Molecular Components of the Immune System

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.

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 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:

• IgM

• IgG

• IgA

• IgD

• IgE

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

• Delta (δ) for IgD

There are also 2 types of light chains:

• Kappa (κ)

• 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], AID [activation-induced cytidine deaminase], UNG [uracil-DNA-glycosylase], 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 re-exposure 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. However, pathogenic IgG antibodies (eg, anti-Rh0[D] antibodies, anti-SSA antibodies [anti–Sjögren-syndrome A-related antigen], and 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. IgG4-generating cells increase in IgG4 related disease.

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 somewhat unclear. Serum IgD levels are very low, and any unique function of circulating IgD is largely unknown, although there is some evidence for an immunoregulatory role on Th2 responses (1) (see table Functions of T Cells).

IgE is present in low levels in serum and in respiratory and gastrointestinal mucous secretions. IgE binds with a strong 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.

1. 1. Shan M, Carrillo J, Yeste A, et al. Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44. Immunity 2018;49(4):709-724.e8. doi:10.1016/j.immuni.2018.08.013

Chemokines induce chemotaxis and migration of leukocytes. There is a large family of chemokines with at least 47 members, which comprise 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. CXCR4 antagonists may have utility in combination therapies for pancreatic ductal adenocarcinoma.

Granulocyte-colony stimulating factor (G-CSF) is produced by endothelial cells and fibroblasts.

The main effect of G-CSF is

• Stimulation of growth of neutrophil precursors

Clinical uses of G-CSF include

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

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

• 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

The development of autoantibodies against GM-CSF can result in alveolar proteinosis.

Macrophage colony stimulating factor (M-CSF) is produced by endothelial cells, epithelial cells, and fibroblasts.

The main effect of M-CSF is

• Stimulation of growth of monocyte precursors

Clinical uses of M-CSF include

• Therapeutic potential for stimulating tissue repair

Interferons are a family of proteins that have antiviral activity and also act as immune modulators. Evidence for excess interferon activity is a feature of patients with systemic lupus erythematosus (1).

IFN-alpha is produced by leukocytes.

The main effects of IFN-alpha are

• Inhibition of viral replication

• Augmentation of class I major histocompatibility complex (MHC) expression

Clinical uses of IFN-alpha include

• Treatment of chronic hepatitis B, chronic hepatitis C, AIDS-related Kaposi sarcoma, condylomata acuminata, hairy cell leukemia, chronic myeloid leukemia, follicular lymphoma, and metastatic melanoma

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 natural killer (NK) cells, cytotoxic type 1 (Tc1) cells, and T helper type 1 (Th1) cells.

The main effects of IFN-gamma are

• Inhibition of viral replication

• Augmentation of classes I and II MHC and of Fc receptor expression

• Activation of macrophages and NK cells

• Antagonism of several actions of IL-4

• Inhibition of Th2 cell proliferation

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, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (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 monoclonal antibody (mAb), treatment of periodic fever syndromes, systemic juvenile idiopathic arthritis, acute gout, and calcium pyrophosphate arthritis (pseudogout)

• For IL-1 receptor antagonist (IL-1RA), treatment of adults with moderate to severe rheumatoid arthritis 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-cell 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-3 (also known as multi-CSF) is produced by T cells and mast cells

The main effects of IL-3 are

• Stimulation of growth and differentiation of hematopoietic precursors

• Stimulation of mast cell growth

Clinical relevance of IL-3 includes

• Targeting of IL-3 receptor alpha chain with monoclonal antibodies or chimeric antigen receptor (CAR) T cells, which may be of benefit in patients with certain disorders, often hematogenous cancers such as 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-cell, T-cell, 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

• Induction of eosinophil and activated B-cell proliferation

• Induction of switch to IgA

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

• 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 rheumatoid arthritis when the response to TNF-antagonists is inadequate and treatment of juvenile idiopathic arthritis, giant cell arteritis, and of severe cytokine release syndromeCOVID-19 with hypoxia and systemic inflammation. 

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-cell and B-cell precursors

• Activation of mature T cells

Clinical relevance of IL-7 includes

• Potential immunostimulation in the treatment of viral infections, cancer, and lymphopenic sepsis

IL-8 (a 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 Th cells.

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 (2).

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 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 relevance of IL-10 includes

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

IL-11 is produced by bone marrow stromal cells

The main effects of IL-11 are

• Promotion of pro-B cell and megakaryocyte differentiation

• Induction of acute phase reactants

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

• 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 vascular cell adhesion molecule 1 (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 cells, NK cells, 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 relevance of IL-15 includes

• Potential as an immunostimulatory agent in the treatment of cancer

IL-16 is produced by helper T cells and cytotoxic T cells

The main effects of IL-16 are

• Chemotactic activity for CD4 T cells, monocytes, and eosinophils

• Induction of MHC class II molecules

Clinical relevance of IL-16 includes

• Potential to promote CD4 T cell reconstitution in patients with HIV infection

• IL-16 antagonists may have utility in allergic and autoimmune conditions

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, but inhibition may trigger inflammatory bowel disease

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-20 is produced by monocytes, macrophages, and dendritic cells.

The main effects of IL-20 are

• Proinflammatory action

• Stimulation of keratinocyte proliferation

Clinical relevance of IL-20 includes

• Receptor for IL-20 is upregulated on keratinocytes in patients with psoriasis

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 T 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, psoriatic arthritis, and Crohn disease

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 relevance of IL-24 includes

• Potential in the treatment of cancer

IL-25 (also called IL-17E) is produced by T cells, macrophages, dendritic cells, mast cells, eosinophils and epithelium.

The main effect of IL-25 is

• Stimulation of Th2 cells

Clinical relevance of IL-25 includes

• Implicated in the development of allergy and autoimmune disorders (3)

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

The main effect of IL-27 is

• Induction of Th1 cells

Clinical relevance of IL-27 includes

• Potential in the treatment of cancer

IL-31 is produced by Th2 cells

The main effect of IL-31 is

• Proinflammatory activity

Clinical relevance of IL-31 includes

• Role in atopic dermatitis, asthma, and inflammatory bowel disease

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 relevance of IL-32 includes

• 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-34 is produced by keratinocytes and neurons.

The main effects of IL-34 are

• Supporting cell growth and survival of monocytes

• Stimulation of monocyte differentiation into macrophages

Clinical relevance of IL-34 includes

• Possible involvement in the pathogenesis of rheumatoid arthritis (4) and inflammatory bowel disease

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 cells and B cells and inhibiting Th17 cells

Clinical relevance of IL-35 includes

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

IL-36 is produced by epithelium, monocytes, macrophages, dendritic cells, and T cells.

The main effect of IL-36

• Proinflammatory activity

Clinical relevance of IL-36 includes

• Promotes inflammation in psoriasis

IL-37 is produced by macrophages and inflamed tissue.

The main effects of IL-37 are

• Anti-inflammatory

• Possible IL-18 receptor antagonist

Clinical relevance of IL-37 includes

• Potential to block inflammation

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

• Stimulation of cell proliferation and differentiation

• Regulation of mucus production

• Inhibition of gastric acid secretion

Clinical relevance of TGF-alpha includes

• TGF-alpha antagonists alleviate symptoms in Menetrier disease

TGF-beta is produced by B cells, macrophages, mast cells, and Th3 cells.

The main effects of the TGF-beta family 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 and fibrosis

Clinical relevance of TGF-beta includes

• Trials of antagonists (eg, antisense oligonucleotides) in cancer are ongoing (5).

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

• Cachexia

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

• Induction of E-selectin on endothelium

• Activation of macrophages

• Antiviral activity

• Cytotoxicity to tumor cells

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 panuveitis. Despite its name, blocking the activity of TNF does not lead to a marked increase in primary or secondary cancers.

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

1. 1. Tanaka Y, Kusuda M, Yamaguchi Y. Interferons and systemic lupus erythematosus: Pathogenesis, clinical features, and treatments in interferon-driven disease. Mod Rheumatol 2023;33(5):857-867. doi:10.1093/mr/roac140

2. 2. Oh CK, Leigh R, McLaurin KK, Kim K, Hultquist M, Molfino NA. A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res 2013;14(1):93. Published 2013 Sep 19. doi:10.1186/1465-9921-14-93

3. 3. Liu Y, Shao Z, Shangguan G, Bie Q, Zhang B. Biological Properties and the Role of IL-25 in Disease Pathogenesis. J Immunol Res 2018;2018:6519465. Published 2018 Sep 23. doi:10.1155/2018/6519465

4. 4. Zhou RP, Wu XS, Xie YY, et al. Functions of interleukin-34 and its emerging association with rheumatoid arthritis. Immunology 2016;149(4):362-373. doi:10.1111/imm.12660

5. 5. Lee HJ. Recent Advances in the Development of TGF-β Signaling Inhibitors for Anticancer Therapy. J Cancer Prev 2020;25(4):213-222. doi:10.15430/JCP.2020.25.4.213