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174 Cards in this Set
- Front
- Back
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Complement
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A series of more than 30 soluble and cell-bound proteins that interact in a very specific way to enhance host defense mechanisms against antigens.
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Who coined the term complement?
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Paul Ehlrich.
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Jules Bordet
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Researched what complement did.
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What does complement promote?
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Opsinization and lysis of foreign cells.
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Chronic activation of complement can lead to what?
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Inflammation and tissue damage.
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Inactive precursor.
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Zymogen. Not activated until needed.
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Work in precise order called ________.
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Cascade.
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Where are most complement proteins synthesized?
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Liver.
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Where are c1 components produced?
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Intestinal epithelial cells.
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Classical pathway.
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Involves 9 proteins that are triggered by antigen-antibody combination.
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What was the alternative pathway originally called?
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Properdin system.
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Alternative pathway.
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A means of activating complement proteins without antigen-antibody combination. Triggered by constituents of microorganisms.
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Lectin pathway
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A pathway for activation of complement based on binding of mannose binding proteins to constituents on bacterial cell walls.
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Mannose binding lectin
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Major component of the lectin pathway. Normal present protein in the blood that binds to mannose on bacterial cells.
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What is the main antibody directed mechanism for triggering complement activation?
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The classical pathway.
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Most efficient immunoglobulin at activating complement and why.
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IgM because it has multiple binding sites.
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Where is factor D made?
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Adipose tissue.
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Beta globulins
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Components found in beta zone: c1q, c1r, and c1s.
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Order of activation in classical pathway.
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1,4,2,3,5,6,7,8,9.
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Complement components with highest concentration.
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C3, C4.
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Functions of complement.
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Opsinization, work with antibody to lyse cells, bind to immune complexes and remove them from blood stream, increase vascoconstrctibility, and chemotaxis.
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How many IgM and IgG molecules does complement need to bind to?
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1 IgM and 2 IgG.
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What class of IgG best binds with complement?
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3. Then, 1 and 2.
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Why can't some IgG fix complement?
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Not close enough together.
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Recognition unit
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The complement component that consists of the C1qrs complex. Must bind to at least 2 fc regions to initiate classical complement cascade.
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Activation unit.
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The combination of complement components C1, C4b, and C2a that form C3 convertase.
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Membrane attack complex
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C5-C9.
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First complement component to bind in classical pathway.
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C1.
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What are C1q, C1r,and C1s stabilized by?
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Calcium.
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What is the C1 complex called once activated?
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C1 esterase.
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Components of C1?
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C1q, C1r, and C1s.
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What do the C1r and C1s subunits generate?
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Enzyme activity.
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What portion of antibody does C1q bind to?
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Fc region.
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Substrates of C1s.
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C4 and C2.
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When does the recognition stage end?
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Once C1s is activated.
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Which C4 attaches to cell?
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C4b.
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How many C4b attach to cell?
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30.
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Why can't some IgG fix complement?
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Must be close together.
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What can directly activate the classical pathway?
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C reactive protein.
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Immune complex.
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Antigen-antibody complex.
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Amboceptor.
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Aka antibody.
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Which C2 sits on the cell?
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C2a.
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What is the cofactor for c3 convertase?
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Magnesium.
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C3 convertase.
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C4b and C2a.
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Which C3 sits on the cell?
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C3b.
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Which pathways is C3 found in?
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All 3.
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How many molecules split when C3 splits?
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200.
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What is the second amplification step in classical pathway?
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Cleavage of C3.
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C3b serves as a powerful _______.
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Opsonin.
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C5 convertase.
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C4b, C2a, and C3b.
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Which C5 sits on cell?
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C5b.
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Beginning of MAC complex.
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C5b sits on cell.
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Binding sequence following C5.
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C6, C7, C8, and C9.
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Function of C8.
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Binds associated molecules and punches hole in cell.
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Function of C9 in classical pathway.
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Binds to the complex and polymerizes to form the transmembrane channel which causes lysis of cells.
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When does the MAC complex begin?
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When C6 binds to C5b.
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Binding of C8 causes leaking of _________.
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Potassium.
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What must be present for lysis of nucleated cells?
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C9.
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Which immunity does the alternative pathway work with?
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Innate or natural immunity.
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Components alternative pathway has that's not in the classical pathway.
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Factor B, properdin, and Factor D.
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Components of classical pathway not found in alternative pathway.
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C1, C4, and C2.
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Stability of C3 in plasma.
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Unstable.
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Triggering substances for alternative pathway.
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Bacterial cell walls (especially those containing LPS), fungal cell walls, yeast, viruses, tumor cell lines, and some parasites, especially trypanosomes.
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What spontaneously activates components of alternative pathway?
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Water.
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Tickover.
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When water causes C3 to spontaneously split.
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What does C3 bind to once activated? (Alternative pathway)
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Factor B.
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Which C3 sits down on cell?
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C3b or ic3.
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Only bound factor b can be split by ________.
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Factor D.
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What happens when factor B is bound to C3b?
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B is split to form C3Bb. Enzyme with C3 convertase activity.
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What happens when Factor B is split?
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More C3 is split to form C3bBb.
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Factor D.
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Splits Factor B and C3b in presence of magnesium. Splits B into Ba and Bb.
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Properdin.
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Stabilizes C3bBb. C3 convertase. Increases half life.
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What happens after C5? Alternative pathway.
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Just like the classical pathway.
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Lectin Pathway
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Represents another antibody-independent pathway.
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C5 convertase, alternative pathway.
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C3bBb3bP.
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Lectins
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Proteins that bind to carbs that body sees as foreign.
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Mannose binding lectin.
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Key lectin. Binds to mannose.
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Where are carbs found?
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Glycoproteins and carbs, large variety of m/o.
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Why is MBL considered an acute phase reactant?
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Produced in liver and normally found in serum, but increases during inflammation.
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What is MBL similar to?
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C1q.
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What enzymes can MBL trigger?
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MASP1, MASP2, and MASP3.
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What serious infections is MBL associated with?
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Neonatal pneumonia and Sepsis.
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What happens once MBL binds to cell surface?
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MASP2 autoactivates.
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What does MASP2 split?
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C4 and C2.
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What happens once C4 and C2 are split? Lectin Pathway.
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The rest of the pathway is like the classical pathway.
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Which defense system is the classical pathway associated with?
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Specific.
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The majority of control proteins are aimed at halting _____.
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C3b.
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C1 inhibitor. Soluble or cell bound?
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Inhibits activation of the first stages of the lectin and classical pathways. Soluble.
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Where is c1 inhibitor primarily produced?
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Liver.
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Main role of c1 inhibitor.
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Inactivate C1 by binding to active sites of C1r and C1s. Causes them to dissociate with C1q.
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What enzyme does C1INH inhibit?
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MASP 2.
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What function is C1INH involved with inhibiting in body function?
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Clot formation.
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C4b Binding Protein
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Soluble inhibitor that works with Factor I. Work together to inactivate C4b.
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Factor I.
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A serine protease that inactivates c3b and c4b when bound to regulator.
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Cr1 (Complement Receptor Type 1)
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Aka cd35. Cell bound. Binds c3b and c4b. Once bound, it can be degraded by Factor I. Mediates transport of immune complexes.
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Main function of Cr1.
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Acts as receptor on platelets and rbcs and to mediate transport of c3b coated immune complexes to liver and spleen.
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Immune adherence
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Ability of cells to bind complement coated particles.
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MCP (Membrane cofactor protein) location.
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Cell bound, not on rbcs. Found on epithelial and endothelial cells. Cofactor for Factor I cleavage of c3b and C4b.
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MCP
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Targets c3b and c4b. Works with Factor I. Serves as cofactor for c4b, but not as effective as c4bp. Can control alternative pathway since binding of Factor B is inhibited.
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Decay accelerating pathway (DAF) location.
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Peripheral blood cells, endothelial cells and fibroblasts, and epithelial cells.
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What pathway is DAF capable of dissociating?
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Classical and alternative.
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What does DAF disassociate?
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C3 convertase.
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How does DAF work?
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Doesn't prevent initial binding of either C2 or Factor B, but can rapidly dissociate both from binding sites.
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Bystander lysis
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When c3b becomes deposited on host cells making them a target for destruction by phagocytic cells.
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Factor H location.
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Present on mature B cells. Cell bound. Found on dendritic cells.
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How does Factor H work?
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Binds to C3b preventing binding of factor B. Cofactor with Factor I to inactivate c3b in alternative pathway. Prevents binding of B to c3b.
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What happens before c3b sits on cell with Factor H?
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Factor H has high affinity for c3b.
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S protein
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Soluble control protein that acts at a deeper level of complement activation.
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Another name for S protein.
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Vitronectin.
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How does S protein function?
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Interacts with c5b, c6, c7 once bound. Prevents c8 and c9 from binding, thus preventing lysis. Acts on MAC complex.
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MIRL (membrane inhibitor of reactive lysis)
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Acts to block MAC. Binds to CD8 and prevents insertion of C9 into host cell membranes. Binds to c8, but not c9. Cell bound.
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Where is Cr2 found?
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Mature B cells and dendritic cells; cell bound.
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How does Cr2 enhance complement activation?
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When it binds to antigen, it causes differentiation of memory cells. Binds to c3b c3d, and other c3 fragments.
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Function of cr2.
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B cell co receptor for antigen with cd19. Binds complement coated antigen.
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Where is c3 found?
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Phagocytes.
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Function of cr3
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Adhesion and increased activity of phagocytic cells. Calcium dependent. Binds to c3b.
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Cr3 deficiency
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Deficient in chemotaxis and phagocytosis. Can't fight invaders well.
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Cr4 function
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Adhesion and increased activity of phagocytic cells that line lumen wall.
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Which receptor is involved in pavementing?
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Cr4.
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C1q receptors are called ___________.
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Collectin receptor.
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Where are C1q receptors found?
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Apc's.
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Function of c1q receptors.
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Binds to complement, enhances phagocytosis, and enhance oxidative burst.
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Anaphylatoxin
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Increase vessel permeability, contract smooth muscle, and release of histamine.
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Which proteins play a part in anaphlytoxin?
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C3a, C4a, and C5a.
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Which protein involved in anaphlytoxin is most potent?
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C5a.
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Which proteins associated with anaphlytoxin attach to C3a receptor?
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C3a and C4a.
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What does C5a cause?
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Causes white cells to undergo oxidative burst which can produce a fever.
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Which proteins make good opsonins?
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C4b, C3b, and iC3b.
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What can excessive amounts of complement cause?
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1. Gram negative sepsis. 2. Tissue damage, heart attack. 3. Red cell lysis.
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Gram negative septicemia.
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Can cause clot formation in blood vessels. (DIC) Also, damage to tiny pulmonary capillaries and interstitial pulmonary edema.
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Receptors of C3a and C5a are found in _____________.
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C3a and C5a, coronary plaques.
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Lysis of red cells causes what damage?
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Hemolytic diseases such as cold hemolytic anemia.
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Complement deficiencies can cause what if hereditary?
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Susceptibility to infection.
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Most hereditary deficiencies are inherited on ____________________.
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Autosomal recessive genes.
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Deficiency of that occurs most often.
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C2; lupislike syndrome, recurrent infection, and glomerlonephritis, and artherosclerosis.
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Persons with c2 deficiencies are said to have decreases in _______.
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Factor B.
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Deficiency of mannose binding lectin.
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Targets babies: pneumonia, sepsis, and meningococcal.
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Most serious deficiency.
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C3; causes severe recurrent infections and glomerlonephritis.
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Deficiency in any terminal components of complement cascade. (C5-C-8)
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Neisseria infections.
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Deficiencies in DAF and MIRL.
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PNH - susceptible to bystander lysis and chronic hemolytic anemia.
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Deficiency of C1INH.
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Hereditary angioedema: disease characterized by swelling of extremities, GI tract, and other mucosal surfaces. Autosomal dominant gene. Acquired form more common.
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What happens when C1 inhibitor is deficient?
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Excessive splitting of C4 and C2.
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2 categories of techniques that determine complement abnormalities.
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1. Measurement of components as antigens in serum. 2. Measurement of functional activity.
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RID (radial immunodiffusion)
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Use plate containing arose gel. Drill hole in middle of the plate. Serum serves as antigen, places in hole. Must have known antibody against specific component in gel. Incubate. Serum will diffuse out. Can take up to 24 hrs. If c4, the antibody will bind to c4 and create a circle of precipitant related to concentration.
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Nephelometry
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Measures concentration according to amount of light scattered by a solution containing a reagent antibody and patient sample. If c4, it will bind. The more complexes present, the more light scatters. Fast and easy, but not cheap.
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Hemolytic assays
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Tell if components work.
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CH50
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Measures complement ability by determining amount of patient serum required to lyse 50% of standardized co veneration of antibody-sensitized sheep rbcs. Need C1-C9.
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Titer
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Diluting serum. Reciprocal of highest dilution that will lyse 50% of cells.
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Sensitized RBC
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Red cells that are coated with antibody.
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Additional CH50 test.
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Based on lysis of liposomes that release enzyme when lysis. More accurate than CH50. If components are there, liposomes release enzymes.
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Agarose Plates
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Rabbit blood cells are sensitized with antibody and implanted in agarose. Serum is added to well. It diffuses in media, binds, and lyses cells. Will completely clear.
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ELISA
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Take known antibody (IgM) and attach to walls of microtiter plate. Add serum. They bind, then anti human globulin is added to alkaline phosphotase. Substrate is added, and if binded, a color reaction indicates a positive test.
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Classical Pathway tests
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1. Ch50 2. Additional CH50 test 3. Agarose plates 4. ELISA
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Test that can determine all 3 pathways.
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Strips used for classical pathway are coated with IgM, strips for alternative pathway are coated with LPS, and strips used for MBL are coated with mannose.
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Decreased levels of complement components may be due to which 3 reasons?
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1. Decreased production. 2. May have illness that is using it up (consumption). 3. In vitro consumption.
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If C4 and C2 are low, which pathway is effected?
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Classical.
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If C1 is normal, and the rest of the components are off, which pathway is effected?
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Lectin.
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If C3-C9 are low, which pathway is effected?
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Alternative.
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Complement fixation test purpose.
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Used to see if complement is present and activated.
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When does complement fixation occur?
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After the binding of antigen and antibody.
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What two stages are involved in the complement fixation testing?
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1. System with antibody and antigen, one of which is unknown. 2. Indicator system consisting of sheep rbcs coated with hemolysin which lyses in presence of complement.
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Process of complement fixation.
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Heat serum at 56 degrees for 30 minutes. This inactivates complement. Then, dilute serum and add to known antigen and a measured amount of guinea pig complement once binded. It's used because it's not species specific. If patient antibody is present, it will be bound. Once this is done, sensitized sheep rbcs are added. If it has antibody, no complement to bind to cells. No lysis is a positive test. Lysis is negative test.
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Immune clearance
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The accelerated removal of an antigen from the bloodstream that follows the initiation of an antibody response by the immune system. This leads to the formation of antigen-antibody complexes, which are ingested by macrophages and other phagocytic cells.
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Decreased complement levels may be associated with what diseases?
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Liver disease, chronic glomerlonephritis, rheumatoid arthritis, hemolytic anemias, graft rejections, SLE, and other autoimmune diseases.
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Increased complement levels are associated with what diseases?
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Inflammatory conditions; leukemia, Hodgkin's disease, sarcoma, and Bechet's disease.
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What is the first amplification step in the classical pathway?
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When c4b binds to protein or carb within seconds. Otherwise, it reacts with water to form iC4b, which is rapidly degraded. For every 1 C1 attached, approximately 30 molecules of C4 are split and attached.
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C3 convertase in alternative pathway.
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C3bBb or iC3Bb.
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Amplification loop for alternative pathway.
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When c3 convertase is capable of cleaving additional C3 into C3a and C3b. Some C3b attaches to cell and acts as binding site for more Factor B.
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If a molecule of C3 remains attached to C3bBbP enzyme, what happens?
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Convertase has capability to cleave C5.
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If a molecule of C3 remains attached to C3bBbP enzyme, what happens?
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Convertase has capability to cleave C5.
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C5 convertase in alternative pathway.
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C3bBb3bP.
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Which component is MASP 2 homologous of?
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C1s.
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PNH
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Have red blood cells that are deficient in DAF. Subject to lysis by means of bystander effect.
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Alexin
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Aka complement.
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