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200 Part III Immunologic Basis of Hematology

TABLE Human Innate Versus Adaptive Immune System signaling components and cytokines. For instance, 10 different
19.1 MBL haplotypes have been identified with serum levels varying
by up to 1000-fold. Low levels can be associated with increased
Feature Innate Adaptive severity of infections with encapsulated organisms in immuno-
Response time Hours to days >5 days compromised or chronically infected hosts. Mutations in TLR3
have been associated with increased susceptibility to encephalitis
Expression Constitutive Induced by pathogen caused by DNA viruses. Many different mutations of signaling
10
exposure
intermediates and cytokines, such as Myd88 and components
Shaped by pathogen exposure No Yes of IL-12, have also been identified, and lead to susceptibility to
Approximate number of gene 10 –10 3 10 –10 14 streptococcal infections and mycobacterial infections, respectively.
10
2
products involved in direct However, it should be noted that the complete lack of certain key
pathogen recognition components of the innate immune system is incompatible with
life, as evidenced by experiments in mice. Hence many of the
Clonal response No Yes
genetic changes found in patients with mild phenotypic changes are
Found in invertebrate species Yes No better viewed as phenotypic variants, rather than as disease-causing
mutations.
phagocytic cell. Internalized pathogens are destroyed by a combina- INNATE IMMUNITY AND TISSUE HOMEOSTASIS
tion of hydrolytic and oxidation reactions within vacuoles inside the
phagocytic cells. Phagocytosis also triggers the release of bactericidal Pathogen recognition molecules or receptors and cells of the innate
or bacteriostatic molecules from intracellular granules into the immune system also play roles in normal tissue homeostasis. Specific
tissue. These products (e.g., lysozyme, lactoferrin, myeloperoxidase, PRRs are involved in the clearance of serum clotting factors, hor-
antimicrobial peptides, nitrous oxide, and superoxide radicals) mones, lysosomal hydrolases, and senescent cells, and in wound
11
are toxic to pathogens and induce a local inflammatory response healing. The class A scavenger receptor on macrophages is involved
that can lead to tissue injury. Other molecules released, including in the internalization of oxidized low-density lipoprotein, the devel-
elastase and collagenase, participate in tissue injury and wound opment of atherosclerosis, and the clearance of apoptotic T cells in
12
healing. 7,8 the thymus. The immune system is actively involved in surveillance
The second stage is cytokine production, which is responsible for against transformed or cancerous cells, much of it via interfaces
initiating, amplifying, and maintaining the innate and adaptive between the innate and adaptive immune systems (IFN-γ, γδ T cells,
immune response. The signaling pathways involved within the cell NK cells, and cytotoxic T lymphocytes [CTLs]).
vary by PRR, but activation of NFκB (nuclear factor κ-light-chain-
enhancer of activated B cells) is a central event in almost every aspect
of the immune response. Other signaling pathways that are activated ADAPTIVE IMMUNE RESPONSE
include the caspases, IRF3/5/7, MyD88, and other kinase cascade
pathways. Also involved in the downstream activation and regulation In juxtaposition to the innate immune system, which is characterized
of the immune response are novel small RNA molecules, known as by rapid, fixed, and broad responses to pathogens, the adaptive
microRNAs. These small RNA molecules can regulate the expression immune system has evolved to respond to pathogens in a remarkably
of critical proteins that can be effectors of the immune response (e.g., specific and long-lasting manner. This is accomplished by the genera-
microRNA-155), and certain microRNAs seem to be key in reigning tion of a receptor repertoire far more diverse than that represented
9
in overactivity of the immune system (e.g., microRNA-146a). by PRRs, and the amplification of populations of pathogen-specific
Downstream of these signaling pathways, cytokines, which include cells as a consequence of pathogen exposure (i.e., generation of spe-
interleukins, interferons (IFNs), and chemokines, are synthesized and cific immunologic memory). The two key receptors, those encoding
secreted. Interleukins, which are produced by monocytes, macro- the T-cell receptor (TCR) and the B-cell receptor/immunoglobulin
phages, lymphocytes, or certain epithelial cells, can amplify the innate (BCR/Ig), are generated by somatic rearrangements and mutations
and initiate the adaptive immune responses. IFNs, produced by virtu- in TCR and BCR/Ig genes during T- and B-cell development. This
ally every cell type, propagate antiviral and antitumor responses by process results in a remarkable diversification and amplification of the
activating T cells and natural killer (NK) cells. Chemokines are repertoire of pathogen-specific recognition molecules (see Table
produced primarily by cells of the innate immune system and func- 19.1). Indeed, the number of possible pathogen detection motifs
tion dually as chemoattractants (i.e., recruiting cells) and cytokines encoded by the TCR and BCR/Ig following genetic rearrangement
(i.e., activating cells). Members of the tissue necrosis factor family vastly outnumber the number of known pathogenic organisms by
mediate the sepsis response and cell death and participate in the many orders of magnitude.
development of lymphoid organs. A simplified organization of some The activation of the adaptive immune system depends on the
of the better-characterized cytokines by biologic effects is presented initial recognition of a pathogenic insult by the innate immune
in Table 19.3, and a more detailed discussion of some cytokines can system. This initial response triggers the production of cytokines that
be found in Chapter 16. activate resident DCs, which then phagocytize and process the
Finally, activation of the adaptive immune response occurs. Both antigens by cleaving them into small peptides. These peptides are
by the production of cytokines, which activate lymphocytes, and by then presented on the DCs’ surfaces bound to major histocompatibil-
the processing, transport, and presentation of antigens directly to T ity complex (MHC) molecules. Recognition of the processed antigens
cells (primarily done by dendritic cells [DCs]), PRRs and cells of the by the TCR leads to activation of T cells, which in turn activate B
innate immune system are essential for the development of adaptive cells, thus initiating the adaptive immune response. This antigen
immune responses. The biology of T cells, B cells, and DCs is dis- presentation step may occur at the site of pathogen exposure, or it
cussed in detail in Chapters 20 to 23. may require the migration of antigen-containing DC from the point
of pathogen entry through lymphatic channels to lymphoid tissues.
IMMUNE DEFICIENCY CONDITIONS CAUSED BY In addition, activation of innate immune cells leads to changes in
vascular permeability, and lymphocyte adhesion. These steps result in
MUTATIONS IN THE INNATE IMMUNE SYSTEM local inflammation and the recruitment of additional lymphocytes to
the site of pathogen entry, hence localizing all the correct cellular
Mutations of several components within the innate immune system players to the site of infection. DCs, B cells, and T cells are discussed
have been identified. These include mutations in PRRs, downstream in depth in Chapters 20 to 23.