http://surgerybook.net/

protein, facilitates survival. It also stimulates the production of other cytokines such as IFNγ and IL-4.4

IL-2 promotes the proliferation and differentiation of many immune cells. NK cells are stimulated to

grow and transform into lymphocyte-activated killer cells. In combination with IFNγ and IL-12, IL-2 can

trigger a positive feedback cycle of NK activation. IL-2 stimulates B-cell growth and antibody synthesis.

Repeated activation of CD4+ T cells in the presence of IL-2 sensitizes these cells to apoptosis by fas-fasligand. IL-2 may also stimulate the development of regulatory T cells, and IL-2 knockout mice develop

autoimmunity. Knockout mice lacking the γ chain develop X-linked severe combined immunodeficiency

syndrome. This is probably due to an inability of immature T cells to respond to IL-7. IL-2 has been used

in the management of cancer, in particular renal cell carcinoma.158

Interleukin-4

IL-4 is the major stimulus for the production of IgE antibodies and for the development of TH2 cells

from naïve CD4+ T cells (Table 7-6). The principle cellular sources are CD4+ T cells, mast cells, and

basophils. The IL-4 receptor belongs to the type I cytokine receptor family and signals through the

JAK/STAT pathway.159 (Fig. 7-8). IgE is integral in orchestrating the defense against parasitic

infections. It stimulates IgE production and mast cell/eosinophil-mediated reactions, and induces B cell

Ig heavy chain class switching to the IgE isotype. However, IL-4 also serves a counterregulatory role by

inducing TH2 cell differentiation and growth. IL-4 antagonizes the macrophage-activating effects of IFNγ

and thus inhibits cell-mediated immunity.

Interleukin-5

IL-5 is produced by TH2 cells and activated mast cells and activates eosinophils, (Table 7-6). It signals

through the type I cytokine receptor and the JAK/STAT pathway (Fig. 7-8). IL-5 is an inducer of

eosinophil growth, differentiation, and activation, and also participates in the eradication of helminthic

infection. IL-5 also stimulates the proliferation of B cells and the production of IgA antibodies.4

Interleukin-13

IL-13 is produced by TH2 cells and some epithelial cells and is structurally homologous and functionally

similar to IL-4 (Table 7-6). The receptor is found mainly on nonlymphoid cells and can be activated by

either IL-13 or IL-4. IL-13 downregulates the expression of Fcγ on monocytes and macrophages, thereby

decreasing antibody-dependent cellular cytotoxicity. It increases 15S-HETE and lipoxin A4

, both of

which antagonize proinflammatory LTs. However, they can increase the expression of MHC class II and

costimulatory molecules on monocytes, and thereby serve an immunostimulatory function. The major

action is to inhibit the activation of macrophages and to antagonize IFNγ.160

Interferon γ

IFNγ is produced by NK cells, TH1 cells, and CD8+ cells, and as the principal stimulus for macrophage

activation, provides necessary functions during both innate and adaptive immune responses (Table 7-6).

It modulates cellular differentiation, cytotoxicity, cytokine production, cellular adhesion, and oxidative

metabolism. During innate immunity, NK cells secrete IFNγ upon exposure to pathogen or stimulation

by IL-12. CD8+ T cells and the TH1 subset of CD4+ T cells produce it in response to MHC-bound peptide

antigen with a costimulatory signal. The IFNγ receptor is composed of two homologous proteins

belonging to the type II cytokine receptor family and functions through the JAK/STAT pathway (Fig. 7-

8).4

The antiviral and antitumor properties of IFNγ are redundant with those of type I interferons. In

concert with TNFα and IL-12 it forms one arm of a positive feedback loop fueling the activation of both

NK cells and macrophages. Stimulated macrophages activate NK cells by releasing TNFα and IL-12.

These NK cells produce IFNγ, which further stimulates macrophages to secrete more TNFα and IL12.161,162

IFNγ induces the genes encoding the enzymatic machinery required for generating ROS generation

and provides the principle stimulus for macrophages to kill phagocytosed microbes. It regulates the

expression of MHC class I and class II molecules and costimulators of APC, and induces the transcription

of enzymes regulating antigen processing.161,162

IFNγ synergizes with TNFα to activate the endothelium and upregulate adhesion molecule expression;

in doing so it facilitates lymphocyte recruitment and leukocyte recruitment. Interferon promotes the

differentiation of naïve CD4+ cells into TH1 cells and inhibits the proliferation of TH2 cells, in part, by

inducing IL-12, the major TH1-inducing cytokine, from activated mononuclear phagocytes. It promotes

199

http://surgerybook.net/

B-cell switching to certain IgG subclasses, notably IgG2a, and inhibits the switching to IL-4–dependent

isotypes such as IgE and IgG1. These IgG subclasses bind the Fcγ receptors on phagocytes and activate

complement, thereby promoting phagocytosis of opsonized microbes. It activates PMNs and stimulates

the cytolytic activity of NK cells. The net effect is to promote macrophage-rich inflammatory reactions

while inhibiting IgE-dependent eosinophil-rich reactions. IL-10, by suppressing macrophage release of

TNFα and IL-12, negatively regulates IFNγ production.

IFNγ also demonstrates counterregulatory properties. It selectively inhibits LPS-induced expression of

CXC chemokines. It upregulates macrophage production of IP-10, MIG, and ELR-negative chemokines

that inhibit neutrophil chemotaxis and activation and decreases macrophage release of ELR-positive CXC

chemokines (e.g., IL-8), which are chemotactic for neutrophils.4

Transforming Growth Factor β

Transforming growth factor β (TGFβ) is a homodimer synthesized and secreted by activated T cells,

macrophages, and many other cells (Table 7-6). It is primarily immunosuppressive and inhibits the

proliferation and activation of lymphocytes and other leukocytes. It promotes wound healing by

increasing extracellular matrix protein synthesis and stimulating mononuclear cell and fibroblast

influx.163–165 Though the family consists of three closely related isoforms, most cells utilize TGFβ. Its

effects are mediated through two high-affinity TGF receptors (type I and II) that signal through a

serine/threonine kinase domain that phosphorylates transcription factors called SMADS.4

TGFβ inhibits the proliferation and differentiation of T cells and the activation of macrophages. It

favors differentiation of CD4+ cells to the TH2 subset, and inhibits MHC class II surface expression. By

suppressing the expression of MHC class II antigen, it abrogates the adaptive immune response.

Macrophages demonstrate diminished ROS production and TNFα and NO release. It directly counteracts

the influence of proinflammatory cytokines on PMNs and endothelial cells, and in combination with IL4, IL-13, and IL-10 can antagonize the production or effects of these proinflammatory mediators.

Knockout mice, deficient in TGFβ develop uncontrolled inflammatory lesions.4,39

Cytokines that Stimulate Hematopoiesis

Cytokines are necessary for normal hematopoiesis. Several of the cytokines stimulated during both

innate and adaptive immune responses are mitogenic for and induce differentiation of bone marrow

progenitor cells. CSFs are cytokines made by activated T cells, macrophages, endothelial cells, and bone

marrow stromal cells that stimulate increased production of inflammatory leukocytes by bone marrow

progenitors. Receptors for GM-CSF and G-CSF are of the class I family of cytokine receptors. GM-CSF is

expressed by T and B cells, macrophages, mast cells, fibroblasts, and endothelium in response to stimuli

such as IL-1, IL-2, LPS, and TNFα. It stimulates neutrophils, monocytes, macrophages, and DC and is a

powerful inducer of hematopoiesis. It enhances cytokine release, degranulation, and phagocytosis of

opsonized particles in neutrophils. In monocytes and macrophages it enhances cytotoxicity and cytokine

release. It promotes the activity of APCs and the maturation of bone marrow cells into DCs and

monocytes.166 G-CSF is produced by macrophages, endothelial cells, fibroblasts, and bone marrow

stromal cells. It functions as an endocrine hormone to mobilize neutrophils and induces subsequent

leukocyte proliferation and maturation. In 1991, the FDA approved the use of G-CSF for use in patients

with neutropenia.167,168

Stem cell factor or c-Kit ligand is synthesized by marrow stromal cells and binds to a cell surface

tyrosine kinase receptor on pluripotent stem cells that is the protein product of the cellular protooncogene c-kit. Its effects appear to be permissive, as it is corequisite for stem cell responsiveness to

other CSFs, yet in isolation does not stimulate colony formation. It may also play a role in sustaining

the viability and proliferative capacity of immature T cells in the thymus.4

IL-3 is a product of CD4+ T cells that promotes the differentiation of immature marrow progenitors

into all known mature cell types. It also promotes the growth and development of mast cells.

Surprisingly, despite these important functions, murine knockouts do not manifest noticeable

impairment of hematopoiesis.4

IL-7 is secreted by bone marrow stromal cells and promotes the growth and survival of immature

precursors committed to the B and T lymphocyte lineages. Knockout mice, deficient in IL-7 or its

receptor, are lymphopenic and possess diminished populations of B and T cells.4

The Complement System

6 The complement system is integral to both innate and adaptive immunity. It has the capacity to

200

http://surgerybook.net/

independently eliminate organisms and to facilitate host defense by marking foreign particles for

phagocytosis through opsonization. Many pathophysiologic inflammatory diseases, immune complex

diseases, ischemia/reperfusion injury, and ARDS are considered consequences of excessive or

unregulated induction of this system.169–172

The system consists of three pathways comprised of approximately 30 serum and cell surface proteins

that interact with one another and with other molecules of the immune system in a highly coordinated

fashion. These cascades involve the sequential proteolytic activation of zymogens to generate enzymes

with proteolytic activity. This mechanism for activation amplifies the response because each individual

enzyme activated can cleave numerous zymogens in the next step and generate multiple activated

enzyme molecules. Ultimately, the products of complement activation adhere to microbial cell surfaces

or to antibody-bound microbes and other antigens to directly or indirectly eliminate these pathogens.

Temporal and spatial regulation to the focus of infection is ensured both by the transience of activation

of these enzymes in the absence of microbes or antigens and by several circulating proteins that provide

surveillance.169,171

The complement cascade is divided into three distinct pathways: (1) the classical pathway (humoral

immunity), which is activated by antibody bound to antigen, (2) the alternative pathway (innate

immunity) in which complement is activated by components of microbial cell surfaces, and (3) the

mannose/lectin pathway (innate immunity), which is activated by a plasma lectin that binds to mannose

residues on microbes. Despite differences in which the cascade is activated, all three complement

pathways ultimately result in the cleavage of C3 and share the same late cascade.169,171

The alternative pathway functions in the absence of antibody and is phylogenetically the oldest

pathway (Fig. 7-9). Bacteria, viruses, fungi, and parasites all function as stimuli. Initial activation begins

with the cleavage of C3 and the stable attachment of its product C3b to the microbial surface. Bound

C3b finds factor B, which is subsequently cleaved by a plasma serine protease called factor D to

generate Bb. The C3bBb complex is called the alternative pathway C3 convertase and functions to

cleave more C3. In doing so the convertase serves as an amplification step in both the classical and

alternative pathways. Properdin prolongs the half-life of C3 convertase by delaying the release of Bb

from C3bBb. C3b is the recognition component of the alternate pathway and is responsible for the

opsonization of bacteria. C3a in conjunction with C5a and C4a induces acute inflammation by activating

mast cells and neutrophils. These inflammatory mediators play a significant role in increasing blood

vessel permeability, vasodilatation, edema formation, neutrophil adhesion and activation, chemotaxis,

and the release of toxic oxygen species and lysosomal enzymes from phagocytic cells. The binding of

another C3b to this complex generates the alternative pathway C5 convertase, C3bBb3b.4,169,171

Figure 7-9. Complement pathways. Alternate Pathway: 1. C3 is cleaved to C3b. 2. C3b binds and cleaves B to Bb to form C3

convertase (C3bBb). 3. Another C3b binds C3 convertase to form C5 convertase (C3bBbC3b). Classical Pathway: 1. C1 binds

immunoglobulin. 2. C1 binds and cleaves C4 and C2 to C4b and C2a to form C3 convertase (C4b2a). 3. C4b2a binds another C3b

to generate C5 convertase (C4b2aC3b). Late Pathway: 1. C5 convertase cleaves C5 to form C5b, which integrates into the

plasmalemma. 2. C6–8 are recruited, forming the C5b-8 complex. 3. C5b-8 recruits numerous C9 subunits, which form a pore in

the pathogen cell wall. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed. Philadelphia, PA:

Saunders; 2003.)

201