BMSC week 6: immune system I

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On what type of cell is P-selectin found? What causes its expression and what does it bind to?: P-selectin is found on the surface of endothelial cells. Histamine and platelet activating factor cause it to be translocated from cytoplasmic granules to the surface. It binds to sialyl-Lewis X glycoprotein on the leukocyte surface.
On what type of cell is sialyl-Lewis X found? What is its purpose?: Sialyl-Lewis X is found on the surface of leukocytes. Binding of this glycoprotein to P-selectin facilitates leukocyte rolling.
On what type of cell is E-selectin found? What causes its expression? When is it expressed?: E-selectin is found on the endothelial cell surface. Its expression is triggered by interleukin 1 and TNF. It appears 2-3 hours after injury.
On what type of cell are integrins found? What activates them? What is their purpose?: Integrins are found in an inactive form on the surface of leukocytes. They are activated by C5a and leukotriene B4. Their purpose is to bind to ICAM-1 and VCAM-1 to promote adhesion/pavementing.
What role do ICAM-1 and VCAM-1 play in leukocyte adhesion? What molecules do they bind to?: ICAM-1 and VCAM-1 are found on the surface of endothelial cells. They bind to the integrins of leukocytes, causing them to adhere to the sides of the blood vessel.
How do neutrophils kill bacteria after they ingest them?: A combination of hydrogen peroxide-myeloperoxidase-halide, which produces hypochlorous acid. This is a potent oxidant and bactericidal agent.
What do kinins do, and how do they do it?: Acute: they cause pain and vasodilation + increased permeability in the capillaries (by activating prostaglandin release). Chronic: they cause scarring (by stimulating collagen synthesis and fibroblast proliferation).
Which types of cells contain histamine?: -mast cells
-basophils
-platelets
What does histamine do?: Produces pain, itching, vasodilation and the immediate-transient type of vascular permeability.
What cells synthesize nitric oxide, and what does it do?: Cells:
-endothelial cells (eNOS)
-macrophages (iNOS, activated by TNF-α and interferon-α)
-CNS neurons (nNOS)
Effects:
-relaxes the smooth muscle to produce vasodilation
-kill microorganisms
-inhibit leukocyte adhesion
-inhibit platelet aggregation
-inhibit mast cell inflammation
What effect does TNF-α have on dendritic cells?: Stimulates their migration to the lymph node and subsequent maturation.
What types of granules do neutrophils have and what do they do?: Azurophilic granules are released intracytoplasmically and are for degradation and killing. Specific granules are released extracellularly for proinflammatory purposes. C particles clear the path for the neutrophil during chemotaxis.
What types of cells are usually involved in acute inflammation?: -neutrophils
-mast cells
-platelets
What inflammatory mediator systems exist in the plasma?: -kinin system
-complement system
-coagulation-fibrinolysis system
What inflammatory mediators exist in the cell? Which are preformed and which are newly synthesized?: Preformed:
-vasoactive amines
-lysosomal enzymes
Newly synthesized:
-lipid-derived factors
-nitric oxide
What are the vasoactive amines?: Histamine and serotonin.
What are the lipid-derived factors?: -platelet activating factor
Arachidonic acid derivatives:
-5-HETE
-leukotrienes
-lipoxin
-prostaglandins
-thromboxanes
What are the lysosomal enzymes?: -cationic proteins
-acid proteases
-neutral proteases
What are the 3 types of proteins that viruses must encode?: -proteins for replicating the genome
-proteins for packaging and delivering the genome
-proteins that modify the host cell
What are the differences between the cell membranes of gram+ and gram- bacteria?: Gram+ has teichoic acid and more peptidoglycan, gram- has lipopolysaccharide and less peptidoglycan.
What are the two areas of adaptive immunity and what is involved with each?: Humoral: B cells and antibody response. Cellular: T cells and cytokine generation.
What are the mechanisms of innate immunity?: -skin
-mucus
-cilia
-peristalsis
-phagocytosis
-pH
-temperature
-iron-binding proteins
-lysozyme
-complement
-superoxide
-nitric oxide
-antimicrobial peptides
What are pattern recognition receptors? Give some examples.: PRRs are receptors on human cells that recognize features of pathogens which are absent in the host. Two examples are C3b from the complement system and Toll-like receptors.
What are pathogen-associated immunostimulants? Give some examples.: PAIs are molecules on the surface of pathogens which are absent in the host. They trigger an inflammatory response and phagocytosis. Examples are formyl-methionine peptides (attract neutrophils), peptidoglycan, teichoic acid, and LPS, which bind to PRRs.
What does TLR2 bind to?: The peptidoglycan of gram+ bacteria and the phosphatidyl inositol of Mycobacteria.
What does TLR3 bind to?: The double stranded RNA of viruses.
What does TLR4 bind to?: The liposaccharide of gram- bacteria.
What does TLR5 bind to?: The flagellin of some bacteria.
Where are TLRs found and what do they do? What signaling pathway do they use?: On the surfaces of macrophages, monocytes, neutrophils, and epithelial cells lining the lung and gut. They alert the immune system to an infection. Most use the NF-κB pathway.
Which leukocytes are phagocytic and where are they found? What receptors do they have?: Macrophages (in the tissues), monocytes (in the blood), and neutrophils (in the blood). They have TLRs, Fc receptors, and C receptors (CR1, CR3, and CR4 which stimulate phagocytosis).
What are the differences between MHC class I molecules and MHC class II molecules?: MHC class I molecules are expressed on all cells and are used for displaying intracellular antigens. MHC class II molecules are only expressed on APCs and are used for displaying extracellular antigens.
What are antigen presenting cells?: Macrophages, B cells, and dendritic cells. They present antigens on MHC class II molecules on their surfaces.
What type of receptor do helper T cells have and what does this receptor interact with? What do helper T cells do?: Helper T cells have CD4 receptors, which interact with MHC class II molecules on APCs. Helper T cells activate phagocytic cells and B cells.
What type of receptor do cytotoxic T cells have and what does this receptor interact with? What do cytotoxic T cells do?: Cytotoxic T cells have CD8 receptors, which interact with MHC class I molecules on all cells. Cytotoxic T cells lyse cells with antigens on their MHC that match the T cell.
What activates B cells? What do B cells do?: B cells are activated by the antigen that matches the antibody on their surface, as well as cytokines from helper T cells. B cells differentiate into plasma B cells and memory B cells.
What are the mechanisms of immunity against extracellular pathogens?: -antibodies
-complement
-phagocytosis
-neutralization
-anti-microbial peptides
What are the mechanisms of immunity against intracellular pathogens?: -cytotoxic T cells
-natural killer cells
What are 5 ways that antibodies contribute to immunity?: Block virus entry into host cell.
Block action of toxins.
Bind to pathogen surface and block attachment to host cells.
Bind to pathogen surface and activate complement.
Bind to pathogen surface and stimulate phagocytosis.
What is polycythemia?: Too many RBCs, can lead to stroke.
What is multiple myeloma?: Elevated IgG level.
What is the difference between plasma and serum?: Plasma has had the clotting factors removed, serum hasn't.
What is the hematocrit?: % volume of the blood sample which is occupied by RBCs after centrifugation.
How long do platelets live?: 10 days
What are the types of granules platelets have and what do they do?: -dense granules: ADP and serotonin (which contracts smooth muscle)
-alpha granules: platelet factors
-lambda granules: are lysosomes
What are some platelet factors and what do they do?: -platelet factor 4 neutralizes heparin
-PDGF stimulates fibroblast proliferation, causes vasodilation, and does other stuff.
-thromboxane A2 is a platelet aggregation factor and it causes vasoconstriction. -thrombospondin is an adhesive glycoprotein.
-platelet fibrinogen, von Willebrand factor, and clotting factor V are clotting factors
-chemotactic factors attract neutrophils.
Which cells are granulocytes?: Neutrophils, eosinophils, basophils, and mast cells. Platelets also have granules but are not leukocytes.
What are the differences in nuclei between neutrophils, eosinophils, basophils, lymphocytes, macrophages, and monocytes?: Neutrophils: multi-lobed nucleus. Eosinophils: large bi-lobular nucleus. Basophils: multi-lobed nucleus but hard to see because of all the granules. Monocytes: horseshoe shaped nucleus with network of heterochromatin. Macrophages: irregularly shaped nucleus. Lymphocytes: nucleus takes up most of cytoplasm.
What type of stuff is in eosinophil granules and what does it do?: Major Basic Protein, eosinophil cationic protein (forms transmembrane pores in Schistosoma), and eosinophil peroxidase.
What makes basophils degranulate? What is inside the granules and what do those things do?: IgE makes basophils degranulate. Basophil granules have histamine (increases vascular permeability), heparin (anti-coagulant), leukotriene C (vasodilator), serotonin (vasoconstrictor), and chemotactic factor for eosinophils.
What are Kupffer cells?: Macrophages which are in the liver.
What are osteoclasts?: Macrophages which are in the bone tissue.
What are microglial cells?: Macrophages which are in the nervous system.
What kinds of things do macrophages secrete?: -complement proteins
-regulatory molecules for chemotaxis and inflammation
-enzymes for tissue remodeling
-prostaglandins for pain and inflammation
Which blood cells are derived from the myeloid precursor? Which blood cells are derived from the lymphoid precursor?: Myeloid: eosinophils, monocytes/macrophages, neutrophils, platelets, erythrocytes, and basophils. Lymphoid: B cells, T cells, NK cells.
How and where is erythropoietin produced? What does it do?: Erythropoietin is produced in the kidney when it senses low oxygen. It promotes erythrocyte development and maturation.
If there is a lot of GM-CSF, what are the cell types that the stem cell becomes committed to?: Monocyte/macrophage
Neutrophil
If there is a lot of M-CSF, what is the cell type that the stem cell becomes committed to?: Monocyte/macrophage
If there is a lot of G-CSF, what is the cell type that the stem cell becomes committed to?: Neutrophil
If there is a lot of thrombopoietin combined with IL-11, what are the cell types that the stem cell becomes committed to?: Platelet
Erythrocyte
Basophil
If there is a lot of thrombopoietin, what is the cell type that the stem cell becomes committed to?: Platelet
How are interleukins produced? Which interleukins promote hematopoiesis?: Interleukins are produced by leukocytes in the circulation, thymus, and bone marrow. IL-1, IL-3, and IL-11 promote hematopoiesis.
If there is a lot of IL-5, what is the cell type that the stem cell becomes committed to?: Eosinophil
If there is a lot of IL-7, what is the cell type that the stem cell becomes committed to?: Lymphocyte (especially T cell)
What is the last RBC precursor that has a nucleus? What comes before and after it?: Normoblast. Proerythroblast comes before it, reticulocyte comes after it.
What is secondary polycythemia?: High RBC count caused by renal adenoma, which leads to erythropoietin overproduction.
What is a normal WBC concentration?: 3000-9000 per μL
What is a normal RBC concentration?: M: 4,200,000-5,600,000 per μL
F: 3,800,000-4,900,000 per μL
What is a normal hemoglobin concentration?: M: 12.3 - 16.3 g/dL
F: 11.5 - 14.6 g/dL
What is a normal hematocrit?: M: 37.4-47.0%
F: 34.0-42.1%
What is a normal platelet count?: 150,000-400,000 per μL
What is a normal mean cell volume?: 75-90 fl
What are some reasons that someone would have a high hematocrit?: High altitude, sleep apnea, dehydration, or erythropoietin.
Compare and contrast IgA, IgM, IgG, and IgE.: -IgA is in a dimer with an attached peptide and is secreted, it is made under wet epithelial surfaces.
-IgE is involved in allergic reactions, and it is also made under wet epithelial surfaces.
-IgM is made quickly and is less specific, it is also secreted.
-IgG is made later and is more specific.
How do white blood cells in the lymph drain into the circulation?: Through the right lymphatic and thoracic duct, or postcapillary venules.
How do white blood cells get from the circulation into the tissues?: Through postcapillary venules (transcytosis or through cell-cell junctions). But during inflammation they can go in between endothelial cells.
Where and how are T cells educated?: T cells are educated in the cortex of the thymus. Self peptides are presented on MHC I molecules on the surface of thymic epithelium so that the T cells will recognize them.
What is a lymphoid follicle?: A clump of B cells (center) and T cells (periphery). The nuclei and cytoplasm of the cells get bigger when they are activated.
What are Peyer's patches?: Aggregations of lymphoid tissue in the GI tract, which get bigger in the more distal intestine.
What are M cells?: Highly modified epithelial cells which transcytose stuff through the epithelial surface.
Where are immature dendritic cells found? Mature?: Immature dendritic cells are found in the blood and tissues. Mature ones are found in the lymph nodes.
What are the functions of dendritic cells?: In the blood and tissues, they take up antigens. In the lymph nodes, they present antigens.
What do eosinophils do?: They are involved in killing antibody-coated parasites.
What receptors does a natural killer cell have? How do they help it decide whether or not to kill the other cell?: The activating receptor is called NKG2D, it binds to stress-induced proteins and/or viral proteins on the other cell. The inhibitory receptor, KIRs or CD94-NKG2A/B, binds to MHC class I. If a cell becomes infected, more stress-induced proteins are produced on the surface and less MHC I is produced, so activating > inhibitory and NK kills the cell.
What is the difference between helper T1 cells and helper T2 cells?: Helper T1 cells activate macrophages when they interact with one that has a matching antigen on its MHC II. Helper T2 cells activate B cells.
What molecules do activated cytotoxic T cells secrete?: -perforin
-granzymes
-granulysin
-Fas ligand
What effector molecules are secreted by activated helper T1 cells?: -IFN-γ
-GM-CSF
-TNF-α
-CD40 ligand
-Fas ligand
What effector molecules are secreted by activated helper T2 cells?: -IL-4
-IL-5
-IL-15
-CD40 ligand
What process do steroids inhibit? What is the physical manifestation of this inhibition?: Steroids inhibit the action of phospholipases (for example PLA2), which prevents the release of arachidonic acid from membrane phospholipids. Therefore, eicosanoids are not produced and inflammation is reduced.
What pathway is blocked by COX-1/COX-2 inhibitors, aspirin, and indomethacin? Which eicosanoids are not produced as a result?: The cyclooxygenase pathway is blocked. Prostaglandins, prostacyclins, and thromboxanes are not produced.
Which pathway is blocked by the drug Zileuton? Which eicosanoids are not produced as a result?: The 5-lipooxygenase pathway is blocked. 5-HETE, the leukotrienes, and the lipoxins are not produced.
What do lipoxins do?: Vasodilation, inhibit leukocyte recruitment, inhibit neutrophil chemotaxis/adhesion, and stimulate monocyte adhesion. They may be negative regulators of LT synthesis.
What do the leukotrienes C4, D4, and E4 do? What receptors do they use?: Vasoconstriction, bronchospasm (1000x more potent than histamine), and increased permeability. They bind cysteiny leukotriene 1 and 2 receptors.
What does the prostaglandin F2α do?: Vasodilation and potentiate edema.
What does prostacyclin PGI2 do? Name an eicosanoid with opposing effects.: Causes vasodilation and inhibits platelet aggregation. Thromboxane A2 causes vasoconstriction and promotes platelet aggregation.
What does leukotriene B4 do?: It is a powerful chemotactic factor that recruits leukocytes in inflammation; it activates integrin on the surface of leukocytes.
Which eicosanoids would not be produced if neutrophils and platelets could not interact? Why?: LTC4, LTCD4, LTCE4, and lipoxin would not be produced. Neutrophils lack LTC4-synthase and 12-lipooxygenase, and platelets lack LTC4; they must work together.
What is the difference between COX-1 and COX-2?: COX-1 is constitutively expressed and COX-2 is inducibly expressed.
What does the prostaglandin D2 do? What cells produce it and when?: Inhibits platelet aggregation, causes vasodilation (relaxation of smooth muscle), and can recruit eosinophils. It is produced by mast cells and macrophages/monocytes during inflammation, esp. hypersensitivity, allergy, and anaphylactic reactions.
What does the prostaglandin E2 do?: -increases vascular permeability
-smooth muscle contraction/dilation
-cell/tissue proliferation
-induction of cytokines
Which eicosanoids act through G-protein coupled receptors?: PGE2, PGF2, PFD2, PFI2, and TXA2.
What are the benefits and risks of taking aspirin (and/or other NSAIDs)?: Benefits:
-reduces pain, fever, inflammation, risk of stroke, risk of colon cancer
-ameliorates heart attack
Risks:
-dyspepsia
-subepithelial hemorrage
-mucosal erosion
-ulceration
What are the two ways that C1 can be activated? What does it do?: C1 can be activated by IgG/IgM-antigen complex, or mannose-binding lectin. It cleaves C4 and C2 to form C4b2b, which is a C3 convertase.
What are the three types of C3 convertase?: -C4b2b
-C3bBb
-plasmin
What are the three types of C5 convertase?: -C4b2b3b
-C3bBb3b
-kallikrein
How is the membrane attack complex formed? What does it do?: -C5b
-C6, C7
-C8
-poly C9,
in that order. It forms a pore in the pathogen's membrane.
How is the alternative complement pathway activated?: Lipopolysaccharide (on gram- membrane), complex polysaccharides, or cobra venom can stabilize spontaneously formed C3b and Bb, which combine to form a C3 convertase.
What do C3a and C4a do?: They are anaphylatoxins; they stimulate histamine release from mast cells.
What does C5a do?: -stimulate histamine release from mast cells
-activate the lipooxygenase pathway in neutrophils and monocytes
-chemoattractant for neutrophils, monocytes, eosinophils, and basophils
-activates integrins on leukocytes
On what cells is the CR1 receptor found? (also called CD35): -erythrocytes
-macrophages
-monocytes
-neutrophils
-B cells
-FDC
Which components of complement bind to CR1 (or CD35)? What happens when they bind?: -C3b
-C4b
-iC3b
C3b and C4b decay are promoted, phagocytosis is stimulated, and erythrocytes transport immune complexes.
On what cells is the CR2 receptor found? (also called CD21): -B cells
-FDC
Which components of complement bind to CR2 (or CD21)?: -C3d
-iC3b
-C3dg
-Epstein-Barr virus
On what cells are the CR3 and CR4 receptors found? (also called CD18): -macrophages
-monocytes
-neutrophils
-FDC (CR3 only)
-dendritic cells (CR4 only)
Which components of complement bind to CR3 and CR4? What happens when they bind?: iC3b. This stimulates phagocytosis.
On what cells are the C5a and C3a receptors found? What does binding activate?: -endothelial cells
-mast cells
-phagocytes
Binding activates a G protein.
What are the ways that the complement system can be inhibited?: -DAF increases the decay rate of C3 and C5
-factor I cleaves C3b
-CiiNH inhibits C1
-CD59 inhibits molecules of MAC
What are the consequences of deficiency in CiiNH?: Episodic edema accumulation in the skin, extremities, intestinal and laryngeal mucosa.
What are the consequences of C2 and C4 deficiency?: Autoimmune disorders such as lupus, because immune complexes cannot be cleared.
What are the consequences of decreased MAC?: Susceptibility to Neisseria.
What activation factor do the kinin system and coagulation-fibrinolysis system have in common? How does it become activated?: Hageman factor (or Factor XII) becomes activated to Factor XIIa:
-upon contact with negatively charged surfaces such as collagen and basement membrane
-due to tissue damage
-by kallikrein
-by high molecular weight kininogen
What does kallikrein do?: -activate Hageman factor
-cleaves high molecular weight kininogen to make bradykinin
-cleaves plasminogen to make plasmin
-converts C5 to C5a
What does activated Hageman factor do?: -cleaves prekallikrein to kallikrein
-cleaves Factor XI to make Factor XIa
What does HMWK do?: -activates Hageman factor
-precursor to bradykinin
How is bradykinin inactivated?: -by kininase in the plasma
-by angiotensis-converting enzyme in the lungs
What does thrombin do?: -cleaves fibrinogen to make fibrin
-activates protease activated receptors to produce chemokines, nitric oxide, and COX-2 expression
What is a difference in quaternary structure between IL-4 and TNF?: IL-4 exists as a monomer, while TNF exists as a trimer.
How do cytokines activate the JAK-STAT pathway?: -cytokine binds to JAKs, causing them to dimerize
-JAKs cross-phosphorylate
-STATs bind to JAKs and become phosphorylated
-STATs activate gene transcription
What effect does IL-6 have on hepatocytes?: Stimulates them to produce serum amyloid protein, C-reactive protein, mannose-binding lectin, and fibrinogen.
What does C-reactive protein do?: Acts as an opsonin by binding to phosphocholine on bacterial surfaces, it also activates complement.
What effect do IL-1, IL-6, and TNF-α have on the hypothalamus, fat cells, and muscle cells?: Increased body temperature, which decreases pathogen replication while increasing antigen processing and adaptive immune response.
What type of cells do beta chemokines mainly attract?: -monocytes
-T cells
-NK cells
-dendritic cells
-eosinophils
-basophils
What are the risks of treating rheumatoid arthritis with anti-TNF therapy? Why?: Susceptibility to infection (esp. TB) and lymphoma. TNF participates in immune system function and tumor suppression.
Why does anti-TNF therapy make multiple sclerosis worse?: TNF is necessary for growth and survival of oligodendrocytes; anti-TNF therapy will hurt them and make MS worse.
What is the difference between signal transduction of classic cytokines and chemokines?: Classic cytokines use the JAK-STAT pathway, while chemokines use trimeric G proteins.
What type of chemokine preferentially attracts neutrophils? What type of motif does it have?: Alpha chemokines; they have an amino acid residue separating the first two conserved cysteines.
What type of chemokines attract lymphocytes?: Gamma chemokines (they have one conserved cysteine).
What enzymes are produced by the host to counter the effects of oxygen radicals?: -ceruloplasmin
-transferrin
-superoxide dismutase
-catalase
-gutathione peroxidase
What is a normal WBC differential (percentages)?: neutrophils: 40-76%
lymphocytes: 15-45%
monocytes: 3-12%
eosinophils: 0-6%
basophils: 0-1%
What is a normal RBC differential (absolutes)?: neutrophils: 1,300-7,000 per μL
lymphocytes: 500-4,200 per μL
monocytes: 100-1,100 per μL
eosinophils: 0-600 per μL
basophils: 0-100 per μL

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