immunology allergic disorders
Molecular Components of the Immune System
Cytokines
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 Chemokines Hematopoietic colony-stimulating factors Interleukins (IL) 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 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 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 (SCID) . Chemokines induce chemotaxis and migration of leukocytes. There are 4 subsets (C, CC, CXC, CX3C), defined by the number and spacing of their amino terminalcysteineresidues. 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 Stimulation of neutrophil precursors growth 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 Macrophage colony stimulating factor(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 Stem cell factor(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 IFN-alphais 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 Hepatitis C, Chronic , AIDS-related IFN-betais 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 (MS) None IFN-gammais 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 expression Activation of macrophages 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 (CGD) None 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 treatment of Hereditary Cryopyrin-Associated Periodic Syndromes (Cryopyrinopathies) , systemic treatment of adults with moderate to severe Rheumatoid Arthritis (RA) and patients with IL-2is 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 ForIL-2,treatment of metastatic renal cell carcinoma and metastatic melanoma Foranti-IL-2 receptor mAb,help with prevention of acute kidney rejection IL-3is produced by T cells, NK 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 CAR T cells, which may be of benefit in patients with relapsed refractory Acute Myeloid Leukemia (AML) None IL-4is 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 treatment of patients with moderate to severe Atopic Dermatitis (Eczema) None IL-5is 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 treatment of patients with severe eosinophilic asthma and Eosinophilic Granulomatosis with Polyangiitis (EGPA) None Foranti-IL-5 receptor mAb,treatment of patients with severe eosinophilic asthma IL-6is 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 None Enhancement of T-cell proliferation Induction of Tc-cell differentiation Pyrogenic activity Clinical relevance of IL-6 includes Foranti–IL-6 mAb,treatment of multicentric Castleman disease in patients who are negative for HIV and human herpesvirus 8 (HHV-8), treatment of Rheumatoid Arthritis (RA) when the response to TNF-antagonists is inadequate and treatment of IL-7is 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 Clinical relevance of IL-7 includes Potential immunostimulation in the treatment of viral infections, cancer, and lymphopenic sepsis 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 ForIL-8 antagonists,potential for the treatment of chronic inflammatory disorders IL-9is 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. IL-10is 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-11is produced by bone marrow stromal cells The main effects of IL-11 are Promotion of pro-B and megakaryocyte differentiation Induction of acute phase reactants Clinical relevance of IL-11 includes Prevention of Immune Thrombocytopenia (ITP) after myelosuppressive chemotherapy IL-12is 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 treatment of Psoriasis and IL-13is 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-15is 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 relevance of IL-15 includes Potential as an immunostimulatory agent in the treatment of cancer IL-16is 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 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 treatment of adults with active Ankylosing Spondylitis , active IL-18is 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-21is 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 ForIL-21 antagonists,potential in the treatment of autoimmune disorders IL-22is 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 ForIL-22 antagonists,potential in the treatment of autoimmune disorders IL-23is produced by dendritic cells and macrophages. The main effect of IL-23 is Induction of Th-cell proliferation Clinical relevance of IL-23 includes treatment of plaque psoriasis, Psoriatic Arthritis , and IL-24is 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-27is 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-32is 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-33is 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 potential in the treatment of Asthma None IL-35is 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 relevance of IL-35 includes Potential to suppress pathogenic immune responses in allergy and autoimmune disorders IL-37is 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-alphaantagonistsalleviate symptoms in Menetrier disease TGF-betais 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 ofTGF-betaincludes Trials ofantagonists(eg, antisense oligonucleotides) in cancer are ongoing. 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 (mAb or soluble receptor), treatment of Rheumatoid Arthritis (RA) , plaque 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 ForTNF-beta antagonists,similar effects to well-established TNF-alpha antagonists but have not been shown to be superior 