Term
| components of Classical Pathway of complement system |
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Definition
antibody dependent
a. IgM and IgG bound to surface of pathogen and c1qrs gets activated
b. C1r autocleavage event
c. C1, C4, C2 major components of activation
d. Antigen-dependent |
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Term
| Components of MBL pathway of complement system |
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Definition
a. Borrows some components of classical pathway
b. In the absence on antibody (antibody-independent)
c. MBL binds to terminal mannose sugar on bacterial carbohydrates, MASP-1, MASP-2 (MASP-1 and MASP 2 behave much like C1qr and C1qs (as serine proteases) but borrow c1 and c2 from classical pathway to generate c3 convertase |
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Term
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Definition
| is the idea that there is cleavage in a pathway to make enzymes and then the enzymes contribute to that pathway |
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Term
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Definition
| Factor b binds to c3b and then factor b is substrate for cleavage by a serine protease called factor D |
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Term
| C3b provides binding site for pathogen surface for what factor? |
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Definition
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Term
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Definition
| it cleaves factor b to generate big b and little b (this is the alternative pathway c3 convertase. A molecule of c3b assembled with a molecule of activated factor b called big b little b) |
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Term
| Bb is also known as what? |
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Definition
| the alternative pathway c3 convertase |
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Term
| Bb can cleave c3 to generate what two fragments? |
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Definition
| c3b and small fragment c3a |
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Term
| explain the positive feedback loop of making c3b |
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Definition
once you generate c3b through Classical or MBL you can make positive feedback loop to make more c3b
c3b will be generated and will be deposited on the surface of the pathogen to prepare it for ingestion (lets say we have some c2b4a and we generate some c3b through the convertase on the surface of the cell and that will serve as an opsonin in and of itself but if we want to amplify the system and really target the pathogen for elimination we would take some factor b and allow that to be cleaved by d and make big b little b and then we can generate more c3b on surface of pathogen) |
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Term
| The more c3b you deposit on surface of pathogen the more likely it is that what will happen? |
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Definition
| more likely it is the pathogen will be engaged by phagocytic cell through the c3b receptor and begin phagocytosis |
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Term
| if you were to explain C3b in one word, what would you say it was? |
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Definition
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Term
| what is special about factor D? |
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Definition
because factor b is the only substrate for factor d when it is assembled with c3b it has the ability to circulate in an active form and cleave factor b when it binds to c3b.
-Enzymes usually exist in zymogen form, but D is circulating always in active form without being pre-activated |
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Term
| What type of bond will C3 bind to the pathogen surface? |
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Definition
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Term
| If one molecule of cleaved c3 binds back on to the c3 convertase you then generate what? |
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Definition
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Term
| what does C5 convertase do? |
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Definition
| cleaves a component of complement called c5; you generate from that c5b and small MW peptide called c5a |
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Term
| why is the C5 convertase step special? |
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Definition
| it is the last enzymatic step in the complement cascade. |
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Term
| when c6 and c5b come together what do they generate? |
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Definition
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Term
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Definition
| binds to c7 to generate trimolecular complex C5b67 |
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Term
| Why is C5b67 an important intermediate? |
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Definition
-the precursors to this trimolecular complex are hydrophilic
when a c5b67 complex is made, they then become hydrophobic ( they often look for a membrane or hydrophobic environment that they can associate with and then bind c8) |
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Term
| what happens after C5b67 becomes hydrophobic and binds to c8? |
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Definition
| This whole complex binds to multimers of c9 |
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Term
| When C5b6789n forms its large molecular complex that is highly hydrophobic and all those molecules disrupt the membrane of the cells, they undergo a process called _________. |
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Definition
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Term
| Osmotic lysis (colloid lysis) |
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Definition
| a cell assembles molecules at a particular site. The cell forms pores in the membrane, and if cell cant control its internal volume this the cell will undergo lysis. |
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Term
| Membrane attack complex (MAC) |
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Definition
| membrane of complement complex including the full group of proteins C5b6789n |
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Term
| what is another name for cell pores? |
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Definition
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Term
| The 4 major components of Biological properties of complement activation |
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Definition
1) C3b-opsonin (opsonization)
2) C5b-9 Membrane Attack Complex (MAC)
3) Anaphylatoxins (C5a, C3a, C4a)
4) Chemotactic factors/chemotaxis |
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Term
| explain C3b-opsonin (opsonization) |
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Definition
a. Receptors for opsonins exist. For pathogen binding in order to make process more efficient
b. Another opsonin by adding IgG on there
c. This is described as being a zipper. Teeth of zipper are the opsonins (C3b and IgG) and teeth of the zipper on the neutrophil are the Fc gamma receptors and the C3b receptors |
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Term
| explain the C5b6789n Membrane Attack Complex (MAC) |
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Definition
a. This can cause osmotic lysis of target cell
b. If you activate complement you have generate short-lived enzyme activities. Chances are that the complement components that are activated are going to deposit on the membrane surface at the site where they are generated. So if it is a bacteria, chances are you are going to deposit some of this on the surface of the bacteria.
c. Complement system is a system that needs to be regulated very tightly
d. These are looking for a hydrophobic environment |
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Term
| Describe how C5a, C3a, and C4a are anaphylatoxins function |
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Definition
| infection --> C3b opsonizes --> get those bacteria ready for phagocytosis --> . Increase vascular permeability to increase # of cells going out of blood vessels and into CT where they can function to phagocytose at infection --> Increase smooth muscle contractions to alter hemodynamic flow & alters expression of adhesion molecules on endothelium. Alteration of adhesion molecules, allows leukocytes to stick to the vascular CT |
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Term
| Explain Chemotactic factors/Chemotaxis |
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Definition
| mediated by small peptide mediators, notably C5a which leukocytes have a receptor for, and allows them to migrate in the appropriate fashion along with gradient where the small MW peptide is being generated |
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Term
| What are some regulators of complement system? |
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Definition
1) soluble regulators
2) membrane-associated regulators |
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Term
| name all the soluble regulators of complement system |
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Definition
1) C1-INH (C1 inhibitor)
2) C4BP (C4 binding protein)
3) Factor H
4) Factor I |
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Term
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Definition
| This inhibitor dissociates r and s from q (can bind and begin activation of classical pathway but doesn’t persist indefinitely) and therefore regulates C1 (if enzyme isn’t properly controlled then the substrate will continue to get cleaved) |
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Term
| what happens if you lack C1-INH? |
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Definition
) if you lack this you have hereditary angioedema (also called Hane hereditary angioneurotic edema-systemic accumulation of fluids)
- this is where enzyme isn’t properly controlled which means that the substrate will continue to get cleaved) |
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Term
| C4BP (C4 binding protein) |
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Definition
this dissociates 2a from C4b
-This is co-regulator/cofactors for factor I |
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Term
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Definition
-dissociates Big b little b from C3b
-This is co-regulator/cofactor for factor I
-C4 binding protein and factor H are said to be cofactors for another regulator called Factor I |
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Term
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Definition
| it cleaves C4b and C3b and renders it inactive |
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Term
| Why do you need factor i? |
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Definition
-when you generated 4b from the classical pathway or the MBL pathway there’s a binding site for c2. When you generate c3b from alternative pathway, that’s a binding site for factor b
-2 cant go onto 4b after it has been cleaved by I) (b cant bind to 3 b after it has been cleaved by I so that’s how cofactors working in concert can facilitate in activation of the convertase. |
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Term
| Name the membrane-associated regulators |
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Definition
1) CD59
2) MCP (membrane cofactor protein)
3) DAF (decay accelerating factor) |
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Term
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Definition
| This membrane associated regulator inhibits formation of MAC complex; found on many cells |
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Term
| MCP (Membrane cofactor protein) |
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Definition
| this is a type of membrane associated regulator that inhibits convertase; Prevents convertases from assembling on membranes |
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Term
| DAF (decay accelerating factor) |
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Definition
| type of membrane associated regulator that reduces formation of the convertases) Prevents convertases from assembling on membranes |
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Term
| Daf and CD59 membrane associated regulators are brought to membrane of cells. How are they expressed there? |
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Definition
| which they are expressed by lipid anchor |
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Term
| Paroxysmal nocturnal hemoglobinuria (PNH) |
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Definition
-a disease where lipid anchor doesn’t work properly and thus DAF and CD59 are not expressed
-bc the cell doesn't have that anchor (that allows DAF and CD59 to be expressed on membrane surface) the membrane attack complex can form on surface of cells and cause membrane damage and osmotic lysis. |
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Term
| What type of cells are particularly at risk when a person has Paroxysmal nocturnal hemoglobinuria (PNH) ? |
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Definition
| erythrocytes are particularly at risk. Nucleated cells have ability to repair plasma membranes. RBC's are anucleated so they are susceptible to membrane damage (cant sleep at night, hemoglobin accumulates in urine and urine has red in it when they wake up) paroxysmal means sudden onset (happens in cyclical fashion related to these defects) |
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Term
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Definition
| its tissue distribution tells us its found on macrophages and neutrophils, and used in phagocytosis (c3b gets deposited on pathogen, and then this receptor is on the phagocytic cell and it recognizes c3b on the pathogen , it binds to c3b and initiates phagocytosis. |
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Term
| CR1 (aka C3b receptor) is on what types of cells? |
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Definition
a. Macrophages
b. Neutrophils
c. Erythrocytes |
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Term
| What does CR1 (c3b receptor) do on a RBC? |
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Definition
| When IgG or IgM bind to antigen you activate classical pathway. RBC’s have capacity at that stage to bind to immune complex through CR1 receptor. If they do so and traffic through blood vessels of body they get filtered through liver/spleen and then get removed from blood and clean the blood. Cr1 can take out immune complexes from circulation |
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Term
| What happens if RBC doesn’t have a Cr1 receptor? |
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Definition
-it gets deposited into the kidney after being filtered & forms large aggregates
-This can damage kidney over time leading to renal disease/failure
-Because of these autoimmune diseases some patients need kidney transplants |
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