1. Chapter 14 Immune Response in Space and Time
immunology

2. 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

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

4. 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

6. 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

7. 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

8. CAMs Integrins Consist of α and β 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

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

10. Chemokines Major regulators of leukocyte traffic Small polypeptides
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

11. Chemokines
Chemokine receptors on leukocytes mediate leukocyte activity

12. 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

14. Extravasation Neutrophils are generally first Monocytes
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)

15. 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

16. 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

17. Lymphocyte Extravasation

18. Lymphocyte Extravasation

19. 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

20. 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

21. Some cytokines are inflammatory mediators

22. 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-γ and TNF-α involved in chronic inflammation
Contributes to tissue wasting

23. IFN-γ role in chronic inflammation

25. 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