Inflammation & Cytokines

Question 1

What are the first cells to respond to pathogens? and what happens after their encounter?

Answer 1

• Tissue macrophages/mast cells are often first to respond by releasing inflammatory mediators that (broadly) increase blood flow and vascular permeability, and chemoattractants that attract phagocytes into the tissues.
• Cytokines, small proteins that induce other cells to help deal with the infection, are also produced. (by tissue macrophages/mast cells)
• Inflammation, triggered by infection and tissue damage, is a critical local response to infection, allowing the phagocytes in blood to gain access to the microbes in tissues
  
  • so inflammation is beneficial in most cases

Question 2

What are the 3 classical signs of inflammation?

Answer 2

• Redness, swelling, heat, pain…
  
  • inflammation caused by Release of inflammatory mediators (e.g.by macrophages)
  • Dilation of local blood vessels (redness)
  • Increased permeability and blood flow (swelling)
  • Immune cell migration into inflammatory site
    
    • imnune cells e.g. nutrophils squeeze out between cells that line capillaries into the tissues
    • pain caused by stimulation of nerve endings which supply the tissues
• Inflammation ensures that immune cells, defence molecules, coagulation factors etc. reach the site of infection or tissue damage.

Question 3

Describe the 5 types of inflammatory mediators produced by sentinel cells, and give examples of each type

Answer 3

• Lipid mediators
  
  • e.g. prostaglandins
    
    • stimulate dilation of blood vessels and act on pain receptors
    • e.g. aspirin stops synthesis of prostaglandins (analgesic)
• Vasoactive amines
  
  • e.g. histamine, bradykinin
  • chemicals which call dilation of blood vessels
• Chemoattractants
  
  • e.g. fmet-leu-phe
  • help phagocytes move into the tissues
• Complement proteins
  
  • e.g. C5a
• Cytokines
  
  • e.g. TNF
  • production of by sentinel cells

Question 4

Describe the differences betwee acute and chronic inflammation

Answer 4

• Acute inflammation is generally beneficial in dealing with infection/injury
  
  • painful but beneficial
  • goes away once infection/injury dealt with
• Chronic inflammation (caused by chronic infection e.g. TB or other conditions e.g. autoimmune disease) can be damaging
  
  • caused by infection that the body isn’t able to deal with or by autoimmune diseases
  • macrophages taken up TB bacteria (bacteria can survive inside macrophages) → chronic inflammatory response → granuloma (build up of cells e.g. macrophages)

Question 5

What is the main role of cytokines?

Answer 5

• Cytokines are crucial in orchestrating and controlling immune responses – important in innate and adaptive immunity.
• once infection dealt with → tell immune system to switch off

Question 6

Describe the general function of cytokines, how they induce their effects, where they act, who can produce them, what they act on etc.

Answer 6

• Stimulus → Cytokine producer (e.g. macrophage) (via. cytokine gene expression) → cytokines bind to cytokine receptor on target cell → gene activation → biological effects
• Cytokines Regulate immune responses by changing cell behaviour or gene expression
  
  • sometimes downregulation of genes
• 5-20kD; >100 identified
  
  • small proteins
• “Hormones” of the immune response
• Most act locally, but can have systemic effects
  
  • cytokines can cause damage if overactive or inappropriately active
• Can be produced by many cell types in response to immune activation
  
  • e.g. epithelial cells
• Act on cells bearing specific cytokine receptors
  
  • cytokine receptors on target cells
• Expression of cytokines and their receptors is tightly regulated
  
  • important!
  • if it goes wrong → damage to body tissue

Question 7

Name the 5 sub-families of cytokines and their functions

Answer 7

1. IL-1 family:
   
   1. most produced as inactive precursors that must be cleaved by inflammasomes
   2. important in inflammation
2. Haematopoietin superfamily:
   
   1. includes factors involved in leukocyte differentiation e.g. GM-CSF but also IL-2, IL-4, IL-6 (important in T cell responses).
   2. broadly, they stimulate the generation of new white blood cells from bone marrow
3. Interferons:
   
   1. involved in responses to viruses
4. TNF family (e.g. TNFα = tumour necrosis factor):
   
   1. many are transmembrane proteins that are shed, important in inflammation.
   2. very potent and toxic
5. Chemokines:
   
   1. involved in cell movement (e.g. IL-8 a.k.a CXCL8 → induce neutrophil movement out of blood stream into tissues)
   2. induce cell movement
   3. act like C5a
      
      • Cytokine receptors for the various subfamilies also tend to have similar structures and to signal in a similar way

Question 8

Describe the local and systemic effects of each of the 5 types of cytokines that may be produces by tissue-resident macrophages in the early stage of immune response

Answer 8

• IL-1-beta
  
  • Local effects:
  • Pro-inflammatory
  • Activates vascular endothelium
  • Activates lymphocytes
  • Local tissue destruction increases access of effector cells
  • Systemic effects: Fever & production of IL-6
• IL-6
  
  • Local effects: activates lymphocytes(B & T cells)
  • increaes antibody production
  • System effects: fever, induces acute-phase protein production
• CXCL8
  
  • local: chemotactic factor recruits neutrophils, basophils and T cells to site of infection
• IL-12
  
  • local: activates NK cells, induces differentiation of CD4 T cells into TH1 cells
• TNF-alpha
  
  • Local effects: Activates vascular endothelium and increases vascular permeability which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes
  • Systemic effects: Fever, mobilisation of metabolites & shock (can cause sepsis)

Question 9

What are interferons and what are the 2 types

Answer 9

• Viral infection induces the production of interferons
• “Intruder alert cytokines”
• Interferons Interfere with viral replication
• Type I interferons: IFN-α ; IFN-β
  
  • IFN-α (several genes) & IFN-β (1 gene) act in a very similar way
  • many (almost any) cell types make type I interferons after viral infection.
  • Induce expression of interferon-stimulated genes (ISGs)
  • Some cell types (e.g. dendritic cells) are specialised for this – express high levels of endosomal TLRs e.g. TLR3 and TLR9.
• Type II interferon: IFN-γ
  
  • Main role is to modulate immune responses
  • different structure to IFN-alfa and beta

Question 10

Describe the mechanism of action of type 1 interferons and how they induce resistance to viral replication

Answer 10

• Virus infected host cell → IFN-α, IFN-β produced
• IF cell has TLRs → inteferon alfa and beta expressed and produced
  1. Induce resistance to viral replication in all cells.
  
  • not only the infected cell but secreted inferons can bind to surrounding cells and help them.
  • How they induced resistance to viral replication? →
    
    • Induce expression of endoribonuclease that degrades viral RNA and also, protein kinase phosphorylates eukaryotic initiation factor 2, inhibiting protein translation. (good because most proteins made by a virus infected cell are viral proteins)
      2. Increase MHC class I expression in all cells
  • MHCI is required for antigen presentation to cytotoxic T cells, so infected cells are more easily recognised and killed.
  • important in inducing adaptive immunity
    
    3. Activate NK cells to kill virally infected cells more efficiently
    4. Induce chemokines to recruit lymphocytes
       1. chemokines are chemoattractants

Question 11

Describe type 2 interferons, who makes them, their function

Answer 11

• Made by neutrophils, NK cells, T cells
  
  • unlike Type I inteferons, not all cells make it
• Primary role in adaptive immunity
  
  • particularly T-cell immunity
• Increases expression of MHCI and MHCII
  
  • helps induce formation of Cytotoxic T cells
  • MHC II expression increased → induce T helper cells
• IFN-γ made by T helper cells activates macrophages in responses to intracellular pathogens
  
  • activates macrophages to kill intracellular pathogens in the macrophage itsself

Question 12

Describe the interactions between innate and adaptive immunity

Answer 12

• Co-evolved and are interdependent
• Innate immune responses initiate adaptive responses (antigen presentation) and different cytokines can “steer” adaptive immune responses by activating different T cell subsets, promoting the production of different antibody classes
• Adaptive responses use elements of innate immunity to eliminate pathogens e.g. classical pathway of complement , activation of macrophages by T cell cytokines, antibodies can help NK cells recognise infected cells, mast cells to respond to parasites.