CHAPTER 3: PART 3 Cytokines

• • “Cytokines are soluble protein secreted by the cells of innate and adaptive immunity and therefore mediate many of the functions of these cells
  • Based on their cellular sources
  • Monokines (mononuclear phagocytes)
  • Lymphokines (lymphocytes)
  • Interleukins (leukocytes) (IL-1, IL-2, etc.)
  • A subfamily of cytokines primarily function in directing migration of cells, these are called “chemotactic cytokines” or “chemokines)
• • Naive lymphocytes
  • Mature lymphocytes that have not previously encountered antigen;
  • function – antigen recognition 
  • Preferential migration to peripheral lymphoid organs (lymph nodes), the sites where immune response start
• Effector lymphocytes

  • Activated lymphocytes capable of performing the function required to eliminate microbes (‘effector functions’)
  • Effector T Lymphocytes: cytokine section (helper cells), killing of infected cells (CTLs)
  • B lymphocytes: antibody-secreting cells (e.g. plasma cells)

  A) adaptive immunity

  B) innate immunity

  
• Phagocytes-identify, ingest and destroy microbes

  True
• Identify the photo

  Mononuclear phagocytes

  
• Identify the photo

  • Neutrophils (polymorphonuclear leukocytes)

  
• • Short lived (6h): most abundant population of circulating WBCs: mediate the earliest phase of inflammatory response


  Neutrophils (polymorphonuclear leukocytes)
• NK cells-kill infected cells and tumor cells

  • perforin/granzyme (cytolysis)
  • Fas/FasL
  • TNF - α/ TNFR-1 
  • Fas/FasL & TNF - α/ TNFR-1 – cell apoptosis
• As a result of cellular activation:

  • Mononuclear phagocytes are the principal source of cytokines of innate immunity
  • Tumor necrosis factor (TNF)
  • IL-1
  • IL-2
  • Type 1 IFNs
  • IL -15
  • IL-18
  • NK cells secrete cytokine, mainly IFN - γ – to activate macrophage to destroy phagocytosed microbes
• • T lymphocytes in response to Ags are the principal sources of cytokine in adaptive immunity
• The function of T helper cells is mediated by cytokines

  True
• • Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation
  • Cytokines initiate their actions by binding to specific membrane receptors on target cells
  • The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferations and the target cells
• • Cytokine actions is only local and not systemic

  False
• answer the following

  A) autocrine action

  B) paracrine action

  C) endocrine action

  
• • Most cytokines act close to where they are produced

  True
• T lymphocytes often secrete cytokines at the site of contact with antigen-presenting cells
• answer the following

  A) pleiotropic

  B) redundant

  C) synergic

  D) antagonistic

  E) cascade induction

  
• Cytokine Antagonist

  • A number of proteins inhibit biological activity of cytokines
  • These proteins act in one of 2 ways:
  • Bind directly to a cytokine receptor but fail to activate the cell
  • Bind directly to a cytokine, inhibiting its activity
  • Best-characterized inhibitor is IL-1 receptor antagonist (IL-1Ra), which bind to the IL-1 receptor but has no activity
  • This receptor blocks binding of IL-1’s
  • Production of IL-1Ra is thought to play in regulating intensity of inflammatory response
  • These inhibitors are in both blood and extracellular fluids
• Functional Categories of Cytokines

  • Mediators and regulators of innate immunity
  • Tumor necrosis factor (TNF), IL-1, IL-6, IL-12, Type 1 IFNs, IL-15, IL-18, chemokines
  • Mediators and regulators of adaptive immunity (lymphocytic growth, activation, and differentiation)
  • IL-2, IL-4, IL-5, IFN-g, TGF - β, IL-13, etc.
  • Stimulators of hematopoiesis
  • granulocyte -CSF, G-CSF
  • macrophage-CSF, M-CSF
  • granulocyte -macrophage-CSF, GM-CSF)
  • Erythropoietin, EPO
  • TPO
  • Stem cells factor, SCF
• Cytokine secretions by TH1 or Th2 cells

  • Differences in cytokine-secretion patterns among TH-cells subsets produce different responses to different types antigens in immune response
  • CD4 + TH cells exert most of their helper function through secreted cytokines
  • Acting on the cells or 
  • Modulating the responses of other cells
  • 2 CD4 + TH-cell subpopulations designated TH1 and TH2, can be distinguished in vitro by the cytokines they secrete
  • Both subsets secrete IL-3 and GM-CSF but differ in the other cytokines they produce
• TH1 subset

  • Responsible for:
  • Many cell-mediated functions (e.g., delayed-type hypersensitivity and activation of TC cells),
  • Production of opsonization-promoting IGg antibodies (i.e. antibodies binding to phagocyte high-affinity Fc receptors and interact with the complement system), and
  • The promotion of excessive inflammation and tissue injury
  • Secretes the important cytokine, IFN - γ
• TH1 subset

  • Activates macrophages, to increase microbicidal activity
  • Up-regulate the level of class II MHC, and
  • Induces antibody-class switching to IgG classes enhancing phagocytosis and fixation of complement 
  • Secretes IL-12, inducing TH cells to differentiate into the TH1 subset
  • Secrete TNF - β and IFN - γ mediating inflammation especially TH1’s activity in delayed hypersensitivity
  • Produce IL-2 and IFN - γ cytokines promoting differentiation of fully cytotoxic TC cells from CD8+ precursors
• TH1 subset produce IL-2 and IFN - γ cytokines promoting differentiation of fully cytotoxic TC cells from CD8+ precursors

  • This cytokine makes the TH1 subset particularly suited to respond to viral infection and intracellular pathogens
• • IFN - γ inhibits the expansion of the TH2 population
• TH2 subset

  • Responsible for:
  • Eosinophil activation and differentiation
  • Providing help B cells that specifically produce increased amount of IgM, IgE, and non-complement-activating IgG isotypes and also
  • Supports allergic reactions
• TH2 subset

  • The secretion of IL-4 and IL-5 induces production of IgE and supports eosinophil-mediated attack on helminth (roundworm)
  • IL-4 promotes class switch IgM to IgG subclass that does not activate the complement pathway
  • IL-4 also increase class witch from IgM to IgE
  • Combined IL-4 and IL-5 action increases Fc receptors on eosinophils
  • IL-4 and IL-10 suppress the expansion of TH1 cell populations
• TH2 subset

  • Many helper T cell do not show either a TH1 or a TH2 profile;
  • Individual cells have shown striking heterogeneity in the TH-cell population
  • One of these if the TH0 subset, which secretes IL-2, IL-4, IL-5, IFN- and IL-10, as well as IL-3 and GM-CSF
• Cytokine Receptors

  • Type I cytokine receptors
  • Type II cytokine receptors
  • Ig superfamily
  • TNF receptors
  • Seven-transmembrane α-helical receptors
  • Classification of cytokine receptors based on structural homologies among the extracellular cytokine-binding domain
• • Cytokine receptors consist of unique ligand-binding chains and one or more signal-transducting chains, which are often shared by receptors for different cytokines
• Biologic actions

  • Cytokines that mediate and regulate innate immunity
  • Cytokines that mediate and regulate adaptive immunity
  • Cytokines that stimulate hematopoiesis
  • Cytokines have many functions, we’ll focus on a few central functions of a few key cytokines
  • Mononuclear phagocytes are the principal source of cytokines of innate immunity
• answer the following

  A) Proinflammatory cytokines

  
• answer the following

  A) cytokines

  B) phagocytosis

  
• • Active recruitment of the cells to the sites of infection → recognition of microbes →  phagocytosis → destruction
• answer the following

  A) chemokines

  
• • The chemokines are classified into families based on the number and location of the N-terminal of cysteine residues CXC. CC. C CX3C 

  A) CXC

  B) CC

  C) C

  D) CX3C

  
• • Chemokines recruit the cells to site of infection

  tRUE
• Cytokines and Inflammation

  • Macrophages or DCs stimulated via microbes make pro-inflammatory cytokines, especially TNF (Tumor necrosis factor), IL-1, and IL-6
  • TNF and IL-1 signal to endothelial cells to make them:
  • Leaky to fluid (Influx of plasma: containing antibodies, complement components, etc.)
  • Sticky for leukocytes, leading to influx of neutrophils first then monocytes, lymphocytes
  • Chemokines induce movement of leukocytes and their migration toward chemical gradient of the cytokine
• Answer the following:

  A) primary lymphoid organs

  B) secondary lymphoid organs

  C) blood

  D) tissue

  
• Chemokines regulate the traffic of lymphocytes and other cells through peripheral lymphoid tissues

  True
• Segregation of B cells and T cells in distinct areas of the lymph node is dependent on cytokines