Molecular Components of the Immune System
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 interleukin (IL)-1 and IL-6 that occur when infection or tissue damage occurs. Most dramatically increased are:
C-reactive protein and mannose-binding lectin fix complement and act as opsonins. Alpha-1 acid glycoprotein is a transport protein. Serum amyloid P component activates complement. Elevated C-reactive protein levels are a nonspecific indicator of infection or inflammation. Fibrinogen levels also increase and are the main reason the erythrocyte sedimentation rate (ESR) is elevated in acute inflammation.
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 act as the antigen receptor on the surface of B cells and, in response to antigen, are subsequently secreted by plasma cells. Antibodies recognize specific configurations (epitopes, or antigenic determinants) on the surfaces of antigens (eg, proteins, polysaccharides, nucleic acids). Antibodies and antigens fit tightly together because their shape and other surface properties (eg, charge) are complementary. The same antibody molecule can cross-react with related antigens if their epitopes are similar enough to those of the original antigen.
Antibodies 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.
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 antibodies. Within the V regions, hypervariable regions determine the specificity of the immunoglobulin (Ig). They also function as antigens (idiotypic determinants) to which certain natural (anti-idiotype) antibodies 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 antibody binds to antigen to form an antibody-antigen complex. The antigen-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.
Antibodies are divided into 5 classes:
The classes are defined by their type of heavy chain: mu (μ) for IgM, gamma (γ) 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 antibody formed after exposure to new antigen. 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 antigens and can activate complement, thereby facilitating phagocytosis. Isohemagglutinins are predominantly IgM. Monomeric IgM acts as a surface antigen 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 present in intravascular and extravascular spaces. It coats antigen to activate complement and facilitate phagocytosis by neutrophils and macrophages. IgG is the primary circulating Ig produced after reexposure to antigen (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-thyroid-stimulating hormone 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 antibody-dependent cellular cytotoxicity; IgG4 and IgG2 are less so.
IgA occurs at mucosal surfaces, in serum, and in secretions (saliva; tears; respiratory, genitourinary, and gastrointestinal 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 gastrointestinal 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 is 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 gastrointestinal 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 antigen 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 are polypeptides secreted by immune and other cells when the cell interacts with a specific antigen, with pathogen-associated molecules such as endotoxin, or with other cytokines. Main categories include
Although lymphocyte interaction with a specific antigen triggers cytokine secretion, cytokines themselves are not antigen-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
Mutations or deletion of the gamma chain is the basis for X-linked severe combined immunodeficiency.
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 co-receptors for entry of HIV into cells.
Granulocyte-colony stimulating factor (G-CSF) is produced by endothelial cells and fibroblasts.
The main effect of G-CSF is
Clinical uses of G-CSF include
Granulocyte-macrophage colony stimulating factor (GM-CSF) is produced by endothelial cells, fibroblasts, macrophages, mast cells, and T helper (Th) cells.
The main effects of GM-CSF are
Clinical uses of GM-CSF include
Macrophage colony stimulating factor (M-CSF) is produced by endothelial cells, epithelial cells, and fibroblasts.
The main effect of M-CSF is
Clinical uses of M-CSF include
Stem cell factor (SCF) is produced by bone marrow stromal cells.
The main effect of SCF is
Clinical uses of SCF include
IFN-alpha is produced by leukocytes.
The main effects of IFN-alpha are
Clinical uses of IFN-alpha include
IFN-beta is produced by fibroblasts.
The main effects of IFN-beta are
Clinical uses of IFN-beta include
Reduction of the number of flare-ups in relapsing multiple sclerosis
IFN-gamma is produced by natural killer (NK) cells, cytotoxic type 1 (Tc1) cells, and T helper type 1 (Th1) cells.
The main effects of IFN-gamma are
Clinical uses of IFN-gamma include
Control of infection in chronic granulomatous disease
Delay of progression in severe malignant osteopetrosis
Interleukins (IL-1 to IL-38) are collectively produced by a wide variety of cells and have multiple effects on cell development and the regulation of immune responses. Interleukins that have been particularly well characterized and investigated for clinical relevance include:
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
IL-2 is produced by Th1 cells.
The main effects of IL-2 are
Clinical relevance of IL-2 includes
IL-3 is produced by T cells, NK cells and mast cells
The main effects of IL-3 are
Clinical relevance of IL-3 includes
Targeting of IL-3 receptor alpha chain with monoclonal antibodies or CAR T cells, which may be of benefit in patients with relapsed refractory acute myeloid leukemia
IL-4 is produced by mast cells, NK cells, natural killer T (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
For anti-IL-4 receptor mAb, treatment of patients with moderate to severe atopic dermatitis
IL-5 is produced by mast cells and Th2 cells.
The main effects of IL-5 are
Clinical relevance of IL-5 includes
For anti–IL-5 mAb, treatment of patients with severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis
For anti-IL-5 receptor mAb, 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
Clinical relevance of IL-6 includes
IL-7 is produced by bone marrow and thymus stromal cells.
The main effects of IL-7 are
Clinical relevance of IL-7 includes
IL-8 (chemokine) is produced by endothelial cells, macrophages, and monocytes.
The main effect of IL-8 is
Clinical relevance of IL-8 includes
IL-9 is produced by Th cells.
The main effects of IL-9 are
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
Clinical relevance of IL-10 includes
IL-11 is produced by bone marrow stromal cells
The main effects of IL-11 are
Clinical relevance of IL-11 includes
Prevention of thrombocytopenia after myelosuppressive chemotherapy
IL-12 is produced by B cells, dendritic cells, macrophages, and monocytes.
The main effects of IL-12 are
Clinical relevance of IL-12 includes
IL-13 is produced by mast cells and Th2 cells.
The main effects of IL-13 are
Clinical relevance of IL-13 includes
IL-15 is produced by B cells, dendritic cells, macrophages, monocytes, NK cells, and T cells.
The main effects of IL-15 are
Clinical relevance of IL-15 includes
IL-16 is produced by helper T cells and cytotoxic T cells
The main effects of IL-16 are
Clinical relevance of IL-16 includes
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
Clinical relevance of IL-17 includes
IL-18 is produced by monocytes, macrophages, and dendritic cells.
The main effects of IL-18 are
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
Clinical relevance of IL-21 includes
IL-22 is produced by NK cells, Th17 cells, and gamma-delta T cells.
The main effects of IL-22 are
Clinical relevance of IL-22 includes
IL-23 is produced by dendritic cells and macrophages.
The main effect of IL-23 is
Clinical relevance of IL-23 includes
IL-24 is produced by B cells, macrophages, monocytes, and T cells.
The main effects of IL-24 are
Clinical relevance of IL-24 includes
IL-27 is produced by dendritic cells, monocytes, and macrophages.
The main effect of IL-27 is
Clinical relevance of IL-27 includes
IL-32 is produced by NK cells and T cells.
The main effects of IL-32 are
Clinical relevance of IL-32 includes
IL-33 is produced by endothelial cells, stromal cells, and dendritic cells.
The main effects of IL-33 are
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
Clinical relevance of IL-35 includes
IL-37 is produced by macrophages and inflamed tissue.
The main effects of IL-37 are
Clinical relevance of IL-37 includes
There are alpha and beta forms of TGFs with 3 TGF-beta subtypes.
TGF-alpha is produced by epithelial cells, monocytes, macrophages, brain cells, and keratinocytes.
The main effects of TGF-alpha are
Clinical relevance of TGF-alpha includes
TGF-beta is produced by B cells, macrophages, mast cells, and Th3 cells.
The main effects of TGF-beta are
Clinical relevance of TGF-beta includes
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
Clinical relevance of TNF-alpha includes
For TNF-alpha antagonists (mAb or soluble receptor), treatment of rheumatoid arthritis, plaque psoriasis, Crohn disease refractory to standard treatments, ulcerative colitis, hidradenitis suppurativa, ankylosing spondylitis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, noninfectious intermediate uveitis, posterior uveitis, and pan-uveitis
TNF-beta (lymphotoxin) is produced by Tc cells, and Th1 cells.
The main effects of TNF-beta include
Clinical relevance of TNF-beta includes