Chapter 14 Immune Response in Space and Time immunology

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

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

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

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

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

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

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

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

Chemokines Chemokine receptors on leukocytes mediate leukocyte activity

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

http://www.youtube.com/watch?v=s8SZ11Wpw2k

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)

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

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

Lymphocyte Extravasation

Lymphocyte Extravasation

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

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

Some cytokines are inflammatory mediators

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

IFN-γ role in chronic inflammation

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