila Interferons
Imd (immunodeficiency) pathway for recognition of Gram-negative Type I IFNs (IFN-α and IFN-β) are expressed immediately in response
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bacteria. The ancient phylogenetic origins of TNF signaling, its large to LPS, dsRNA, or unmethylated DNA, and have broad activity in
representation in distant species, the therapeutic efficacy of TNF neu- the containment of viral infections. LPS-induced type I IFN produc-
tralization in the diseases just mentioned, and the immunocompromis- tion depends upon TLR4 and the adapters TRIF and TRAM. dsRNA-
ing effects of TNF and TNF receptor mutations in animals all suggest induced type I IFN depends upon TLR3 and TRIF (but not TRAM).
that TNF is one of the most important of the cytokines utilized by the Unmethylated CpG motifs in DNA stimulate type I IFN production that
innate immune system for effective containment of infection.
depends upon MyD88. Although many cells are induced into an antivi-
ral state as the result of IFN stimulation, NK cells, which are specialized
Interleukin-1α and β for the elimination of virus-infected targets, are particularly dependent
Once known as pleiotropic inflammatory cytokines, IL-1α and IL-1β, upon type I IFN signaling (Chap. 77), and require it for the elimina-
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two distantly related ligands that share the same set of receptors, are tion of specific pathogens such as cytomegalovirus. The type I IFNs
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produced in response to innate immune stimuli and evoke fever, swell- are also involved in protection against bacterial infection, and type
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ing, and neutrophil adhesion in the region of an infectious nidus. The I IFN signaling has been shown to be important to the development
type I IL-1 receptor, responsible for most or all of the agonist activity of endotoxic shock. Plasmacytoid dendritic cells are a particularly
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of the IL-1 proteins, has two chains, each of which is endowed with important source of type I IFN. 113
a cytoplasmic TIR domain. The receptor complex signals via MyD88 Type II IFN (IFN-γ) has less antiviral activity than type I IFN, is
and no other adapters are known to be required. IL-1 signaling may act produced by T cells in response to IL-12 receptor stimulation, and is
as an amplification mechanism that augments the primary infectious crucial for the elimination of intracellular pathogens such as mycobac-
signal, and transmits awareness of infection to cells that lack the innate teria, which reside within macrophages of the infected host.
immune sensors required for detection of microbes.

Interleukin-6 THE ACTIVATION OF ADAPTIVE
Signaling via a receptor that uses the JAK/STAT pathway, IL-6 activates IMMUNITY
many elements of the “acute phase response”; that is, hepatic production
of fibrinogen, serum amyloid A protein, and C-reactive protein. It also The adjuvant effect of microbes has been known since the classic
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has thrombopoietic activity, both directly (minor effect) and through its studies of Lewis and Loomis who coined the term “allergic irrita-
stimulation of thrombopoietin production (major effect) (Chap. 111), bility” to describe the augmented production of antibodies against a

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