Page 58 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 3 Innate Immunity 43

the earliest responders to infection. Those not recruited to sites complex, including the complement fragment C5a; formylated
of infection undergo apoptosis and are cleared by the reticulo- peptides, such as FMLP (N-formyl-methionine-leucine-phenyl-
endothelial system. Individuals with severely low numbers alanine); LTB4 (leukotriene B4); PAF (platelet-activating factor);
of neutrophils (<500 cells/µL [microliter]) are susceptible to and pattern recognition receptors, such as TLR4. Upon cellular
overwhelming bacterial infections. activation, p40 phox , p47 phox , and p67 phox are phosphorylated and
recruited to cellular membranes, where they associate with
membrane-bound gp91 phox and p22 phox (flavocytochrome b 558 )
CLINICaL PEarLS and GTP-bound Rac1 (monocytes) or Rac2 (PMNs). The
29
Neutrophils activated enzyme generates superoxide radicals, which are
then converted to hydrogen peroxide by superoxide dismutase.
• Myeloperoxidase deficiency is asymptomatic in the majority of individu- Hydrogen peroxide is combined with halide ions by myeloper-
als, although Candida infections (mucocutaneous and invasive) have oxidase to generate hypohalous acids, which are toxic to
been reported. bacteria.
• Impaired production of reactive oxygen intermediates causes chronic
granulomatous disease, which manifests as susceptibility to invasive The phagocyte oxidase complex also generates an environment
bacterial and fungal infections and impaired wound healing. within the phagolysosome conducive to proteolytic enzyme
• Severe primary, or secondary, neutropenia (<500 cells/µL [microliter]) activation. The oxidase functions as an electron pump that
creates susceptibility to overwhelming bacterial infections. generates an electrochemical gradient across the phagolysosomal
membranes, which is compensated by the movement of ions
into the vacuole. This results in the increase in vacuolar pH and
Mononuclear phagocytes include monocytes and macrophages. osmolarity required for activation of the anti-microbial proteases
Monocytes originate in bone marrow and migrate into the elastase and cathepsin G. 30
+
peripheral circulation. CD14 monocytes are effective at phago- Macrophages (Chapter 6) produce reactive nitrogen intermedi-
cytosis and production of reactive oxygen intermediates (ROIs) ates in response to microbes. Nitric oxide (NO) is produced by
and proinflammatory cytokines in response to a wide variety of inducible nitric oxide synthetase (iNOS). Expression of iNOS
microbial stimuli. A subset of monocytes with low CD14 expres- is induced by activation of Toll-like receptors (TLRs), and expres-
31
dim
sion (CD14 ), but expressing CD16, is associated with vascular sion is augmented further by IFN-γ. iNOS catalyzes the conver-
endothelia and appears to be specialized for response to viruses sion of arginine to citrulline, releasing diffusible nitric oxide gas.
and nucleic acid–containing immune complexes and may also Within phagolysosomes, NO combines with hydrogen peroxide
+
26
be involved in the pathogenesis of autoimmune disorders. CD14 or superoxide to produce peroxynitrite radicals, which contribute
monocytes enter tissues where they mature into macrophages. to microbial killing. Although ROIs and NO are effective anti-
Distinct macrophages populations in different tissues are given microbial agents, they are nonspecific and are also capable of
specific names, including Kupffer cells in the liver, alveolar inducing damage to host tissues.
macrophages in the lung, osteoclasts in bone, and microglia within DCs (Chapter 6) have long membranous extensions for
the brain. Macrophages differ from PMNs in that they are not surveying the local environment and are highly phagocytic. They
terminally differentiated and can proliferate at sites of infection. link innate to adaptive immune responses after activation by
They are longer lived than PMNs and are the predominant innate microbes. DCs express a variety of PRRs, which allow them to
immune cell several days after an infection. Macrophages display respond to microbes by antigen uptake and cytokine secretion.
plasticity in their functions, depending on the cytokine milieu. Activated DCs rapidly uptake antigen and then home to draining
Classically activated macrophages (M1) are induced by interferon-γ lymph nodes where they localize to T-cell zones. During their
(IFN-γ) and bacterial products. They have microbicidal activity migration to lymph nodes, DCs mature and become efficient
and proinflammatory functions. In contrast, alternatively activated antigen presenting cells (APCs). Once in the lymph node, DCs
macrophages (M2) are induced by IL-4 and IL-13 and have express high levels of costimulatory molecules, such as B7 and
anti-inflammatory functions. M2 macrophages have been shown IL-12p70, and present antigen to naïve T cells, inducing their
to inhibit T-cell activation through production of IL-10 and differentiation into effector T cells (Th1 T cells). Plasmacytoid
transforming growth factor-β (TGF-β). 27 dendritic cells (pDCs) are specialized for response to viral infec-
Activated PMNs and macrophages kill phagocytosed bacteria tion and secrete large amounts of type 1 IFNs.
+
by releasing microbicidal molecules both extracellularly and One subset of DC characterized by CD11c high CD103 expres-
within phagolysosomes. Microbes are detected by pattern recogni- sion in the lamina propria of the small intestine facilitates
28
tion receptors, as well as by Fc and complement C3 receptors. the differentiation of regulatory T cells in a retinoic acid-
Bacteria are internalized into phagosomes. Phagosomes fuse with and TGF-β–dependent manner. Such DC subsets may play a
lysosomes containing proteolytic enzymes (elastase, cathepsin role in the development of tolerance to commensal bacteria
G) to form phagolysosomes. (Chapter 14).
Activated PMNs and macrophages produce ROIs, which are NK cells are derived from common lymphoid progenitor cells
toxic to microbes. ROIs are produced by phagocyte-derived and constitute 5% to 20% of mononuclear cells in the periphery
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, (Chapter 17). They do not express somatically rearranged antigen
a multisubunit enzyme that consists of five subunits, p22 phox , receptors. Target cells are identified using germline DNA-encoded
−
p40 phox , p47 phox , p67 phox , and gp91 phox . The phagocyte oxidase is receptors. NK cells are divided into two subsets, CD56 bright CD16
+
dim
dim
activated following engulfment of opsonized bacteria (oxidative and CD56 CD16 , which have different functions. CD56 NK
burst). Genetic defects in components of the NADPH oxidase cells account for roughly 90% of NK cells in the periphery and
complex create susceptibility to invasive infections with bacteria express the low affinity Fcγ receptor (CD16), which mediates
and fungi (chronic granulomatous disease), as well as impaired antibody-dependent, cell-mediated cytotoxicity. CD56 bright NK
wound healing. A variety of stimuli activate the phagocyte oxidase cells are poorly cytotoxic but produce large amounts of cytokine