LECTURE 6 drh. Teridah

• Cytokines


  Small (10-30 kDa), usually secreted & glycosylated peptides, that regulate the nature, intensity and duration of the immune response by exerting a variety of effects on lymphocytes and/or other cells

  
• Chemokine


  Cytokine that functions as chemoattractant (mobilizes leukocytes)
• General functions of cytokines

  • Promote proinflammatory responses
  • Mediators of natural/innate immunity
  • Regulators of lymphocytic growth, activation and differentiation
  • Activators of inflammatory cells
  • Stimulators of hematopoiesis

  
• Properties of cytokines


  • Pleiotropy: the ability to induce varied responses in target cells
  • Redundancy: the ability of different cytokines to induce the same response
  • Synergy: the ability of different cytokines to cooperate in inducing certain cell responses
  • Antagonism: the ability of certain cytokines to antagonise the activity of other cytokines
  • Cytokines cascade: Activation of one cytokine produced by one cell type leads to induction of cytokine production by other cell types

  
• Classifications of cytokines


  • By role/functional of cytokines: Innate/adaptive, Th1, Th2, Th17, Pro-inflammatory/anti-inflammatory
  • By structural homologies of cytokines: The four α-helix bundle family, TNF family, TGF family, IL-1 family, IL-17 family

  
• Classes of cytokine receptors

  • Hematopoietin receptor family (Class I cytokine receptor family)
  • Interferon receptor family (Class II cytokine receptor)
  • TNF receptor family
  • IL-1 family of cytokine receptors
  • Chemokine receptor family (seven transmembrane GPCR)
  • IL-17 receptor family

  
• Hematopoietin receptor family (Class I cytokine receptor family)


  Bind type I cytokines (have 4 alpha-helix structure), Subfamilies have identical signaling subunits: GM-CSF receptor subfamily, IL-6 receptor subfamily, IL-2 receptor subfamily

  
• Interferon (IFN) receptor family

  Ligands: IFN-α, IFN-β, IFN-γ, IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29
• Immunoglobulin superfamily receptor (IL-1 family receptor)

  Ligands: IL-1, IL-18, IL-33, M-CSF, C-Kit

  
• IL-17 family receptor


  Ligands: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, IL-17 (ORF13), Composed of 5 protein chains: IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE

  
• Chemokine receptor (7TM-GPCR)


  Ligands: chemokines e.g CCL21, IL-8, RANTES, MIP-1, PF4, MCAF, NAP-2
• NF-κB signaling induced by cytokines

  NF-κB is a transcription factor that plays a central role in inflammation, lymphocyte activation, cell survival, and the formation of secondary lymphoid organs

  
• Chemokines


  A large family of structurally homologous cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues. Produced by leukocytes and other cells such as vascular epithelial

  
• Chemokine families


  • CC (also called β) chemokines
  • CXC (or α) chemokines
  • C family chemokines
  • CX3C family chemokines
• Chemokine functions


  • Roles in inflammation: Increased adhesion of leukocytes to endothelium, Migration of leukocytes to site of infection or tissue damage
  • Involved in the development of lymphoid organs, and they regulate the traffic of lymphocytes and other leukocytes through different regions of peripheral lymphoid tissues
  • Required for the migration of dendritic cells from sites of infection into draining lymph nodes

  
• Cytokines in innate and adaptive immune system

  • Hematopoietic cytokines
  • Lymphocyte Production
  • Myelocyte Production
  • Stem Cell Production
  • Proinflammatory and anti-inflammatory cytokines

  
• Septic shock is a severe pathologic consequence of disseminated infection by some Gram-negative and Gram-positive bacteria, caused by cytokines produced by macrophages that are activated by bacterial cell wall components, including LPS and peptidoglycans or bacterial superantigen. Tumor necrosis factor (TNF), IL-6, also IFN-γ and IL-12. This early burst of large amounts of cytokines is sometimes called a cytokine storm. Highly pathogenic viral diseases, such as EV and HPAI, cause cytokine storm.
• Septic shock is a syndrome characterized by circulatory collapse and disseminated intravascular coagulation.
• Types of hypersensitivity reactions

  • Type I (Ab-mediated)
  • Type II (Ab-mediated)
  • Type III (Ab-mediated)
  • Type IV (Cell-mediated)
• Type I hypersensitivity occurs on a proportion of individuals (atopic individuals) in response to allergens, and involves activation of B cells to produce IgE, which binds to mast cells and causes release of mediators (immediate) and cytokines (late).

  
• Type II and III hypersensitivity reactions occur in any individual, e.g. haemolytic transfusion reactions (HTR) when a blood transfusion between ABO incompatible individuals is carried out.