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Molecular Components of the Immune System

By Peter J. Delves, PhD, University College London, London, UK

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The immune system consists of cellular components and molecular components that work together to destroy antigens (Ags).

Acute Phase Reactants

Acute phase reactants are plasma proteins whose levels dramatically increase (called positive acute phase reactants) or, in some cases, decrease (called negative acute phase reactants) in response to the elevated circulating levels of IL-1 and IL-6 that occur when infection or tissue damage occurs. Most dramatically increased are C-reactive protein (CRP) and mannose-binding lectin (which fix complement and act as opsonins), the transport protein alpha-1 acid glycoprotein, and serum amyloid P component. CRP and ESR are often measured; elevated levels are a nonspecific indicator suggesting infection or inflammation. Increased fibrinogen is the main reason ESR is elevated.

Many acute phase reactants are made in the liver. Collectively, they may help limit tissue injury, enhance host resistance to infection, and promote tissue repair and resolution of inflammation.

Antibodies

Antibodies (Abs) act as the antigen (Ag) receptor on the surface of B cells and, in response to Ag, are subsequently secreted by plasma cells. Abs recognize specific configurations (epitopes, or antigenic determinants) on the surfaces of Ags (eg, proteins, polysaccharides, nucleic acids). Abs and Ags fit tightly together because their shape and other surface properties (eg, charge) are complementary. The same Ab molecule can cross-react with related Ags if their epitopes are similar enough to those of the original Ag.

Antibody structure

Abs consist of 4 polypeptide chains (2 identical heavy chains and 2 identical light chains) joined by disulfide bonds to produce a Y configuration (see Figure: B-cell receptor.). The heavy and light chains are divided into a variable (V) region and a constant (C) region.

B-cell receptor.

The B-cell receptor consists of an Ig molecule anchored to the cell’s surface. CH = heavy chain constant region; CL = light chain constant region; Fab = antigen-binding fragment; Fc = crystallizable fragment; Ig = immunoglobulin; L-kappa (κ) or lambda (λ) = 2 types of light chains; VH = heavy chain variable region; VL = light chain variable region.

V regions are located at the amino-terminal ends of the Y arms; they are called variable because the amino acids they contain are different in different Abs. Within the V regions, hypervariable regions determine the specificity of the Ig. They also function as antigens (idiotypic determinants) to which certain natural (anti-idiotype) Abs can bind; this binding may help regulate B-cell responses.

The C region of the heavy chains contains a relatively constant sequence of amino acids (isotype) that is distinctive for each Ig class. A B cell can change the isotype it produces and thus switch the class of Ig it produces. Because the Ig retains the variable part of the heavy chain V region and the entire light chain, it retains its antigenic specificity.

The amino-terminal (variable) end of the Ab binds to Ag to form an Ab-Ag complex. The Ag-binding (Fab) portion of Ig consists of a light chain and part of a heavy chain and contains the V region of the Ig molecule (ie, the combining sites). The crystallizable fragment (Fc) contains most of the C region of the heavy chains; Fc is responsible for complement activation and binds to Fc receptors on cells.

Antibody classes

Antibodies are divided into 5 classes:

  • IgM

  • IgG

  • IgA

  • IgD

  • IgE

The classes are defined by their type of heavy chain: mu (μ) for IgM, gamma ) for IgG, alpha (α) for IgA, epsilon (ε) for IgE, and delta (δ) for IgD. There are also 2 types of light chains: kappa (κ) and lambda (λ). Each of the 5 Ig classes can bear either kappa or lambda light chains.

IgM is the first Ab formed after exposure to new Ag. It has 5 Y-shaped molecules (10 heavy chains and 10 light chains), linked by a single joining (J) chain. IgM circulates primarily in the intravascular space; it complexes with and agglutinates Ag and can activate complement, thereby facilitating phagocytosis. Isohemagglutinins are predominantly IgM. Monomeric IgM acts as a surface Ag receptor on B cells. Patients with hyper-IgM syndrome have a defect in the genes involved in antibody class switching (eg, genes that encode CD40, CD154 [also known as CD40L], or NEMO [nuclear factor–kappa-B essential modulator]); therefore, IgA, IgG, and IgE levels are low or absent, and levels of circulating IgM are often high.

IgG is the most prevalent Ig isotype in serum and is also present in intravascular and extravascular spaces. It coats Ag to activate complement and facilitate phagocytosis by neutrophils and macrophages. IgG is the primary circulating Ig produced after reexposure to Ag (secondary immune response) and is the predominant isotype contained in commercial gamma-globulin products. IgG protects against bacteria, viruses, and toxins; it is the only Ig isotype that crosses the placenta. Therefore, this class of antibody is important for protecting neonates, but pathogenic IgG antibodies (eg, anti-Rh0[D] antibodies, stimulatory anti-TSH receptor autoantibodies), if present in the mother, can potentially cause significant disease in the fetus.

There are 4 subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. They are numbered in descending order of serum concentration. IgG subclasses differ functionally mainly in their ability to activate complement; IgG1 and IgG3 are most efficient, IgG2 is less efficient, and IgG4 is inefficient. IgG1 and IgG3 are efficient mediators of Ab-dependent cellular cytotoxicity; IgG4 and IgG2 are less so.

IgA occurs at mucosal surfaces, in serum, and in secretions (saliva; tears; respiratory, GU, and GI tract secretions; colostrum), where it provides an early antibacterial and antiviral defense. J chain links IgA into a dimer to form secretory IgA. Secretory IgA is synthesized by plasma cells in the subepithelial regions of the GI and respiratory tracts. Selective IgA deficiency is relatively common but often has little clinical impact because there is cross-functionality with other classes of antibody.

IgD is coexpressed with IgM on the surface of naive B cells. Whether these 2 classes function differently on the surface of the B cell and, if so, how differently are unclear. They may simply be an example of molecular degeneracy. Serum IgD levels are very low, and the function of circulating IgD is unknown.

IgE is present in low levels in serum and in respiratory and GI mucous secretions. IgE binds with high affinity to receptors present in high levels on mast cells and basophils and to a lesser extent on several other hematopoietic cells, including dendritic cells. If Ag bridges 2 IgE molecules bound to the mast cell or basophil surface, the cells degranulate, releasing chemical mediators that cause an inflammatory response. IgE levels are elevated in atopic disorders (eg, allergic or extrinsic asthma, hay fever, atopic dermatitis) and parasitic infections.

Cytokines

Cytokines are polypeptides secreted by immune and other cells when the cell interacts with a specific Ag, with pathogen-associated molecules such as endotoxin, or with other cytokines. Main categories include

  • Chemokines

  • Hematopoietic colony-stimulating factors (CSFs)

  • Interleukins

  • Interferons (IFN-alpha, IFN-beta, IFN-gamma)

  • Transforming growth factors (TGFs)

  • Tumor necrosis factors (TNF-alpha, lymphotoxin-alpha, lymphotoxin-beta)

Although lymphocyte interaction with a specific Ag triggers cytokine secretion, cytokines themselves are not Ag-specific; thus, they bridge innate and acquired immunity and generally influence the magnitude of inflammatory or immune responses. They act sequentially, synergistically, or antagonistically. They may act in an autocrine or paracrine manner.

Cytokines deliver their signals via cell surface receptors. For example, the IL-2 receptor consists of 3 chains: alpha (α), beta (β), and gamma (γ). The receptor’s affinity for IL-2 is

  • High if all 3 chains are expressed

  • Intermediate if only the beta and gamma chains are expressed

  • Low if only the alpha chain is expressed

Mutations or deletion of the gamma chain is the basis for X-linked severe combined immunodeficiency.

Chemokines

Chemokines induce chemotaxis and migration of leukocytes. There are 4 subsets (C, CC, CXC, CX3C), defined by the number and spacing of their amino terminal cysteine residues. Chemokine receptors (CCR5 on memory T cells, monocytes/macrophages, and dendritic cells; CXCR4 on resting T cells) act as coreceptors for entry of HIV into cells.

Colony-stimulating factors (CSF)

G-CSF is produced by endothelial cells and fibroblasts.

The main effect of G-CSF is

  • Stimulation of neutrophil precursors growth

Clinical uses of G-CSF include

  • Reversal of neutropenia after chemotherapy, radiation therapy, or both

GM-CSF is produced by endothelial cells, fibroblasts, macrophages, mast cells, and THcells.

The main effects of GM-CSF are

  • Stimulation of growth of monocyte, neutrophil, eosinophil, and basophil precursors

  • Activation of macrophages

Clinical uses of GM-CSF include

  • Reversal of neutropenia after chemotherapy, radiation therapy, or both

M-CSF is produced by endothelial cells, epithelial cells, and fibroblasts.

The main effect of M-CSF is

  • Stimulation of monocyte precursor growth

Clinical uses of M-CSF include

  • Therapeutic potential for stimulating tissue repair

SCF is produced by bone marrow stromal cells.

The main effect of SCF is

  • Stimulation of stem cell division

Clinical uses of SCF include

  • Therapeutic potential for stimulating tissue repair

Interferons

IFN-alpha is produced by leukocytes.

The main effects of IFN-alpha are

  • Inhibition of viral replication

  • Augmentation of class I MHC expression

Clinical uses of IFN-alpha include

IFN-beta is produced by fibroblasts.

The main effects of IFN-beta are

  • Inhibition of viral replication

  • Augmentation of class I MHC expression

Clinical uses of IFN-beta include

  • Reduction of the number of flare-ups in relapsing multiple sclerosis

IFN-gamma is produced by NK cells, TC1 cells, and TH1 cells.

The main effects of IFN-gamma are

  • Inhibition of viral replication

  • Augmentation of classes I and II MHC expression

  • Activation of macrophages

  • Antagonism of several actions of IL-4

  • Inhibition of TH2 cell proliferation

Clinical uses of IFN-gamma include

Interleukins

IL-1 (alpha and beta) is produced by B cells, dendritic cells, endothelium, macrophages, monocytes, and natural killer (NK) cells.

The main effects of IL-1 are

  • Costimulation of T-cell activation by enhancing production of cytokines (eg, IL-2 and its receptor)

  • Enhancement of B-cell proliferation and maturation

  • Enhancement of NK-cell cytotoxicity

  • Induction of IL-1, IL-6, IL-8, TNF, GM-CSF, and prostaglandin E2 production by macrophages

  • Proinflammatory activity by inducing chemokines, ICAM-1, and VCAM-1 on endothelium

  • Induction of sleep, anorexia, release of tissue factor, acute phase reactants, and bone resorption by osteoclasts

  • Endogenous pyrogenic activity

Clinical relevance of IL-1 includes

  • For anti–IL-1 beta mAb, treatment of cryopyrin-associated periodic syndromes and juvenile idiopathic arthritis

  • For IL-1 receptor antagonist (IL-1RA), treatment of adults with moderate to severe RA and patients with neonatal-onset multisystem inflammatory disease (NOMID)

IL-2 is produced by TH1 cells.

The main effects of IL-2 are

  • Induction of activated T- and B-cell proliferation

  • Enhancement of NK-cell cytotoxicity and killing of tumor cells and bacteria by monocytes and macrophages

Clinical relevance of IL-2 includes

  • For IL-2, treatment of metastatic renal cell carcinoma and metastatic melanoma

  • For anti-IL-2 receptor mAb, help with prevention of acute kidney rejection

IL-4 is produced by mast cells, NK cells, NKT cells, gamma-delta T cells, TC2 cells, and TH2 cells.

The main effects of IL-4 are

  • Induction of TH2 cells

  • Stimulation of activated B-, T-, and mast cell proliferation

  • Upregulation of class II MHC molecules on B cells and on macrophages and CD23 on B cells

  • Downregulation of IL-12 production, thereby inhibiting TH1 cell-differentiation

  • Augmentation of macrophage phagocytosis

  • Induction of switch to IgG1 and IgE

Clinical relevance of IL-4 includes

  • Involvement of IL-4 (with IL-13) in the production of IgE in atopic allergy

IL-5 is produced by mast cells and TH2 cells.

The main effects of IL-5 are

  • Induction of eosinophil and activated B-cell proliferation

  • Induction of switch to IgA

Clinical relevance of IL-5 includes

  • For anti–IL-5 mAb, efficacy in the treatment of patients with severe eosinophilic asthma

IL-6 is produced by dendritic cells, fibroblasts, macrophages, monocytes, and TH2 cells.

The main effects of IL-6 are

  • Induction of differentiation of B cells into plasma cells and differentiation of myeloid stem cells

  • Induction of acute phase reactants

  • Enhancement of T-cell proliferation

  • Induction of TC-cell differentiation

  • Pyrogenic activity

Clinical relevance of IL-6 includes

  • For anti–IL-6 mAb, treatment of multicentric Castleman disease in patients who are negative for HIV and human herpesvirus 8 (HHV-8)

  • For anti–IL-6 receptor mAb, treatment of RA when the response to TNF-antagonists is inadequate and treatment of juvenile idiopathic arthritis

IL-7 is produced by bone marrow and thymus stromal cells.

The main effects of IL-7 are

  • Induction of differentiation of lymphoid stem cells into T- and B-cell precursors

  • Activation of mature T cells

The role of IL-7 in T-cell differentiation has led to clinical trials of IL-7 as a potential immunostimulatory agent in the treatment of viral infections and cancer.

IL-8 (chemokine) is produced by endothelial cells, macrophages, and monocytes.

The main effect of IL-8 is

  • Mediation of chemotaxis and activation of neutrophils

Clinical relevance of IL-8 includes.

  • For IL-8 antagonists, potential for the treatment of chronic inflammatory disorders

IL-9 is produced by THcells.

The main effects of IL-9 are

  • Induction of thymocyte proliferation

  • Enhancement of mast cell growth

  • Synergistic action with IL-4 to induce switch to IgG1 and IgE

Clinical trials of anti-IL-9 mAb in asthma have generally failed to demonstrate efficacy.

IL-10 is produced by B cells, macrophages, monocytes, TC cells, TH2 cells, and regulatory T cells.

The main effects of IL-10 are

  • Inhibition of IL-2 secretion by human TH1 cells

  • Downregulation of production of class II MHC molecules and cytokines (eg, IL-12) by monocytes, macrophages, and dendritic cells, thereby inhibiting TH1-cell differentiation

  • Inhibition of T-cell proliferation

  • Enhancement of B-cell differentiation

Clinical uses of IL-10 include

  • Possible suppression of pathogenic immune response in allergy and autoimmune disorders

IL-12 is produced by B cells, dendritic cells, macrophages, and monocytes.

The main effects of IL-12 are

  • A critical role in TH1 differentiation

  • Induction of proliferation of TH1 cells, CD8 T cells, gamma-delta T cells, and NK cells and their production of IFN-gamma

  • Enhancement of NK and CD8 T-cell cytotoxicity

Clinical relevance of IL-12 includes

  • For anti–IL-12 mAb, treatment of plaque psoriasis and psoriatic arthritis

IL-13 is produced by mast cells and TH2 cells.

The main effects of IL-13 are

  • Inhibition of activation and cytokine secretion by macrophages

  • Coactivation of B-cell proliferation

  • Upregulation of class II MHC molecules and CD23 on B cells and monocytes

  • Induction of switch to IgG1 and IgE

  • Induction of VCAM-1 on endothelium

Clinical relevance of IL-13 includes

  • Involvement of IL-13 (with IL-4) in the production of IgE in atopic allergy

IL-15 is produced by B cells, dendritic cells, macrophages, monocytes, NK cells, and T cells.

The main effects of IL-15 are

  • Induction of proliferation of T, NK, and activated B cells

  • Induction of cytokine production and cytotoxicity of NK cells and CD8 T cells

  • Chemotactic activity for T cells

  • Stimulation of intestinal epithelium growth

Clinical uses of IL-15 include

  • Potential as an immunostimulatory agent in the treatment of cancer

IL-17 (A and F) is produced by TH17 cells, gamma-delta T cells, NKT cells, and macrophages

The main effects of IL-17 are

  • Proinflammatory action

  • Stimulation of production of cytokines (eg, TNF, IL-1 beta, IL-6, IL-8, G-CSF)

Clinical relevance of IL-17 includes

  • For anti-IL-17A mAb, treatment of adults with active ankylosing spondylitis, active psoriatic arthritis, or moderate to severe plaque psoriasis

IL-18 is produced by monocytes, macrophages, and dendritic cells.

The main effects of IL-18 are

  • Induction of IFN-gamma production by T cells

  • Enhancement of NK-cell cytotoxicity

IL-18 has been investigated as an immunotherapeutic agent in cancer, but efficacy has not been established.

IL-21 is produced by NKT cells and TH cells.

The main effects of IL-21 are

  • Stimulation of B-cell proliferation after CD40 cross-linking

  • Stimulation of NK cells

  • Costimulation of T cells

  • Stimulation of bone marrow precursor cell proliferation

Clinical relevance of IL-21 includes

  • In clinical trials, stimulation of cytotoxic T-cells and NK cells in cancer

  • For IL-21 antagonists, potential in the treatment of autoimmune disorders

IL-22 is produced by NK cells, TH17 cells, and gamma-delta cells.

The main effects of IL-22 are

  • Proinflammatory activity

  • Induction of acute phase reactant synthesis

Clinical relevance of IL-22 includes

  • For IL-22 antagonists, potential in the treatment of autoimmune disorders

IL-23 is produced by dendritic cells and macrophages.

The main effect of IL-23 is

  • Induction of TH-cell proliferation

Clinical relevance of IL-23 includes

  • For anti–IL-23 mAb, treatment of plaque psoriasis and psoriatic arthritis

IL-24 is produced by B cells, macrophages, monocytes, and T cells.

The main effects of IL-24 are

  • Suppression of tumor cell growth

  • Induction of apoptosis in tumor cells

Clinical uses of IL-24 include

  • Potential in the treatment of cancer

IL-27 is produced by dendritic cells, monocytes, and macrophages.

The main effect of IL-27 is

  • Induction of TH1 cells

Clinical uses of IL-27 include

  • Potential in the treatment of cancer

IL-32 is produced by NK cells and T cells.

The main effects of IL-32 are

  • Proinflammatory activity

  • Participation in activation-induced T cell apoptosis

Clinical uses of IL-32 include

  • Potential in the treatment of autoimmune disorders

IL-33 is produced by endothelial cells, stromal cells, and dendritic cells.

The main effects of IL-33 are

  • Induction of TH2 cytokines

  • Promotion of eosinophilia

Clinical relevance of IL-33 includes

  • For IL-33 antagonists, potential in the treatment of asthma

IL-35 is produced by regulatory T cells, macrophages, and dendritic cells.

The main effect of IL-35 is

  • Suppression of inflammation, eg, by inducing regulatory T and B cells and inhibiting TH17 cells

Clinical uses of IL-35 include

  • Potential to suppress pathogenic immune responses in allergy and autoimmune disorders

Transforming growth factors (TGF)

TGF-beta is produced by B cells, macrophages, mast cells, and TH3 cells.

The main effects of TGF-beta are

  • Proinflammatory activity (eg, by chemoattraction of monocytes and macrophages) but also anti-inflammatory activity (eg, by inhibiting lymphocyte proliferation)

  • Induction of switch to IgA

  • Promotion of tissue repair

Clinical trials of TGF-beta antagonists (eg, antisense oligonucleotides) in cancer are ongoing.

Tumor necrosis factors (TNFs)

TNF-alpha (cachectin) is produced by B cells, dendritic cells, macrophages, mast cells, monocytes, NK cells, and TH cells.

The main effects of TNF-alpha include

  • Cytotoxicity to tumor cells

  • Cachexia

  • Induction of secretion of several cytokines (eg, IL-1, GM-CSF, IFN-gamma)

  • Induction of E-selectin on endothelium

  • Activation of macrophages

  • Antiviral activity

Clinical relevance of TNF-alpha includes

TNF-beta (lymphotoxin) is produced by TC cells, and TH1 cells.

The main effects of TNF-beta include

  • Cytotoxicity to tumor cells

  • Antiviral activity

  • Enhancement of phagocytosis by neutrophils and macrophages

  • Involvement in lymphoid organ development

Clinical relevance of TNF-beta includes

  • For TNF-beta antagonists, similar effects to well-established TNF-alpha antagonists but have not been shown to be superior

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* This is the Professional Version. *