Immunopharmacology Flashcards
Chemokines and chemokine receptors
Chemokines - polypeptide mediators of directed migration of immune cells. Dimeric form is biologically active. Have highly conserved Cys amino acid residues that defjne classification.
1. CXC family - the first two NH2 terminal Cys groups are separated by one amino acid.
2. CC family - the first two NH2 terminal Cys groups are in juxtaposition.
>50 chemokines and 14 receptors (all GPCRs).
Chemokine/Chemokine receptor distribution varies between cell types and is regulated by cytokine/PAMP exposure.
One chemokine receptor can interact with one or more chemokines.
Chemokines initiate chemotaxis
Chemotaxis - movement down an increasing concentration gradient of chemotaxin.
Chemokine receptor binding activates Gi, this in utrn activates PI-3 kinase which makes PIP3 then Rac and Rho, two small Ras like G proteins.
Rac is responsible for the speading at the leadjng edge of celk towards chemokine.
Rho is responsible for retraction at the back end.
This allows neutrophils to track and Chase bacteria for phagocytosis and destruction.
Cellular response of inflammation
Migration of white blood cells Pavementing (rolling and adhesion) Emigration Chemotaxis Phagocytosis
Neutrophils
Most abundant polymorphonuclear leukocytes.
7HR half-life
General purpose phagocyte, digests anything.
Typicalky 1st on scene, specialises in destroying extracellular microbes that have not yet invaded host cell.
Count increases markedly during infection
Neutropenic patients are very prone to infection
Monocytes and macrophages
Derived from blood monocytes,become macrophages following tissue cytokine exposure.
Widespread tissue distribution
Sentinel scavenger cellsm arrive on scene hours after neutrophils.
Produce multiple inflammatory cytokinesand growth factors (to begin repair).
Important in antigen processing/presentation to kick start adaptive immune response.
Natural kilker cells
Large granular lymphocytes important jn defence against viral infection, tumour cells and intracellular bacterial pathogens.
Attach to and kill infected host cells (release of toxic granules).
Secrete IFNgamma to potentiate macrophage mediated phagocytosis.
Antibody directed cellular cytotoxicity (ADCC)
Receptors for FC region og IgG on the surface of jmmune effector cells bind the FC region of an antibody that is specifically bound to a target cell.
Receptor activation triggers the activation of the effector cell and Secretion of substances that mediate the destruction of the target cell.
Cells that mediate ADCC - NK cells, macrophages, neutrophils, eosinophils.
Macrophages and NK cells cooperate to kill microbes.
Mast cells
Settle in connective tissue, do not normally circulate.
Many cytoplasmic granules, contents is released upon activation by IgE receptors and C5a complement receptors.
Involved in type I hypersensitivity reactions.
Phagocytosis
Bind bacteria to cell membrane Internalise in a vacuole/vesicle Vesicle fuses with lysosome Digestion of bacteria Exocytosis
Opsonisation by Ab and complement facilitates uotake of microbes by phagocytic cells
Bacterium is coated with IgG antibody and complement.
When C3b binds to CR1 and antibody binds FC receptor, bacteria are phagocytosed.
Macrophage membranes fuse creating a phagosome (membrane bound vesicle).
Lysosomes fuse with these, delivering enzymes that degrade the bacteria.
Phagocytosis destroys microbes by…
Acidic environment (bacteriostatic/bacteriocidal) Toxins Enzymes Defensins Competitors
Activated macrophages and DCs as APCs
Both uptake antigen via phagocytosis.
DCs present bacterial/viral antigens
Macrophages present intra/extracellular bacteria.
DCs take up bacterial antigens in skin, migrate to enter the draining lymph vessel where they settle in the T cell areas readg to initiate T cell activation.
TCR and co-receptor interactions
CD28 is expressed by all T cells, CTLA4 is expressed by activated T cells.
Signals from both TCR and CD28 are required for activation of T cells.
CD28/CTLA4 are T celk receptors for B7 molecules on APCs.
TCR activation without CD28/B7 costimulation leads to T cell anergy.
Induced CTLA4 binds B7 and blocks costimulation, therefore limiting T celk expansion.
Anti-inflammatory and immunosuppressive drugs
NSAIDs and other eicosanoid pathway antagonists
Histamine antagonists
Anti-rheumatoids
Immunosuppressants (glucocorticoids, cyclosporin)
Clinical uses of immunosuppressive drugs
Supression of immune rejection of transplanted organ
Suppression of graft vs host disease in bone marrow transplants.
Treatment of diseases with an autoimune component.
