immunology

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immunology

• Chapter 14
• Immune Response in Space and Time

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• Invaders infect our bodies
• Cells of innate immune system arrive first
• Adaptive immune response provides longer
  protection
• Leukocytes are constantly monitoring for
  infection
• When detected, cells cross the blood barrier and
  travel to site of infection

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• Inflammatory response
• Redness
• Heat
• Swelling
• Pain
• Needs controlled migration of leukocyte
  populations

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• Our tissues are held together by molecular
  interactions
• Cell adhesion molecules (CAMs)
• Selectins, mucins, integrins, Ig-Superfamily CAMs
  (ICAMs)
• Can be used by leukocytes to interact with
  tissues
• For leukocytes to enter inflamed tissues, cells
  must adhere and pass between endothelial cells
  lining blood vessel - EXTRAVASATION
• Endothelial cells can express certain leukocyte
  specific CAMs

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CAMs

• Selectins
• Membrane glycoproteins
• Bind to specific carbohydrate groups
• Interact with mucin-like molecules
• Example
• P-selectin (platelet) is stored in granule in
  endothelial cell
• Upon activation, granule fuses with membrane so
  that p-selectin is expressed

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CAMs

• Mucins
• Serine and threonine-rich proteins
• Binding sites for selectins
• Mucins' key characteristic is their ability to
  form gels therefore they are a key component in
  most gel-like secretions, serving functions from
  lubrication to cell signalling to forming
  chemical barriers

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CAMs

• Integrins
• Consist of a and ß chains
• Bind cell surface molecules involved with cell to
  cell interactions
• provide essential links between the extracellular
  environment and the intracellular signalling
  pathways, which can play roles in cell behaviours
  such as apoptosis, differentiation, survival, and
  transcription
• Leukocyte adhesion deficiency
• Autosomal recessive disease
• Characterized by recurrent bacterial infections
  and slow healing

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CAMs

• Ig-Superfamily CAMs (ICAMs)
• Immunoglobulin-like domains
• Bind to various integrin molecules

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Chemokines

• Major regulators of leukocyte traffic
• Cytokines that are responsible for movement of
  immune cells
• Small polypeptides
• Some involved in inflammation, some involved in
  homeostatic roles (house keeping)
• Induce adherence of leukocytes to endothelial
  lining

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Chemokines

• Chemokine receptors on leukocytes mediate
  leukocyte activity

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Leukocyte extravasation

• Various cytokines and inflammatory mediators act
  on local blood vessels
• 4 steps of extravasation
• Rolling, mediated by selectins
• Activation by chemoattractant stimulus
• Arrest and adhesion, mediated by integrins
  binding to Ig-family
• Transendothelial migration

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http//www.youtube.com/watch?vs8SZ11Wpw2k
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Extravasation

• Neutrophils are generally first
• Bind to endothelium when E-selectin and
  P-selectin are expressed by endothelium
• Monocytes
• Come in much later
• This is because it takes time for inflamed
  endothelial cells to express CAMs (such as ICAM-1
  and VCAM-1)

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• Lymphocyte Recirculation
• Unlike other leukocytes, lymphocytes recirculate
  continuously from blood to tissues to lymph (1 to
  2 times a day)
• Lymphocytes are antigenically committed
• This recirculation increases chances of
  lymphocyte coming into contact with particular
  antigen

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• Lymphocyte Extravasation
• Involves interaction of CAMs
• Ensures proper populations of B and T cell make
  it into certain tissues
• Capillaries
• Flattened endothelial cells
• HEVs high endothelial venules
• Areas of capillaries that have cells that are
  more cubodial in shape
• Express variety of CAMs

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Lymphocyte Extravasation
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Lymphocyte Extravasation
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• Although lymphocyte extravasation is similar to
  neutrophils, different subsets of lymphocytes
  must make it into different tissues
• Naïve lymphocytes
• Migrate to secondary lymphoid tissue to encounter
  antigen
• Effector and memory lymphocytes
• Home to regions of infection
• Memory cells will tend to home to tissues in
  which they first encountered antigen

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Other mediators of inflammation

• Kinin System
• induce vasodilation and contraction of smooth
  muscle
• Clotting system
• Fibrinolytic system
• breaks up clots
• Complement system
• Anaphylatoxins (C3a and C5a)
• Release of histamines by mast cells
• Some lipids
• Released by tissues from damage

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Some cytokines are inflammatory mediators
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Inflammation response may be localized or systemic

• Localized Inflammatory Response
• Duration and intensity must be carefully
  regulated to control tissue damage
• Systemic Acute Phase Response
• Localized accompanied by acute phase response
• Induction of fever
• Increased production of WBCs
• IFN-? and TNF-a involved in chronic inflammation
• Contributes to tissue wasting

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IFN-? role in chronic inflammation
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Anti-Inflammatory Agents

• Antibody therapies can reduce leukocyte
  extravasation
• Monoclonal Abs to CAMs
• Corticosteroids
• Cholesterol derivatives
• Decreases number of circulating lymphocytes
• Reduces phagocytosis
• NSAIDs
• Found in plants, aspirin
• Pain and inflammation
• Reduces prostaglandins, lowers vascular
  permeability