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202 Cards in this Set
- Front
- Back
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white blood cells/Leuokocytes
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made in bone marrow, found in blood and lymphatic circulation, but enter connective and lymphatic tissues to exert their functions
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Granulocytes
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Neutrophils
Eosinophils Basophils -specific granules and non specific granules -lysosomes are granules |
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Agranulocytes
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monocytes
lymphocytes -non specific granules |
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neutrophils
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-multilobed nucleus
-specific clear granules in cytoplasm -60-7-% of total leuokocytes in circulation -function in phagocytosis |
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Eosinophils
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-1-5% of the leukocytes in circulation
-function in phagocytosis -bilobed nucleus -specific granules; pink-orange-red |
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Eosinophil Specific Granules
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-major basic protein
-peroxidase -histaminase -arylsulfatase -acid phosphatase -eosinophil derived inhibitor |
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Basophils
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-.5-1% of circulating leuokocytes
-function : immune responses, fight parasitic worms -specific granules: dark staining -segmented nucleus |
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Basophil Granules
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-hydrolytic enzymes
-heparin -histamine -chondroitin sulfate -eosinophilic chemotactic factor of anaphylaxis |
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Monocytes
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-2-10% of the circulating leukocytes largest type of leukocyte
-blue gray cytoplasm -kidney shaped nucleus |
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monocyte/macrophage function
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Phagocytosis
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lymphocytes
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-the major cell of the immune system
-20-40% of the circulating leukocytes -dark purple circular nucleus |
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lymphocytes function
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B lymphocytes: humoral immunity
T lymphocytes: cell mediated immunity |
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primary lymphatic organs
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Bone marrow: B and T cell from here(lymphocytes)
Thymus: T cells become immunocompetent |
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secondary lymphatic organs
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-where immunocompetent lymphyocytes contact antigens
-lymph nodes -spleen -mucosa associated lymphoid tissue (MALT) |
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Bone marrow
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B and T cell precursors formed here
B cells mature or become immunocompetent |
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Thymus
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T cells mature to become immunocompetent
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components of bone marrow
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sinuses
cords of developing cells |
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components of thymus
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-two three lobes, surrounded by a connective tissue capsule.
-capsule sens trabeculae that subdivide cortex into lobules -cortex site of T cell maturation, dense T cells -Medulla : fewer T cells -capillary beds in the cortex |
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T cell path in thymus
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- T cells enter the cortex from apillaries. Migrate to the outer edge of the cortex. Mature from the outer cortex inwards towards medulla
-mature ,surviving T cells leave the thymus through the veins in the medulla |
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Blood-Thymic Border
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-continuous capillaries with tight junctions . Epithelial reticular cells line up along the capillaries. Thick basal lamina formed by capillary endothelium and epithelial reticular cells
-prevents immature T cells from contacting foreign antigens |
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Hassall's Corpuscles
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-found in thymic medulla
-concentric arrangements of remnants of apoptotic epithelial reticular cells and T cells -involution of the thymus -thymus becomes covered with adipose tissue. hassals corpuscles increase in size and number |
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lymph node organization
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-capsule of connective tissue surrounding cortex(paracortex) and medulla
-function in filtering lymph borne antigens |
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lymphoid follicles
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-in cortex of lymph node
-contain B lymphocytes -following stimulation, B cells proliferate and rearrange. Follicles develop a lighter staining germinal center with B lymphoblasts surrounded by a darker corona of B lymphocytes |
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lymphatic vascularization of the lymph node
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-afferent lymphatic vessels enter on convex side; drain into subcapsular sinuses that drain to trabecular and medullary sinuses
-efferent lymphatic vessels exit at the hilum of the node |
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supporting framework of the lymph node
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-the cells of the lymph node are surrounded and supported by fine reticular fibers (collagen type III)
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organization of the spleen
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surrounded by connective tissue, capsule with trabeculae that penetrate into parenchyma
-subdivided into white pulp and red pulp -filters blood borne antigens |
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White Pulp
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-splenic artery branches into central arteries in white pulp
-sheaths of T cells (PALS- peri-arteriolar-lymphatic sheaths) with embedded B cell follicles surround central arteries White Pulp= PALS(T cells)+ follicles(B cells)+ central arteries |
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Red Pulp in Spleen
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-cords of cells
-venous sinuses |
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blood flow in spleen
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-from white pulp to red pulp
-central arteries (in WP) branch into penicillar arteries which give rise to sheathed capillaries (in RP) -blood drains from sheathed capillaries into cords of cells and/or venous sinuses in the red pulp |
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how many families of viruses are there
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16 families
-rabies, common cold, AIDS |
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how many groups of bacteria and other prokaryotes
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10 groups
-syphilis, pneumonia, diptheria |
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how many major fungi and yeast groups
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-aspergilosis, thrush, PCP pneuomonia
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how many protozoa families
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8 families
- malaria, trypanosomes |
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how many species of worms
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12 species
-tapeworms, roundworms |
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Innate immunity
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-non specific
-no memory -fast -constant -epithelial barriers -phagocytosis -complement -NK cells |
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Adaptive Immunity
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-highly specific
-has memory -slow -improves - b lymphocytes -antibodies -t lymphocytes -effector T cells |
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Antibodies, T cell receptors and antigen recognition
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-antibody (immunoglobin) binds large and small molecules
-TCR: oligopeptides+MHC molecules -MHC I and II: oligopeptides -antibodies bind everything , we make antibodies to everything T cell recognized pieces of proteins, and MHC molecule is what the T cell receptor sees |
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B lymphocytes
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-secrete antibodies as plasma cells
-present antigen |
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T lymphocytes
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-kill infected cells
-secrete cytokines -activate phagocytes, T and B cells |
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Nk cells
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-large granular lymphocytes
-kill tumor and virally infected cells |
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monocytes/macrophages
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-phagocytic cells
-present antigen |
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dendritic cells
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-present antigen
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neutrophils
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-phagocytic cells
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eosinophils
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anti-helminth immunity
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Basophils
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anti helminth immunity?
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Mast cells
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-inflammatory responses
-innate immunity -anti helminth immunity |
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B cells
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-present antigen to T cells
-capture antigens via cell surface antibody molecules |
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monocytes/macrophages
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-present antigen to T cells
-capture antigen by phagocytosis of pathogens |
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Dendritic Cells
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- present antigen to T cells
-capture antigen by endocytosis -deliver antigen to lymph nodes |
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clonal selection
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-can also occur with T lymphocytes
-multiple daughter cells with multiple, different specificities -proliferation and differentiation of pathogen specific lymphocytes -lymphocytes clones with diverse receptors arise in generative lymphoid organs -clones of mature lymphocytes specific for many antigens enter lymphoid tissues -antigen-specific clones are activated or selected by antigens -antigen specific immune responses occur |
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what happens with infection
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when you have an infection it goes from:
blood to lymphnode to tissues, -B cells, when no infection, leave and return to the same place. when you have an infection, they are drawn to the site of infection |
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Lymphocytes
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-circulate in the blood and enter lymph nodes by crossing high endothelial venules
-lymphocytes home to sites of infection and leave the blood in tissues |
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Phases of an immune response
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-recognition phase
-activation phase -antigen elimination -contraction homeostasis -memory |
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memory responses are a hallmark of vertebrate immunity
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-faster induction
-longer lasting -more potent |
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what makes a good antigen
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-protein>carbs>lipids
-large>small -route of immunization: subcutaneous, intramuscular> intraperotoneal> IV, oral for: particulate or complex>> simple |
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why study immunology
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-autoimmune diseases
-allergies -HIV /AIDS -organ and bone marrow transplantation -immunopharmacology -vaccination immunology -immunodeficiency diseases -assessment of the immune system -infectious disease diagnosis -cancer immunology -oncology |
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Lymphatic valves
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-proteins can move across the lymphatic system, unlike blood system
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lymphatic system functions
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- maintaining fluid balance: transports interstitial fluid back to circulation, transports proteins back to circulation
-purification and defense: clears extracellular space of particulate matter, exudates, bacteria, and brings immune cells in contact with invaders -nutrition: absorption of fats from small intestine |
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lymphatic vessels transport interstitial fluid back into the circulation
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-the lymphatic vessels circulate 3 liters a day
- 27 L/day of ISF enters the blood system -30 L/day of blood enters the ISF from blood -the extra 3 left over in the blood enters the lymphatic system |
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lymphatic system
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-removes proteins from interstitial space
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Factors affecting lymph flow
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1) interstitial pressure
2)lymphatic pumping |
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Factors influencing interstitial pressure
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capillary hydrostatic pressure
plasma protein interstitial protein capillary permeability interstitial hydrostatic pressure |
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lymphatic pumping
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-intrinsic pumping by smooth muscle
-extrinsic pumping |
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T cells
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they see peptides displayed by molecules of the major histocompatibility complex
-peptides bind to the MHC molecules via anchor residues -T cell receptor sees both the peptide and the MHC molecule |
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three types of professional antigen presenting cell; these activate T cells
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-macrophages
-dendritic cells -b cells |
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macrophages
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-antigen uptake via phagocytosis
-MHC expression inducible by bacteria and cytokines - to +++ -antigen presented: particulate antigens, intracellular and extracellular pathogens -located in lymphoid tissue, connective tissue, body cavities |
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Dendritic Cells
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-antigen uptake by phagocytosis by tissue dendritic cells +++, viral infection ++++
-MHC expression is consituitive ++++ -Antigen presented is peptides, viral antigens, perhaps allergins -located in the lymphoid tissue, connective tissue, epithelia |
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B cells
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-antigen uptake via antigen specific receptor (Ig) ++++
-MHC exrpession is consituitive; increases on activation , +++ to++++ -antigen presented is soluble antigens, toxins, viruses -located in lymphoid tissue, peripheral blood |
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APC take up antigen in the periphery and present antigens to T cells. Different types of antigens reach different lymphoid tissues by:
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-lymphoid drainage
-transport via APC's -bloodstream |
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What are the best APC?
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-dendritic cells
-most found in skin or mucosal tissues as Langerhans cells |
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what is the MHC
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-cluster of closely linked genes on Chr. 6 in humans that encode proteins which:
-control T cell mediated immune responses -determine the fate of transplanted tissues |
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MHC genes are co dominant and inherited as haplotypes
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boo
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The expression of MHC molecules differs between tissues and cell types
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-MHC II molecules only are activated by B cells, macrophages, dendritic cells.
-MHC I molecules are activated by everything except red blood cells |
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MHC I
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-binds to CD8
-CD8 binds the alpha 3 domain of MHC class I -these are these the killer cells -antigen uptake is via cytosolic microbe, which gets broken down into peptides in cytosol, which then get presented to the MHC I on the ER.. the Er then moves the MHC via vesicle with antigen peptide, outside the cell, where the CD8 killer cell recognizes it |
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MHC II
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-bind CD4 cells
- binds the beta 2 domain of the MHC class II molecule -antigen presenting cell -MHC II antigen gets processed first by endocytosis of an extracellular microbe. the endoyctic vesicle breaks down the antigen into peptides, meanwhile, the ER releases a vesicle containing invariant chain, Ii, and it meets up with the peptide vesicle in the cytosol. These vesicles fuse and go on to activate the CD3 helper cell |
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How B cells talk to T cells
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-there is b cell recognition of native protein antigen
-Recpetor-mediated endocytosis of antigen then takes place -The antigen is processed, and presented on the B cell via MHC II class peptide complex - T cell recognizes the MHC II on the B cell |
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T cell effector functions
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- once the CD4 T lymphocytes is activated, it releases cytokines which can activate macrophages, or activated B cell antibody secretion: antibody binding to microbe. (if the MHC II is on a B cell to begin with)
-MHC I CD8 effector function is the killing of antigen expressing infected cells. |
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antibodies or immunoglobulins are antigen specific proteins secreted by B lymphocytes
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-once they recognize and bind a bacteria, the plasma cells secrete antibodies
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structure of antibody molecule
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-consist of heavy chain and light chain
-has a hinge region -the stem is the Fc receptor complement binding sites -they Y is the Fab region, and antigen binding site -domains held together by disulfide bonds |
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light chains
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-they are not identical
-in some regions not identical at all, these are hypervariable regions -discrete islands of hypervariable amino acids V regions of Ig heavy and light chains, and in the TcR, form the antigen binding site |
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Antibodies can be enzymatically cleaved into functionally distinct fragments
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-protealitic enzymes cut just above the hinge, and creates two Fab fragments; cleavage by papain
- If pepsin cuts, it cuts below the hings, and Fab arms stay in tact, along with on Fc |
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The Fc portions of antibodies also have functional regions
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- the Fc portions of Ig bind to Fc receptors on phagocytes and other cells
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Heavy and light chains come in different isotypes
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-five heavy (antibody names)
-IgG; y -IgM; u -IgD; s -IgA: a -IgE: e -light chains have only two types; kappa and lambda, and all are glycoprotiens |
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Regions of an antigen that specifically bind an antibody are antigenic determinants or epitopes
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-linear; bacterial cell walls
-conformational; proteins -antibodies, B cells recogize intact proteins -T cells recognize degraded peptides bound by MHC molecules -antigens containing more than one epitope are called multivalent |
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Most antigens are multivalent
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-can have multivalent antigen with different epitopes
-can have multivalent antigen with a repeated epitope -there are no class MHC II only cells -Ther are only class MHC I only cells -sometimes the specificity of antibodies is cross reactive due to the sharing of epitopes |
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affinity vs. avidity
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affinity: the relative strength of a single antibody binding site for antigen , qualitative
-avidity: overall strength of the combined binding sites , 2 for IgG, and 10 for IgM, of a given antibody molecule, quantitative - IgM forms pentamers -IgA forms a dimer in secretions -IgG has higher affinity -IgM has higher avidity |
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Haptens are a special class of antigen
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-can't provoke antibody response by themselves
-must be coupled to a larger molecule , often a protein called a carrier -haptenylation reactions can occur for both B and T cells -allergic to penicllin.. it acts as a hapten after it bonds a protein on the surface of red blood cells, and induces antibody production |
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Both the T cell receptor and surface immunoglobulin are made up of antigen recognition and signaling proteins
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-both cause signal transduction in the cell they are located on
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comparison of the TcR and immunoglobulin
Ig specificaly |
-Ig: recognizes antigens that are macromolecules and small chemicals, and they can be either conformational or linear eptitopes
-each clone has a uniqe specificty; potential for ten to the ninth distinct specificities'' -antigen recognition is mediated by V regions of heavy and light chains of membrane Ig -signaling functions are mediated by proteins, Iga and Igb, associated with membrane Ig -effector functions are mediated by constant C regions of secreted Ig |
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comparison of the TcR and immunoglobulin
TcR specifically |
-recognzes antigens displayed as peptides by MHC molecules on PC's
-linear epitopes only -each clone has a unique specificity; potential for ten to the eleventh distinct specificities -antigen recognition is mediated by Variable (V) regions of alpha and beta chains -signaling functions are mediated by protiens CD3 and ones associated with TCR -TCR does not perform effector functions -T cell receptors are not secreted |
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antibodies and TcR result from the recombination of gene segments
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-catalyzed by V(DJ) recombinase, consisting of at least six different proteins
-two of the most important components are RAG 1 and RAG 2 proteins -failure of any of these enzymes leads to SCID |
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V region gene segments are present in multiple copies in germline DNA
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-lambda light cain located on chromosome 22
-kappa light chain located on chromosome 2 -heavy chain located on chromosome 14 -kappa reasorting occurs before lambda reassorting in light chain |
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Mechanisms of recombinatorial diversity
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-multiply V segments, by D segments, by J segments, and that gives you the possibility in any light or heavy chain
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mechanisms of diversity: junctional diversity
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-nucleotides can be removed or added by TdT
-it catalyzes this reaction -changes the receptor |
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Antibody diversity is generated by four main processes
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-multiple V,D,J gene segments(recombinatorial diversity)
-multiple heavy (8) and light (2) chains (combinatorial diversity) -junctional diversity -somatic hypermutation -possible combinations are ten to the 14 |
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Steps in B cell development
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-BONE MARROW: Ig DNA, RNA- germline stem cell DNA, to pro-B, to Pre -B (recombined H chain gene: u mRNA) to immature B cell( IgM: recombined H chain gene kappa or lambda genes, u and s or y mRNA) to leaving the bone marrow
-in the lymphoid tissue and blood the B cell matures; alternative splicing of primary transcript to form Cu and Cs mRNA; expresses IgM or IgD - Ig expression does not begin until the Pre-B cell stage. Here, cytoplasmic u an dpre-B receptors associated u. Ig expression in immature B cell inmembrane IgM, u+k or lambda light chain only..... -mature B cell has membrane IgM and IgD |
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know allelic exclusion
know monoclonal antibodies and how they differ from polyclonal antibodies know what is an ELISA, and what is it used form clinically |
look up
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Changes in cell surface molecules differentiates stages of T cell development
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T cell undergoes rearrangement in the thymus
Known as thymic education 95% of lymphocytes that enter the thymus , die during process Hemapoietic stem cell gives rice to lymphocytes, which gives rise to t cells…. Double negative, no cd8 or cd4. pre t cell, double positive, cd4 and cd8. Also expressing CD3, signaling molecule goes hand in hand with t cell receptor Double negative to double positive.. T cells have narrow window where they learn how to respond to antigen, but not too much Undergo positive and negative selection Positive, have to recognized own self molecules Cannot react too much to self molecule Don’t want T cells to recognize self This process is not perfect T cell that fails at negative selection, they are either given death signals, or if they don’t react enough(positive selection ), then they die.. Not given right growth signal When this process is done they are either Cd4 or CD8 Migrate to medulla, and off they go to periphery -JIST -stem cell is a double negative pro t cell, which becomes a pre t cell, which then becomes a double positive cell. -if there is weak recognition of class II MHC plus peptide, then it is positive selection, and the cell becomes a CD4 T cell -If it is weak recognition of class I MHC plus peptide, the cell becomes a mature CD8 cell, and this too is positive selection -if no recognition of MHC then apoptosis occurs, and this is failure of positive selection, death by neglect - if MHC I or MHC II are too strongly recognized, then apoptosis by negative selection |
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thymic selection occurs in discrete steps
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In cortex of thymus:
TCR rearranges, DN to DPCD3 positive selection on DP cells in concert with epithelial cells negative selection of DP cells, in concert with dendritic cells in medulla: mature , self tolerant, self MHC restricted SP T cells |
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Fc receptors
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-bind Fc region on antibodies. Can deliver growth or inhibitory signals
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cytokine receptors
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bind cytokines. deliver activation, growth, and differentiation signals; some are inhibitory. Now targets of biologic therapeutics
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chemokine receptors
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-bind chemokines. can trigger movement towars a site, or keeps a cell at a site
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complement receptors and pattern recognition molecules
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-CR bind C components. Activate phagocytosis or clear immune complexes
-pattern recognition molecules initiate innate immune responses |
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Effector T cells have roles in humoral and cellular immunity
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-cytotoxic T cells
-Th1 cells -TH2 cells |
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Cytotoxic T cells
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-kill virus infected cells
-killed by apoptosis |
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TH1 cells
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-activated by macrophages containing intra cellular bacteria
-TH1 activates macrophages |
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TH2
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-Activate B cells presenting specfic antigen, bacterial toxin
-TH2 causes plasma cells to produce anti toxin antibodies |
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types of intracellular microbes combated by T cell -mediated immunity
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-phagocytic and non phagocytic
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steps in the activation of T cells for CD8 T cell
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-antigen presenting cell activates CD8 T cell
-then there is clonal expansion -the CD8 cells move from the lymphoid organs to the peripheral tissues -can become memory CD8 cells -can become effector cell , CTL, killing of infected target cells; macrophage activation |
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Steps in activation of T cells for CD4 cells
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-APC activates CD4 cell
-activated CD4 activates it's IL-2R to release IL-2 cytokines -clonal expansion -The CD4 cells then move to the peripheral tissues -can become memory cell -can activate macrophages, B cells, and other cells |
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Receptors of CD4 helper T lymphocyte
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CD4-signal transduction
TCR-antigen recognition of MHC II -CD3-signal transduction -CD28-signal transduction; reacts with CD80/86 on MHC II -LFA-1- Adesion: attaches to ICAM-1 on MHC II -jist: know the adhesionn molecule!!! |
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Engagement of the T cell receptor triggers several intracellular signaling pathways
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1- receptor associated tyrosine kinases activate PLCy. PLCy cleaves PIP2 to DAG and IP3
2-DAG and calcium activate protein kinase C,PKC 3-IP3 causes the release of calcium from Ca stores (from ER) 4-release of calcium activates the phosphatase calcineurin 5- PKC and calcineurin activate the transcription factors NFkB and NFAT, respectively. -immunosuppressive drugs cyclosporin and tacrolimus interfere with this pathway -the above transcription factors drive the transcription of cytokines |
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Co-stimulation: engagement of the T cell via the TcR is not enough
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-The CD80 and CD86 molecules on APCs bind the CD28 on naive T cells and delivers a necessary co stimulatory signal to the T cell
-once the response to the non self antigen is completed, the T cells up regulates the expression of CTLA4 -CTLA4 has a higher affinity for CD80 and 86. This effectively shuts down down the T cell response -in the lack of co stimulation, T cells will become anergic |
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co stimulation delivers a required second signal for T cell activation
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1)binding of TcR and CD4 to MHC class II delivers signal to cell
2)Clonal expansion of T cell can occur only after second signal is delivered by CD80/86:CD28 interaction 2)clonal expansion of T cell can occur only after second signal is delivered by CD80/86:CD28 3)This process is down regulated on T cells by CTLA4 -therapies for treating autoimmune diseases and graft therapies from blocking CD28 |
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cytokines are crucial hormones for the activation and function of lymphocytes
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lala
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IL1
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located on APCs, causes inflammation
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IL2, IL12
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located on Th1 and CTL cells. Causes T cell growth
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IL4, IL5
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located on Th2 cells, causes IgA, IgG1, IgE antibody production class switching
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IL10
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-Th2 (Treg) , located on those
-inhibits Th1, upregulates MHC class II |
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IFNg
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-located on Th1, CTL. causes inhibtion of Th2,upregulates MHC class I and II
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TNF
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located on Th1, and CTL. Causes inflammation
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Activated T cells secrete and respond to IL2
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-resting T cells express low affinity IL2r only
-activated T cells express high affinity IL2r and secrete IL2 -signaling through the IL2 receptor (IL2 AKA CD25) is mediated via the PI3 pathway -crucial signaling molecule in this pathway is a kinase called mTOR -mTOR is part of PIP3 signaling -mTOR is the target of the T cell specific immunosuppressive drug sirolmus. CD25 is the target of immunosuppressive monoclonal antibodies |
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Activated T cells secrete and respond to IL2
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-binding of IL2 to the high affinity receptor sends a growth signal to the T cell
-smaller amounts of IL2 can now drive T cell growth and differentiation -binding of IL2 to tis receptor signals the T cell to proliferate |
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The three types of effector T cells produce definitive sets of effector molecules
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-cytotoxic T cells
-Th1 cells -Th2 cells |
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Cytotoxic T cells
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-release cytotoxins that kill virus infected cells
-inject perforin, granzymes, and Fas into the infected cell -Fas ligand on CTL cell |
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Th1 cells
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-release cytokines
-has a CD40 ligand which binds to CD40 receptor -activates macrophage containing bacteria -inflammatory response -cytokines involved are IFNy, TNF, IL2, IL12 |
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Th2 cells
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-releases cytokines
-CD40 ligand on Th2 bind CD40 receptor on B cell presenting specific antigen -B cell presents specific bacterial antigens on its surface -cytokines involved are IL4, IL5, and IL10 -humoral response |
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Cell mediated immunity against intracellular microbes is mediated by CD4 +Th1 and CD8+CTL
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-phagocytes with ingested microbes: microbial antigens in vesicles
-Infected cell with microbes in cytoplasm |
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Phagocytes with ingested microbial antigens in vesicles
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- CD4 effector T cells, Th1 cells
-cytokine secretion -macrophage activation: killing of ingested microbes -inflammation |
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Infected cell with microbes in cytoplasm
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-CD8 T cells (CTL's)
-killing of infected cell |
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T cells become activated in lympoid tissues, but kill pathogen infected cells at sites of infection
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-antigen recognition in lymphoid organs
-T cell expansion and differentiation in lymphoid organs -differentiated effector T cells enter circualtion -migration of effector T cells and other leukocytes to site of antigen - effector T cells encounter antigens in peripheral tissues -activation of effector T cells T cell effector functions: 1)macrophage activation killing of phagocytosed microbes 2)CTL killing of target cell |
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Activated effector T cells are guided to site of infection by newly expressed adhesion molecules
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-naive T cell: homes to high endothelial venule
-activated T cell: homes to peripheral vascular endothelium |
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Naive T cell
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-guided by L selectin on cell, and addressin on the lymph node HEV
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Activated T cell
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has integrin and adhesion molecules
-binds to vascular epithelium |
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There are three different effector populations of CD4 cells
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- IL 12, IFNy
-IL4 -IL6, 22 |
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Th1 cells
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-IFN-y secretion: host defense against intracellular microbes: inflammation
-associated with IL12 and IFN-y |
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Th2 cells
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-IL-4, IL-5, Il-13 secretion, host defense against helminths; allergic reactions
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Th17 cells
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-IL-17 secretion; host defense against some bacteria; inflammatory disorders
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The two types of CD4 cells produce cytokines that inhibit the other type of cell
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-Th2 secrete TGFb and IL10
-Th1 secrete IFNy |
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Th2
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-IL-10 and TGF B inhibit activation and growth of Th1 cells
-TFG- beta is just like interleukin 10; promotes cellular response -Th2 secretes cytokines that turns of cellular response and turns on humoral response |
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Th1
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-IFN-y inhibits proliferation of Th2 cells
-Th1 secretes cytokines that turn off humoral response and turns on cellular response |
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Th1 cells activate macrophages to become highly microbiocidal and provide help to B cells
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-Th1 cells release IFN-y to active macrophages
-Th1 cells secrete IFN-y which activates B cells, and causes opsonization and phagocytosis in macrophages |
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The immune response to intracellular bacteria is coordinated by activated Th1 cells
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-activated macrophages destroy engulfed bacteria, and are better at antigen presentation
-causes killing of phagocytosed microbes -increased expression of MHC molecules and costimulators (B7) -and, secretion of cytokines (TNF, IL-1, chemokines, IL-12) |
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how cytokines drive T cell: macrophage interactions in cell mediated immunity
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--an antigen presenting cell, dendritic or macrophage, with ingested microbes
-releases IL-12, which causes naive CD4 cell to produce a Th1 cell -which then releases IFN-y, which causes activation of macrophages, killing of microbes -IL-12 drives everything |
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the immune response to intracellular bacteria is coordinated by activated Th1 cells-II
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-Th1 induce bacteria-specific t cell (CD4 and CD8) proliferation via IL2.
-phagocytosed microbes in vesicles and cytoplasm interacts with CD4 T cell, and IFN-y is released by CD4 T cell -the macrophage then interacts with CD8 cell... -killing of microbes in phagolysosomes via CD4 -kiling of infected cell by CD8 |
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Th1 cells also induce granuloma formation when intracellular pathogens cannot be totally eliminated
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-mycobacteria in phagosomes of macrophages
-syncytia formation (multi nucleated giant cells) -T cell surround on the outside -commonly seen in TB -mycobacteria and other pathogens have evolved to resist macrophage mediated killing -genetic defects in NO or O2, production |
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CTL kill thier targets by inducing apoptosis
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1- CTL recognizes and binds virus infected cell
2- CTL programs target for death by secreting perforins and granzymes into target cell, inducing DNA fragmentation 3-Target cell dies by apoptosis; uninfected neighboring cells will be spared 4-CTL migrates to a new target. apoptosis can also be triggered by interaction of CTL FasL with target cell Fas -perforin forms pores in the target cell membrane |
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summary of T cells
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- T cells become activatede when APCs present peptides on MHC I or MHC II
-this process is multi step and inolves cell-cell interactions , co stimulatory molecules , and cytokines -effector T cells kill infected cells, activated macrophage cells to produce antibody |
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Required Reading
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concept of allelic exclusion
how monoclonal antibodies differ from polyclonal antibodies what is an ELISA and what is it used for clinically What is flow cytometry and what is it used for clinically |
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steps in B cell development
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- B cell precursor rarranges immunoglobulin genes
-mature B cells are acativated by antigen -activated B cells differentiate into plasma and memory cells |
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phases of humoral immune response
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primary lymphoid follicle: antigen recognition; naive IgM and IgD b cells bind to microbe. B cell is activated by antigen recognition and helper T cells
Second lymphoid follicle germinal center: activation of B lymphocytes; clonal expansion and differentiation. They become effector cells which are antibody secreting plasma cells, IgG expressing cells, and high affinity Ig expressing B cell -Effector cells: IgM for antibody secretion( medullary chords; bone marrow mucosal lamina propria) -IgG expressing cells: Isotype switching (occurs in secondary lymphoid follicle-germinal center) -High affinity Ig expressing B cells: become memory cells and affinity maturation ( blood and lymphoid tissues) |
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clonal selection of lymphocytes by a pathogen: Antigen specific B lymphocytes are the daughter clones of a single progenitor
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-a single progenitor cell gives rise to multiple daughter cells with multiple specificities
-removal of self reactive lymphocytes, which react with self antigens -Pool of mature naive b lymphocytes; foreign antigen -Activation of specific lymphocytes; effector cells eliminate antigen |
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-immunoglobulin on the B cell surface (sig) is a receptor for antigen
B cells are activated by sig crosslinking with antigens |
-once the IgM is crosslinked, the B cell sends a signal into itself
-IgD is also on the surface and can be crosslinked with either teself,or an IgM molcule |
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Like T cells, B cell receptors have co receptors
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-complement activation
-recognition by B cells -signals form Ig and CR2 complex Co receptors (including CD19) cooperate with sig in B cell activtion These co receptors are analogous in fucntion to CD4 and CD8 on T cels CD19is a marker for B cells, and is used as a target for therapy in lymphome and autoimmune diseases |
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Different subsets of B cells respond preferentially to protein and non protein antigens, and these occupy different anatomical compartments
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- T dependent TD;protein antigen and helper T cell
-T independent,TI: Pollysaccharides, lipids, ect. - |
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B cell response to protein antigen and helper T cells in spleen and other lymphoid organs
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Spleen , other lymphoid Organs: Follicular B cells (IgM and IgD) recognize protein antigen along with helper T cells. Germinal center reaction.
Isotype switched, hight affinity antibodies, long lived plasma cells... T dependent |
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B cell response to polysaccharides, lipids, ect. in Spleen and other lymphoid organs
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-marginal zone B cells ( IgM) recognize polysaccharides and lipids
- creates IgM and short lived plasma cells |
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B cell response in mucosal tissues and peritoneal cavity
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- IgM and CD5 on B cells
-mainly IgM, short lived, plasma cells |
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Properties of antigens that induce antibody responses
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-children under 2 years make poor anti T1 responses
-TI antigens can stimulate some B cells without T cell help -thymus dependent antigen -thymus independent antigen vaccines are T indpendent antigens |
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Thymus dependent Antigens
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-proteins
-antibody response includes isotype switching, affinity maturation, and secondary response to memory cells |
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Thymus independent antigen
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-polymeric antigens such as polysacharrides, glycolipids and nucleic acids
-istoype switching to IgG -no affinity maturation, secondary response seen only with some antigens |
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B cell activation in response to TD antigens requires T cell help
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-This activity requires interaction of the CD40 and CD40 L antigens and cytokines, which are also required for class switching
1-B cell presents antigen to helper T cell 2-Helper T cell is activated; expresses CD40L, secretes cytokines 3-B cells are activated by CD40 engagement, cytokines 4- B cell proliferation and differentiation |
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Isotype or class switching; changes in antibody structure occurring during the course of a humoral immune resposne
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changes in antibody structure causes:
Affinity maturation (somatic mutations in variable region) Switch from membrane to secreted form- changes from B cell to effector function Isotype switching- each isotype serves a different set of effector functions |
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Isotype switching occurs via alternative exon usage in the Ig heavy chain locus
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-occurs at DNA level
-is mediated by the enzyme AID and by cytokines from Th2 cells -results in secondary antibody responses -happens within the B cell in response to T cell signals, recombination of Su and Sy or Se; deletion of intervening c genes -transccription , RNA splicing -translation |
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Th2 derived cytokines drive Isotype switching, and the production and differentiation of antigen specific B cells
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-CD40:CD40L interactions are required
-the cytokines include IL4, IL5, IFNy, TGFb. IL4-IgG and Ige IL-5: augments IgA production IFNy- IgG3 and IgG2a IFN-y: IgG3 and IgG2a TGF-B: IgG1 and IgA |
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IgA
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mucosal surface immunity
neutralization transport across epithelial cells |
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IgE
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anti parasite helminth and cestode immunity
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IgD
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B cell signaling activation
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IgM
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primary immune responses
C’ fixation opsonization |
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IgG
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opsonization
C’ fixation neutralization maternal-derived passive fetal immunity extra-vascular diffusion -memory antibody |
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Rearranged V-region sequences are further diversified by somatic hypermutation
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These are changes accrued in the CDR regions of Ig genes
These serve to “fine-tune” antibody specificity -somatic hypermutation does not occur in the tCR -affinity increases over time |
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Somatic hypermutation drives affinity maturation
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Affinity maturation is the process by which the affinity of antibodies for an antigen increase with prolonged or repeated exposure to that antigen.
Affinity maturation occurs in germinal centers. B cells with the highest affinity for an antigen have a selective advantage in growth over those with less affinity (see Fig 7.13). This insures only the best binding antibodies are produced. |
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Plasma cells are terminally differentiated b cells
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-plasma cells are typically found in the bone marrow, medullary chords of LN, and lamina propria of mucosal tissues
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Plasma cells vs. Resting B cells
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- resting b cells have surface Ig, Surface MHC II, and can induce growth, somatic hypermutation and isotype switching
-plasma cells can only have high rates of Ig secretion |
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Anatomy of the humoral immune response
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-activation and migration of T and B lymphocytes
-T cell and B cell interaction -Early B cell response : Ig secretion, some isotype switching -germinal center reaction: affinity maturation, isotype switching, memory B cell generation |
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Effector function of antibodies
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neutralization, opsonization, complement activation
-neutralization of microbe and toxins -opsonization and phagocytosis of microbes -antibody dependent cellular cytotoxicity -lysis of microbes -phagocytosis of microbes opsonized with complement fragments |
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IgG effector function
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neutralization of microbes and toxins
opsonization of antigens for phagocytosis by macrophages and neutrophils activation of the classical pathway of complement antibody dependent cellular cytotoxicity mediated by NK cells Neonatal immunity: transfer of maternal antibody across placenta and gut feedback inhbition of B cell activation |
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IgM
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activation of the classical pathway of complement
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IgA
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mucosal immunity: secretion of Iga into lumens of gastrointestinal and respiratory tracts, neutralization of microbes and toxins
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IgE
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Defense against helminths
mast cells degranulation , immediate hypersensitivity reactions |
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IgD
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signaling only
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immunoglobulin isotypes are selectively distributed in the body
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IgG-blood, tissue
IgM; blood IgA; body cavities IgE; epithelial surfaces, gut , lung |
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Maternal antibodies protect the fetus and neonate until the baby’s immune system can generate its own antibodies
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passive immunity
.. for up to nine months baby is passively covered. newly synthesized IgM a little before birth, full levels at 1 year, same with IgG which starts to be synthesized three months after birth |
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IgA crosses epithelial surfaces by the use of a poly-Ig receptor
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-IgA binds to basolateral face of epithelial cell
-receptor mediated endocytosis of IgA -Transport of Iga to apical face of cell -Cleavage of receptor releases IgA from cell -the Poly Ig receptor with bound IgA binds to epithelial cell |
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IgG and IgA protect by neutralizing toxins, viruses and bacteria
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-the antiobodies block microbes and toxins from infecting skin adn tissue and cells
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Opsonized extracellular pathogens are more readily engulfed by phagocytes bearing Fc receptors
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-antibody binds bacteria'
-coated bacterium binds to FcR on phagocyte surface -Phagocyte engulfs bacterium, forming phagosome -Lysosomes fuse with phagosome, forming phagolysosome |
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Th2 cells provide help to B cells and coordinate anti-parasite immunity
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Th2 secrete cytokines IL-4 and IL-5
-IL-4 aids in neutralizing IgG antibodies,and IgE which does mast cell degranulation -IL-5 Eosinophil activation |
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IgE crosslinking on mast cell surfaces leads to a rapid releease of inflammatory mediators
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resting mast cell contains granules with histamine and other inflammatory mediators
-multivalent antigen binds and crosslinks IgE, causing release of granule contents |
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The complement (C’) system
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Complement is a group of serum proenzymes that are activated by antigen bound immunoglobulin or by membrane components on gram negative bacteria or fungi.
C’ interacts with antibodies and surface receptors to aid in the elimination of pathogens. Classical complement components are named by placing a C before the number of the component; e.g. C1 is the first component. |
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The three C’ pathways and their early steps
The key step is the activation of C3. |
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alternative classical lectin |
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The classical C’ pathway is initiated by the binding of C1q to antibody coated bacterial surfaces
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C1q can bind to IgM or IgG
-this activates C1r which cleaves C1s |
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C1 inhibitor (C1INH) inhibits the first stage of the classical C’ pathway
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C1 INH prevents C1r2s2 from becoming proteolytically active
-Lack of C1NH leads to the disease known as hereditary angiodema |
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The classical C’ pathway generates C4b/C2b, a C3 convertase that deposits large numbers of C3 molecules on a pathogen
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- C1s cleaves C4 to C4a and C4b
-C4b cleaves C2, forming C4b/C2b complex -C4b/C2b complex cleaves C3 to C3a and C3b -Lots of c3b either binds C4b/C2b or deposits directly on microbial surface |
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The terminal C’ components polymerize to form pores in membranes to kill pathogens
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-membrane attack complex catalyzed by C5b/c6/c7/c8
-lysis of pathogen -C4b/C2b/C3b or C3b/Bb cleaves C5 into C5a and C5b |
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The functions of complement
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-phagocytosis and killing of microbe
-osmotic lysis of microbe -destruction of microbes by leukocytes |
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Opsonization: C’ enhances phagocytosis of encapsulated bacteria
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- encapsulated bacteria cannot be engulfed by neutrophils
-Antibody bound to bacteria activates complement and bonding of c3b to bacteria |
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C’ enhances phagocytosis of encapsulated bacteria-II
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-engulfment of bacteria by neutrophils is mediated by Fc receptors and complement receptors
-granuls fuse with phagosomes, releasing toxic oxygen metabolites that kill bacteria |
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Local inflammatory responses can be induced by small C’ fragments, especially C5a
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C3a, C4a and C5a are known as anaphylatoxins
C3a and C5a can trigger mast cell degranulation C5a is a potent neutrophil chemoattractant -C3a, C4a, c5a act on blood vessels to increase vascular permeability -increaed permeability allows extravasation of Ig and c molecules -migration of macrophages, PMNs, and lymphocytes is increased. Phagocytes are also activated |
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Protective immunity and immunological memory are distinct
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initial immune response is 7-14 days
protective immunity within 28 days immunological memory in 2.5 years |
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Generation of secondary antibody responses differs from primary responses
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primary immune response: lage after immunization is 5-10 days. Smaller peak response, lots of IgM, lower average affinity
-secondary response: 1-3 days,, larger peak response, increase in IgG, A, or E, higher average affinity |
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Antibody affinity and amounts increase with repeated antigen exposure
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-IgM first time
-IgG second time |
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B cells go through several stages of development
These stages coincide with immunoglobulin gene rearrangement or surface immunoglobulin expression Antigen-activated B cells differentiate into plasma and memory cells Humoral responses to infection involve the production of antibodies |
Antibodies eliminate pathogens by opsonization, activating C’, or neutralization
Different antibody isotypes have different effector functions C’ has four functions in the immune response, some of which overlap with antibodies C3b is the key component of the C’ cascade. T helper cells direct many humoral immune responses, especially isotype switching |
