Cytokines Non-antibody proteins acting as mediators between cells, termed: Monokines – mononuclear phagocytes Lymphokines – activated T cells, especially helper T cells Interleukins – abbreviated IL with a number

Properties of Cytokines Produced by cells involved in both natural and specific immunity Mediate and regulate immune responses Secretion brief and limited - not stored pre-formed - synthesis initiated by gene transcription - cytokines produced as needed

Properties of Cytokines (continued) Can be produced by many cell types and act on many cell types (pleiotropic) Can have similar actions (redundant) IL2 Rα IL2 Rβ IL2 Rγ IL15 Rα IL7 R ? IL9 R IL4 R IL-2 IL-15 IL-7 IL-9 IL-4 Receptor for:

Properties of Cytokines (continued) 6. Can influence synthesis of other cytokines - produce cascades - enhance or suppress production of other cytokines - exert positive or negative regulatory mechanisms for immune responses Influence action of other cytokines - can be antagonistic, additive, synergistic

Properties of Cytokines (continued) Bind to receptors with high affinity Cells responding to cytokine can be: - same cell (autocrine) - nearby cell (paracrine) - distant cell by circulation (endocrine) Cellular responses to cytokines are slow, require new mRNA and protein synthesis

Mediators and Regulators of Natural Immunity Tumor Necrosis Factor-alpha (TNF-α) Interleukin-1 (IL-1) Chemokines (Chemotactic cytokines) Type I Interferons (IFN-α and IFN-β) Interleukin-12 (IL-12) Interleukin-10 (IL-10)

Tumor Necrosis Factor (TNF-α) Produced by activated macrophages Most important mediator of acute inflammation in response to microbes, especially Gram-negative bacteria (LPS) Mediates recruitment of neutrophils and macrophages to site of inflammation Acts on hypothalamus to produce fever Promotes production of acute phase proteins

Interleukin-1 (IL-1) Produced by activated macrophages Effects similar to those of TNF-α

Chemokines Produced by many different leukocytes and tissue cells Large family of >50 substances Recruit leukocytes to sites of infection Play a role in lymphocyte trafficking

Type I Interferons (IFN-α and β) IFN-α a family of many proteins produced by macrophages, IFN-β a single protein produced by many cells Both IFNs inhibit viral replication Both increase expression of class I MHC Both activate NK cells

Interleukin-12 (IL-12) Produced by activated macrophages and dendritic cells Stimulates production of IFN-γ Induces differentiation of TH cells to become TH1 cells Enhances cytolytic functions of cytotoxic T cells and NK cells

Interleukin-10 (IL-10) Produced by activated macrophages, TH2 cells An inhibitory cytokine Inhibits cytokine production by activated macrophages Inhibits expression of class II MHC and costimulatory molecules on macrophages

Mediators and Regulators of Specific Immunity Interleukin-2 (IL-2) Interleukin-4 (IL-4) Interleukin-5 (IL-5) Interleukin-10 (IL-10) Interferon-gamma (IFN-γ)

of division and IFN gamma release (and other mediators) Interleukin-2 (IL-2) Produced by TH>>Tc Main growth factor for T cells IL-2 secretion T cell NK Increase in NK Cell activity B cell Stimulation of division of division and IFN gamma release (and other mediators) Monocyte Activation

Autocrine Function of IL-2 Activated T cell Resting Class II MHC APC IL2 IL4 IL7 Binds to IL-2 receptor Receptor decay Division

Interleukin-4 (IL-4) Produced by TH2 cells Stimulates Ig class switching to IgE isotype Stimulates development of TH2 cells from naïve TH cells Promotes growth of differentiated TH2 cells

Interleukin-5 (IL-5) Produced by TH2 cells Promotes growth and differentiation of eosinophils Activates mature eosinophils IL-4 and IL-5 can work together Helminths opsonized with IgE can be killed by activated eosinophils

Interleukin-10 (IL-10) Produced by activated macrophages, TH2 cells Inhibits production of IFN-γ by TH1 cells needed to activate macrophages

Interferon-gamma (IFN-γ) Produced by TH cells >> Tc and NK cells Numerous functions in both natural and specific immunity B cell Macrophage NK T cell TH1 cell > Tc cell Many cell types Induction of class I and class II MHC Increase in NK cell activity Differentiation, Stops cell division T cell activation Weak anti-viral activity, Stops cell division, Stops hematopoiesis Activation Granulocyte Endothelial cell IFN gamma secretion

Stimulators of Hematopoiesis Colony-Stimulating Factors (CSF) Granulocyte-macrophage CSF (GM-CSF) promotes growth and differentiation of bone marrow progenitors Macrophage CSF (M-CSF) is involved in development and function of monocytes and macrophages Granulocyte CSF (G-CSF) stimulates production of polymorphonuclear leucocytes (PMN)

Cytokines Regulate Ig Class Switching Fc region of antibodies determines effector function in different anatomical locations Class (isotype) switching produces class or subclass of antibody most effective in host defense Cytokines acting alone or in combination regulate class switching

Cytokine Network Many cytokines have effects on many cells and organ systems in addition to functions in immune systems Referred to as the “cytokine network”

Effects on Cells of Immune System NK LAK T cell B cell Activation of cells of immune system Proliferation, Differentiation, Ig secretion and selection Proliferation, Differentiation, Cytokine production Cytokine production IL1 IL2 IL4 IL1 IL2 IL4 IL5 IL6 IFNγ Macrophage Lymphocyte cytokines

Cytokine Effects on Organ Systems Lymphocyte Macrophage Hypothalmus ACTH Adrenal gland Corticosteroid Liver Acute phase proteins Pituitary IL1 IL6 TNF Fever -cortisol +DHEA IL 6 cytokines

Cytokine Effects on Various Cells Lymphocyte Macrophage Fibrogenesis Extracellular matrix cytokines IL1 TNF Endothelial cell Fibroblasts Fibrinogen Permeability change adhesion Endothelial cells TNF IL1 IFNγ Hematopoiesis Bone marrow IL3 CSFs Angiogenesis Fibroblast Extracellular matrix Osteoclasts Tissue remodeling Tissue repair Anti-viral state Many cell types IL1 TNF IFNα IFNβ IFNγ

Complement functions Host benefit: Host detriment: opsonization to enhance phagocytosis phagocyte attraction and activation lysis of bacteria and infected cells regulation of antibody responses clearance of immune complexes clearance of apoptotic cells Host detriment: Inflammation, anaphylaxis

Pathways of complement activation CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY

Complement Activation Digestion in lysosome Bacteria in plasma Complement activation Lysis and ingestion

Monocytes Macrophages Fibroblasts Epithelial cells Endothelial cells FEATURES OF CYTOKINES Cytokine Cell Source Cell Target Primary Effects IL-1 Monocytes  Macrophages Fibroblasts Epithelial cells Endothelial cells T cells; B cells Endothelial cells Hypothalamus Liver Costimulatory molecule Activation (inflammation) Fever Acute phase reactants IL-2 T cells; NK cells   T cells B cells Monocytes Growth Growth Activation IL-3 T cells Bone marrow progenitors Growth and differentiation IL-4 Naive T cells T cells B cells Differentiation into a TH 2 cell Growth Activation and growth; Isotype switching to IgE IL-5 B cells Eosinophils Growth and activation IL-6 T cells; Macrophages; Fibroblasts T cells; B cells Mature B cells Liver Costimulatory molecule Growth (in humans) Acute phase reactants IL-8 family Macrophages; Epithelial cells; Platelets Neutrophils Activation and chemotaxis IL-10 T cells (TH2) Macrophages T cells Inhibits APC activity Inhibits cytokine production IL-12 Macrophages; NK cells Naive T cells Differentiation into a TH 1 cell IFN-gamma Monocytes Endothelial cells Many tissue cells -  especially macrophages Activation Activation Increased class I and II MHC TGF-beta T cells; Macrophages T cells Macrophages Inhibits activation and growth Inhibits activation GM-CSF T cells; Macrophages; Endothelial cells, Fibroblasts TNF-alpha Macrophages; T-cells Similar to IL-1 IL = interleukin GM-CSF = granulocyte-macrophage colony stimulating factor IFN = interferon TNF = tumor necrosis factor TGF = transforming growth factor