I

Neutralizing IL IFN antibody

Diffusion, protection of many other cells

Fig. 2.15 Certain viruses destroy the infected host cells (right), others do not (left). Cytotoxic T cells can destroy freshly infected cells by direct contact (with the help of perforin), thus inhibiting viral replication (middle). Whether the result of this lysis is clinically desirable depends on the balance between protection from viral proliferation, and the damage caused by immunologically mediated cell destruction. In perforin knockout mice (perforino/o), T cells are unable to produce perforin and therefore do not destroy the infected host cells. Replication of non-cytopathic viruses thus continues unabated in these mice. Soluble anti-viral interleukins (especially IFNy and TNFa), and neutralizing antibodies, combat cyto-pathic viruses (which replicate comparatively rapidly) more efficiently than do cytolytic T cells; this is because interleukin and antibody molecules can readily diffuse through tissues and reach a greater number of cells, more rapidly, than can killer T cells.

Table 2.6 The Most Important Immunological Cytokines and Costimulators plus Their Receptors and Functions

Cytokines/costimula-tors/chemokines Receptor

Cytokines/cytokine receptors produced by Functions

Interleukins

L-2 (T-cell growth factor)

L-3 (multicolony stimulating factor)

L-4 (BCGF-1, BSF-1) (B-cell growth factor, B-cell stimulating factor)

Macrophages Endothelial cells

Tcells

CD123, bc T cells, B cells, thymic epithelial cells

CD124, yc T cells, mast cells

CD125, ßc T cells, mast cells

L-6 (interferon/IFNß2, CD126, BSF-2, BCDF) CDw130

L-10

IL-11

CDw127, yc

IL-11R,

T cells, macrophages

Bone marrow stroma

T cells

T cells

T helper cells (especially mouse TH2), macrophages,

Epstein-Barr virus

Stromal fibroblasts

Hypothalamic fever, NK cell activation, T and B stimulation

T-cell proliferation

Synergistic effect in hematopoiesis

B-cell activation, switch to IgE

Growth and differentiation of eosinophilis

Growth and differentiation of T and B cells, acute-phase immune response

Growth of pre-B and pre-T cells

Macrophages, reduction ofTH1 cytokines

Effect on mast cells

Efficient inhibitor for macrophage functions, inhibits inflammatory reactions

Synergistic effect with IL-3 and IL-4 in hemato-poiesis

CDw130

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Cytokines/costimula-tors/chemokines

Receptor

Cytokines/cytokine receptors produced by Functions

IL-12

IL-13

IL-15

GM-CSF (granulocyte macrophage colony stimulating factor)

LIF (leukemia inhibitory factor)

IL-13R, yc T cells

IL-15R, yc

B cells, Activates natural killer macrophages cells, induces differentiation of CD4+ T cells into TH1-like cells, encourages IFNy production

Growth and differentiation of B cells, inhibits production of inflammatory cytokines by means of macrophages

T cells, placenta, IL-2-like, mainly muscle cells intestinal effects

Macrophages, Stimulates growth and T cells differentiation of the myelomonocytic lineage

Bone marrow Maintains embryonal stroma, fibroblasts stem cells; like IL-6, IL-11

Interferons (IFN)

IFNy CD119

CD118

CD118

T cells, natural killer cells

Leukocytes Fibroblasts

Activation of macrophages, enhances MHC expression, antiviral

Antiviral, enhances MHC class I expression

Antiviral, enhances MHC class I expression

Immunoglobulin superfamily

CD28

(promoter);

CTLA-4

(inhibitor)

CD28; CTLA-4

Antigen-presenting cells

Antigen-presenting cells

Costimulation of T cell responses

Costimulation of T cell responses

LIFR, CDw130

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Table 2.6 Continued: The Most Important Immunological Cytokines...

Cytokines/costimula-tors/chemokines Receptor

Cytokines/cytokine receptors produced by Functions

TNF (tumor necrosis factor) family

TNFa (cachexin)

CD120a,

CD120b p55, p75,

CD120a,

CD120b

CD40 ligand (CD40-L) CD40 Fas ligand CD95 (Fas) T cells

Macrophages, natural killer cells

T cells, B cells

T cells, B cells

T cells, mast cells

Local inflammations, endothelial activation

Endothelial activation, organization of secondary lymphoid tissues

Organization of secondary lymphoid tissues

B-cell activation, class switching

Apoptosis, Ca2+-inde-pendent cytotoxicity

Chemokines

IL-8 (prototype) CXCL8

CXCR1, CXCR2

CCR2

Activated endo- Attraction of neutro-thelium, activated phils, degranulation of

MCP-1 (monocyte chemoattractant protein) CCL2

MIP-1a (macrophage CCR5, CCR1

inflammatory protein)

CCL3

RANTES (regulated on activation, normal T cell expressed and secreted) CCL5

IP-10 (interferon gamma-inducible protein) CXCL10

CCR5

CCR5, CCR1, CCR3

CXCR3

fibroblasts

Activated endothelium, tissue macrophages, synovial cells

T cells, activated Mf

T cells, activated Mf

T cells, blood platelets

Inflamed tissue due to effects of IFNy neutrophils Inflammation

Proinflammatory HIVa receptor

Proinflammatory HIVa receptor

Inhibits cellular entry by M-trophic HIV, proinflammatory

Proinflammatory

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Cytokines/costimuIa-tors/chemokines

Receptor

Cytokines/cytokine receptors produced by Functions

Chemokines

MIG (monokine CXCR3

induced by interferon gamma) CXCL11

Eotaxin CCR3

CCL22

MDC (macrophage- CCR4 derived chemokine)

Fractalkine CX3CR1

CXCL1

Inflamed tissue, Proinflammatory due to effects of IFNy

Endothelium, epithelial cells

T-cell zone DCs, activated B cells, monocytes

Intestinal epithelium, endothelium tion of thrombocytes

Buildup of infiltrate in allergic diseases, e.g., asthma

Supports T-B cell collaboration during humoral immune responses

Endothelial cells activa-

Constitutive chemokines

LARC (liver and activation-regulated chemokine) MIP-3a

SLC (secondary lymphoid organ chemokine)

TECK (thymus-expressed chemokine)

SDF-1a (stromal cell-derived factor)

BCA-1 (B-cell attractant)

CCR6

CCR7

CCR9

CXCR4 (also known as fusin)

CXCR5

Intestinal epithelia, Peyer's patches

High endothelial lymph nodes, T-cell zone

Thymic and intestinal epithelia

Stromal cells of bone marrow

Follicular DCs (?)

Participation in mucosal immune responses

Facilitates entry of naive T cells, contact between T cells and DCs

Presumed role in T-cell selection

Involved in hemato-poiesis, inhibits cellular entry by T-trophic HIV

Contact between TH and B cells, and between TH and follicular DCs

Others:

TGFß (transforming growth factor ß)

Many cells, including monocytes and T cells

Inhibits cell growth, inhibits macrophages and production of IL-1 and TNFa, represents a switching factor for IgA

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Cell adhesion molecules often play an essential role in cell-to-cell interactions. Two lympho-hematopoietic cells can only establish contact if one of them expresses surface molecules that interact with ligands expressed on the surface of the other cell. As for APC and T cell interactions, the result of such contact may be that a signal capable of inducing differentiation and functional changes will be induced. Adhesion proteins are usually comprised of several chains which can induce different effects when present in various combinations. Interaction of several cascades is often required for the final differentiation of a cell. Cell adhesion molecules normally form part of the Ig superfamily (e.g., ICAM, VCAM, CD2), integrin family (lymphocyte function antigen, LFA-1), selectin family, cadherin family, or various other families. Selectins and integrins also play an important role in interactions between leukocytes and the vascular wall, and thus mediate the migration of leukocytes from the bloodstream into inflamed tissues, or the entry of recirculating lymphocytes into the lymph node parenchyma through high endothelial venules (HEV).

Chemokines (chemoattractant cytokines) comprise a family of over 30 small (8-12 kDa) secreted proteins. These contribute to the recruitment of "inflammatory cells" (e.g., monocytes) into inflamed tissues, and influence the recirculation of all classes of leukocytes (Table 2.6). Some chemokines result in the activation of their target cell in addition to exerting chemotatic properties. Chemokines can be classified into three families based on their N terminus structure: CC chemokines feature two contiguous cysteine residues at the terminus; CXC chemokines have an amino acid between the two residues; and CX3Cand C chemokines thus far comprise only one member each (fractalkine and lymphotactin, respectively). Although the N terminus carries bioactive determinants, using a chemokines amino acid sequence to predict its biological function is not reliable. The chemokine system forms a redundant network, or in other words, a single chemokine can often act upon a number of receptors, and the same receptor may recognize a number of different chemokines. Many of the chemokines also overlap in terms of biological function.

Chemokines can be grouped in two functional classes: inflammatory che-mokines which are secreted by inflamed or infected tissues as mediators of the nonspecific immune response; and constitutive chemokines which are produced in primary or secondary lymphoid organs. Together with endothe-lial adhesion molecules, inflammatory chemokines determine the cellular composition of the immigrating infiltrate. In contrast, the function of constitutive chemokines is to direct lymphocytes to precise locations within lym-phoid compartments. Thus, chemokines play a major role in the establishment of inflammatory and lymphoid microenvironments. Chemokine receptors are G protein-coupled membrane receptors with seven transmembrane sequences. In keeping with the above nomenclature, they are designated as CCR, CXCR, or CX3CR plus consecutive numbering. Some viruses, for instance

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the cytomegaly virus, encode proteins that are functionally analogous to chemokine receptors. This allows a rapid neutralization of locally induced chemokines, and may offer an advantage to the virus. The Duffy antigen receptor for chemokines, DARC, is expressed on endothelial cells and is capable of a high-affinity binding interaction with various chemokine types. Since this receptor has no downstream signaling cascade, it is assumed to function in the presentation of chemokines to leukocytes as they flow past. DARC also functions as a receptor for Plasmodium vivax. CCR5 and CXCR4 are co-receptors for HIV infection of CD4+ T cells.

Antibody-Dependent Cellular Immunity and Natural Killer Cells

Lymphocytes can nonspecifically bind IgG antibodies by means of Fc receptors, then specifically attack targets cells (e.g., infected or transformed cells) using the bound antibody. This phenomenon, known as antibody-dependent cellular cytotoxicity (ADCC), has been demonstrated in vitro—however its in-vivo function remains unclear. Natural killer (NK) cells also play a role in ADCC. The genesis of NK cells appears to be mainly thymus-independent. These cells can produce IFNy very early following activation and do not require a specific receptor. These cells are therefore early contributors to the IFNy-oriented TH1 immune response. NK cells can respond to cells that do not express MHC class I molecules, and are inactivated by contact with MHC molecules. This recognition process functions via special receptors that are not expressed in a clonal manner. NK cells probably play an important role in the early defensive stages of infectious diseases, although the exact nature of their role remains to be clarified (virus-induced IFNa and IFNb promote NK activation). NK cells also appear to contribute to rejection reactions, particularly the rejection of stem cells.

Humoral, Antibody-Dependent Effector Mechanisms

The objectives of the immune response include: the inactivation (neutralization) and removal of foreign substances, microorganisms, and viruses; the rejection of exogenous cells; and the prevention of proliferation of pathologically altered cells (tumors). The systems and mechanisms involved in these effector functions are largely non-specific. Specific immune recognition by B and T cells directs these effector mechanisms to specific targets. For instance, immunoglobulins opsonize microbes (e.g., pneumococci) which are equipped with polysaccharide capsules enabling them to resist phagocyte

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digestion. Opsonization involves the coating of such microbes with Fc-expressing antibodies which facilitates their phagocytosis by granulocytes. Many cells, particularly phagocytes (and interestingly enough also some bacteria like staphylococci), bear surface Fc receptors that interact with different Ig classes and subclasses. Mast cells and basophils bear IgE molecules, and undergo a process of degranulation following interaction with allergens against which the IgE molecules are directed. This induces the release of pharmacologically active biogenic amines (e.g., histamine). In turn, these amines represent the causative agent for physiological and clinical symptoms observed during allergic reactions (see also types I-IV, p. 108ff.).

The Complement System

The complement system (C system, Fig. 2.16) represents a non-specific defense system against pathogens, but can also be directed toward specific targets by antibodies. It is made up of a co-operative network of plasma proteins and cellular receptors, and is largely charged with the following tasks:

■ Opsonization of infectious pathogens and other foreign substances, with the aim of more efficient pathogen elimination. Bound complement factors can: enhance the binding of microbes to phagocytozing cells; result in the activation of inflammatory cells; mediate chemotaxis; induce release of inflammatory mediators; direct bactericidal effects; and induce cell lysis (Fig. 2.17, p. 88).

Fig. 2.16 The classic activation pathway is initiated by antigen-antibody complexes, the alternative pathway by components of microbial pathogens. The production of a C3 convertase, which splits C3 into C3a and C3b, is common to both pathways. C3b combines with C3 convertase to generate C5 convertase. C5b, produced by C5 convertase, binds to the complement factors 6-9 to form a membrane attack complex (MAC). C3b degradation products are recognized by receptors on B lymphocytes; they stimulate the production of antibodies as well as pathogen phagocytosis. The cleavage products C3a and C4a are chemotactic in their action, and stimulate expression of adhesion molecules. Nomenclature: the components of the alternative pathway (or cascade) are designated by capital letters (B, D, H, I; P for properdin), those of the classical pathway (or cascade) plus terminal lysis are designated by "C" and an Arabic numeral (1-9). Component fragments are designated by small letters, whereby the first fragment to be split off (usually of low molecular weight) is termed "a" (e.g., C3a), the remaining (still bound) part is called "b" (e.g., C3b), the next split-off piece "c," and so on. Molecules often group to form complexes; in their designations the individual components are lined up together and are usually topped by a line. ►

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■ Solubilization of otherwise insoluble antigen-antibody complexes.

■ Promotion of the transport of immune complexes, and their elimination and degradation.

■ Regulation of the immune response, achieved via their influence on antigen presentation and lymphocyte function.

Over 20 proteins of the complement system have been identified to date, and are classified as either activation or control proteins. These substances account for about 5% of the total plasma proteins (i.e., 3-4g/l). C3 is not only present in the largest amount, but also represents a central structure for complement activation. A clear difference exists between "classic"

The Complement System: Classic and Alternative Activation -

Classic pathway Alternative pathway

Immune complexes (IgG, IgM) + CI

I Microorganisms +

Immune complexes (IgG, IgM) + CI

I Microorganisms +

Medical Microbiology

Degradation M— IC3b, C3c, C3d C3dg,C3g

Degradation M— IC3b, C3c, C3d C3dg,C3g

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Immunological Cell Death

Activated Antigen-macrophages, antibody monocytes, complex other cells

Complement activation (lytic complex)

l\tembrane attack complex îmah

CD8 Tcells

Cells (e.g., macrophages), CD4+ and CD8+ T cells with TNF-family ligands, e.g., Fas/APOl Normal ligands cells

Corticosteroids

Target cell

CD8 Tcells

Medical Microbiology

Target cell

Membrane damage

' Apoptosis

IL-1 converting enzyme (ICE) (inhibited by Bcl2)

Fig. 2.17 Oxygen radicals and nitrous oxides (a), MAC resulting from complement activation (b) and perforin (c) all cause membrane damage which results in cell death. Ligand binding of Fas/APO (d), interrupted signal receptor conduction (e), corticosteroid binding to receptors and intracellular structures (f), and DNA damage (g) all result in alterations of intracellular signaling cascades and lead to cellular apoptosis. (Fas = F antigen; APO = apoptosis antigen; TNF = tumor necrosis factor; Bcl2 = B-cell leukemia-2 antigen [a protein that inhibits apoptosis].)

Corticosteroid- r „ receptor A

Membrane damage

' Apoptosis

IL-1 converting enzyme (ICE) (inhibited by Bcl2)

Fig. 2.17 Oxygen radicals and nitrous oxides (a), MAC resulting from complement activation (b) and perforin (c) all cause membrane damage which results in cell death. Ligand binding of Fas/APO (d), interrupted signal receptor conduction (e), corticosteroid binding to receptors and intracellular structures (f), and DNA damage (g) all result in alterations of intracellular signaling cascades and lead to cellular apoptosis. (Fas = F antigen; APO = apoptosis antigen; TNF = tumor necrosis factor; Bcl2 = B-cell leukemia-2 antigen [a protein that inhibits apoptosis].)

antibody-induced complement activation and "alternative" activation via C3 (Fig. 2.16).

During classic activation of complement, C1q must be bound by at least two antigen-antibody immune complexes, to which C4 and C2 then attach themselves. Together, these three components form a C3 convertase, which then splits C3. Pentameric IgM represents a particularly efficient C activator since at least two Ig Fc components in close proximity are required for C1q binding and activation.

During alternative activation of complement, the splitting of C3 occurs directly via the action of products derived from microorganisms, endotoxins, polysaccharides, or aggregated IgA. C3b, which is produced in both cases, is activated by the factors B and D, then itself acts as C3 convertase. Subsequent formation of the lytic complex, C5-C9 (C5-9), is identical for both classic

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and alternative activation, but is not necessarily essential since the released chemotaxins and opsonins are often alone enough to mediate the functions of microbe neutralization and elimination. Some viruses can activate the complement system without the intervention of antibodies by virtue of their ability to directly bind C1q. This appears to be largely restricted to retroviruses (including HIV). Importantly, without a stringent control mechanism complement would be activated in an uncontrolled manner, resulting in the lysis of the hosts own cells (for instance erythrocytes).

■ Complement Control Proteins

The following regulatory proteins of the complement system have been characterized to date:

C1 inhibitor, prevents classic complement activation.

DAF (decay accelerating factor), prevents the association of C3b with factor B, or of C4b with C2, on the cell surface. DAF can also mediate the dissolution of existing complexes, and is responsible for the regulation of classic and alternative C activities. MCP (membrane cofactor protein), enhances the activity of the factor which degrades C3b to iC3b. Factor Hand CR1 (complement receptor 1) have similar effects. HRF (homologous restriction factor). Synonyms: MAC (membrane attack complex), inhibitory protein, C8-binding protein. HRF protects cells from C5-9-mediated lysis. This protein is lacking in patients suffering from paroxysmal nocturnal hemoglobinuria. CD59. Synonyms: HRF20, membrane attack complex (MAC)-inhibiting factor, protec-tin. This is a glycolipid anchored within the cell surface which prevents C9 from binding to the C5b-8 complex, thus protecting the cell from lysis.

Those complement components with the most important biological effects include:

■ C3b, results in the opsonization of microorganisms and other antigens, either directly or in the form of immune complexes. "C-marked" microorganisms then bind to the appropriate receptors (R) (e.g., CRI on macrophages and erythrocytes, or CR2 on B cells).

■ C3a and C5a, contribute to the degranulation of basophils and mast cells and are therefore called anaphylatoxins. The secreted vasoactive amines (e.g., histamine) raise the level of vascular permeability, induce contraction of the smooth musculature, and stimulate arachidonic acid metabolism. C5a initiates the chemotactic recruitment of granulocytes and monocytes, promotes their aggregation, stimulates the oxidative processes, and promotes the release of the thrombocyte activating factor.

■ "Early" C factors, in particular C4, interact with immune complexes and inhibit their precipitation.

■ Terminal components (C5-9), together form the so-called membrane attack complex, MAC, which lyses microorganisms and other cells.

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Some components mediate general regulatory functions on B-cell responses, especially via CR1 and CR2.

Immunological Cell Death

Fig. 2.17 summarizes the mechanisms of cell death resulting from immunological cell interactions and differentiation processes, as they are understood to date.

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