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PCB 5235 - Section 10 questions and
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What is the complement system? - correct answer The major effector of the humoral branch of the immune system made up of >20 interdisciplinary proteins. What are the three pathways of complement activation? - correct answer Classical in the presence of specific Ab. Alternative in the absence of specific Ab. Lectin in the absence of specific Ab & presence on mannose (MBL binds to PAMPs). Major role of complement - correct answer Recognition and destruction of pathogens based on PAMPs. Zymogen/proenzyme - correct answer Inactive form of complement proteins that circulate in serum. Remain inactive until proteolytic cleavage removes the inhibitory fragment, exposing active site. Activation initiates enzyme cascade. What type(s) of cells make complement proteins? - correct answer Hepatocytes, monocytes, macrophages, and epithelial cells. Protein fragments after cleavage - correct answer Smaller fragments diffuse from site and initiate localized inflammation (suffix "a"). Larger fragments bind to target near activation site (suffix "b"). Fragments interact to form functional complexes (complexes with enzymatic activity have overbars). Complement inflammatory response - correct answer Localized pain, swelling, redness, heat, and loss of function. Mediated by anaphylatoxin (C3a/C5a yield degranulation of histamine, prostaglandins, leukotrienes). Produces chemotactic factors (C3a/C5a attract macrophages). Binding to receptors on endothelial cells causes vasodilation, blood volume to area, and vascular permeability.
What is the result of granulocyte activation? - correct answer Increased expression of complement and Fc receptors. Differences between complement activation pathways - correct answer Start by differing activation sequences, but eventually all make C5b and are the same afterwards, ending at MAC formation. MBL recognizes surface carbohydrates on what? - correct answer Bacteria, some tumor cells, fungus, enveloped viruses, etc. Classical pathway part 1 - correct answer C1q binds Ag-Ab and induces a conformational change in one C1r molecule, activating it. This C1r then activate the second C1r and the two C1s molecules. Classical pathway part 2 - correct answer C1s cleaves C4 and C2. C4 is cleaved first and C4b binds to the membrane close to C1q. C2 binds to the active site of C4b and is exposed to the action of C1s. C1s cleaves C2, creating the C3 convertase, C4b2a. Classical pathway part 3 - correct answer C3 convertase hydrolyzes many C3 molecules. Some combine with C3 convertase to form C5 convertase. The C3b component of C5 convertase binds C5, permitting C5 cleavage by C4b2a. Activated C5 initiates MAC. How much C3b does a single C3 convertase generate? - correct answer Over 200 molecules. What are the functions of C3b? - correct answer Opsonization and phagocytosis. What is the function of smaller fragments such as C2b, C3a, C4a, and C5a? - correct answer They are anaphylatoxins. What initiates MAC? - correct answer Activated C5.
Component of T-independent B cell activation. C3 convertases - correct answer Alternative - C3bBb Classical/lectin - C4b2a C5 convertases - correct answer Classical/lectin: C4b2a3b Alternative: C3bBbC3b MAC formation - correct answer C5b binds target cell and forms binding site for other MAC components. C6 binds C5b on cell surface. C7 binds C5b6 and inserts into phospholipid bilayer. C8 binds C5b67 and undergoes a conformational change to reveal a hydrophobic region and create a small hole in the target cell. This hole can lyse RBCs, but NOT nucleated cells. C9 binds C5b678, undergoes a conformational change, then inserts into bilayer. Multiple C9 copies (10-17) form pore. Abilities of MAC pore - correct answer Creates channel where ions and small molecules can freely diffuse. Osmotic stability is lost as H2O flows in and electrolytes flow out. Causes cell lysis of even nucleated cells. CR1 (CD35) - correct answer Receptor for C3b, C4b, C1q, and iC3b. Present on phagocytic cells, erythrocytes, granulocytes, B cells, and some T cells. Functions include clearance of immune complexes, enhancement of phagocytosis, and regulation of C3 breakdown. CR2 (CD21) - correct answer Receptor for C3d, C3dg, and iC3b. Present on B cells and follicular DCs. Functions include enhancement of B cell activation, B cell co-receptor, and retention of C3d-tagged immune complexes.
CR3 (CD11b/CD18, MAC-1) - correct answer Receptor for iC3b and factor H. Present on phagocytes, granulocytes, and T cells. Functions include binding to adhesion molecules on leukocytes, facilitating extravasation, and iC3b binding enhances opsonization of immune complexes. CR4 (CD11c/CD18) - correct answer Receptor for iC3b. Present on phagocytes, granulocytes, and T cells. Functions include iC3b-mediated phagocytosis. C3aR - correct answer Receptor for C3a. Present on mast cells, basophils, and granulocytes. Functions include inducing degranulation. C5aR (CD88) - correct answer Receptor for C5a. Present on mast cells, basophils, granulocytes, monocytes, macrophages, platelets, endothelial cells, and T cells. Functions include inducing degranulation, chemoattraction, acts with IL-1beta and/or TNF-alpha to induce acute phase response, and induced respiratory burst in neutrophils. Methods of complement system regulation. - correct answer Spontaneous inactivation - many complement proteins are highly labile and undergo spontaneous inactivation if not stabilized by other components. Difference in carbohydrate composition - example is sialic acid hiding mannose. Short consensus repeats - repeating AA sequences on human chromosome 1 prevent increased expression. Regulatory proteins in C3 convertase assembly. Regulating C3 convertase pre-assembly. - correct answer C1 inhibitor binds C1r2s2, causing dissociation from C1q. Association of C4b and C2a is blocked by binding C4b-binding protein, complement receptor type I, or membrane cofactors protein. Inhibitor-bound C4b is cleaved by Factor I. In alternative pathway, CR1, MCP, or Factor H prevents binding of C3b and Factor B. Inhibitor-bound C3b is cleaved by Factor I.
Systemic lupus erythematosus (SLE) - correct answer Patients produce large quantities of immune complexes and suffer tissue damage through complement mediated lysis and hypersensitivity. Also produce auto-antibodies to many tissue Ag like DNA, RBC, histones, leukocytes, etc. Considered a systemic autoimmune disease because of the numerous tissues involved. Deficiencies in C1, C2, and C4 contribute to rescue C3b levels on immune complexes and their clearance. Fever, weakness, arthritis, skin rashes, kidney dysfunction. Complement clearance of apoptotic blebs. - correct answer C1q binds to phosphatidylserine and DNA. Without complement, apoptotic blebs act as auto-Ag and can cause autoimmune diseases like SLE. What is the advantage of immune complexes becoming insoluble? - correct answer It makes it easier for them to be phagocytosed.
