CH7 (from book)

able to increase vascular permeability,
recruit monocytes / neutrophils to area of antigen concentration, and
trigger secretion of immunoreg molecules that amplify the response

recognizes cellular debris and tags for removal by innate immune cells

lead to inflammation and tissue damage

increased susceptibility to infection or the accumulation of immune complexes
resulting in possible autoimmune disease

1. classical pathway
2. lectin pathway
3. alternative pathway

proteins triggered by antigen-antibody combination

antibody-independent means of activating complement proteins with mannose binding lectin (MBL)

liver (except C1 components)

intestinal epithelial cells and factor D in adipose tissue

inactive precursors that are then converted to active enzymes

lysis of invading cell

cytolysis of pathogens
opsonization and phagocytosis
activation and directing migration of WBC
solubilization and clearance of immune complexes
enhancement of humoral immune responses

main antibody-directed mechanism for triggering complement activation

IgM, IgG1, IgG2, IgG3

IgG4. IgA, IgE

IgM (due to multiple binding sites)

Rh isotopes (too far apart on cell to fix complement)

IgG3

CRP, several viruses, mycoplasmas, some protozoa, and some gram neg bacteria (e. coli)

1. recognition unit
2. activation unit
3. membrane attack complex (MAC)

C1qrs

activation of C4, C2, and C3

C5 through C9

lysis of foreign particles

presence of calcium to maintain structure

part that binds the antibody molecule
recognizes the Fc region of 2 adjacent antibody molecules

generate enzyme activity to begin the cascade

serine protease proenzymes (zymogens)

binding of C1q

cleaves thioester bond on C1s (activating it)

C4 and C2

when C1s is activated

when C1s cleaves C4

production of C5 convertase enzyme

C1s cleaves C4 to C4a and C4b

C4b

C4b binding (for every C1 attached, 30 C4 and split and binded)

C1s cleaves C2 to form C2a and C2b and C2a joins C4b

C2a

short life keeping the reaction localized

becomes C3 convertase (C4bC2a)

complex is an active enzyme

C3 is cleaved into C3a and C3b

cleavage of C3 to C3b

C3b

able to bind to hydroxyl groups on carbs and proteins

hydrolyzed by water and decay in fluid

cleavage of C3 (200 C3 split for every C4b2a)

opsonization

creates C5 convertase (C4b2a3b)

splits C5a and C5b

C5b attaches to cell membrane, forming the beginning of MAC

rapidly inactivated

subsequent binding of C7. C8, C9

carboxy terminal end is hydrophobic, to anchor MAC within the target membrane

activated by recognition of surface moieties from pathogens (instead of activation through ab binding)

involves nonspecific recognition of carbs that are common of microbial cell walls and that are distinct from human cells

lectins, ficolin, and CL-K1

collectins

mannose binding lectin (MBL)

binds to mannose or related sugars in calcium-dependent manner to initiate pathway

mainly in the cell walls or outer coating of bacteria, viruses, yeast, and protozoa

C1r and C1s

serine proteases - MBL-associated serine proteases

MASP-24

as a defense mechanisms in infancy between loss of mom antibody and acquisition of full antibody response to pathogens

amplification loop for activation started from classical or lectin pathways

stabilize the C3 convertase formed from activation of other factors

properdin
factor B
factor D

bacterial cell walls
fungal cell walls
yeast
viruses
virally infected cells
tumors
parasites

the conversion of C3

spontaneously hydrolyzed by water to become C3b

Factor B is cleaved by Factor D

(same as C2 in classical)
forms integral part of C3 convertase

cleaves Factor B into Ba and Bb

Bb

Cleaves C3a and C3b

yes but at less efficiency than cleaving C3

Becomes C3bBb3bP which has high affinity for C5 convertase activity (cleaving C5)

produces C5b which is part of the MAC (continue pathway)

to keep the reaction localized

C3b because it is a pivotal step in all pathways

inhibits activation at the first stages of both classical and lectin pathways

inactivate C1 by binding to active sites of C1r and C1s (so they become dissociated from C1q)

inactivates MASP-2 binding (halting lectin pathway)

1. C4-binding protein (C4BP)
2. complement receptor type 1 (CR1)
3. membrane cofactor protein (MCP)
4. decay-accelerating factor (DAF)

Factor I

serine protease that inhibits C3b and C4b when bound to one of the regulators

combines with C4b so that C4b cannot bind with C2

dissociates from C4b2a complexes, stopping classical pathway

peripheral blood cells (PMNs, monocytes, mq, RBC, eosinophils, B cells, some T cells, and dc)

binds C3b and C4b (mostly C3b) so that they can be degraded by factor I

receptor on platelets and RBCs that helps mediate transport of C3b coated immune complexes to liver and spleen

ability of cells to bind complement-coated particles

cofactor for Factor I-mediated cleavage of C3b

binding of Factor B to C3b is inhibited

on epithelial and endothelial cells (except erythrocytes)

peripheral blood cells, endothelial, fibroblasts, and numerous epithelial

dissociating classical and alternative C3 convertases by binding to both C3b and C4b; prevents assembly of C3 convertase

covalently attached to glycophospholipid into outer layer of membrane that allows mobility so that it can reach C3 convertases that are not next to it

protects from bystander lysis, main mechanisms of discrimination of self from nonself because foreign cells do not have DAF

no, capable of reforming elsewhere

Factor H

binds to C3b, preventing the binding of Factor B

Bb becomes displaced. Accelerating the dissociation of C3bBb complex on cell surface; C3 convertase activity is curtailed

allows Factor I to break down C3b

interactors with C5b-7 complex and prevents it from binding to cell membrane

C8 and C9 still bind but no polymerization of C9, therefore complex cannot insert self into membrane to produce lysis

acts to block formation of MAC

cell membranes of all circulating blood cells, endothelial, epithelial

mature B cells and dc but is lost when conversion to plasma occurs

B cell coreceptor for antigen, (alongside CD19) binds complement coated antigen to membrane immunoglobulin to activate B cells

enhancing B cell differentiation and production of memory cells than is antigen by itself

binds particles opsonized with iC3b (C3b degradation product)

mediating phagocytosis of particles coated with complement fragments

surface adhesion and increased activity of phagocytic cells

fail function in chemotaxis, surface adherence, and aggregation; subject to recurrent infections

calcium dependent

PMN, monocytes, tissue mq, activated T cells, DC, NK, activated B cells

similar to CR3: assist neutrophil adhesion to the endothelium during inflammation

bind to collagen portion of C1q and enhance binding of C1q to Fc receptors

increase phagocytic cells' uptake of immune complexes opsonized with C1q

act to enhance the respiratory burst triggered by IgG binding to FC receptors

1. act as opsonins
2. uptake and presentation of ag
3. facilitate B cell activation
4. maintaining immunologic memory

links innate and adaptive
amplifies inflammatory response
effector molecules

1. anaphylatoxins
2. chemotaxins
3. opsonins

small peptide that increases vascular permeability, contraction of smooth muscle, and release of histamine from basophils and mast

C3a and C5a, cleavage products from larger complement; C5a is stronger

receptors of PMNs, basophils, mast, eosinophils, smooth muscle cells, vascular endothelium

histamine is released

PMN release hydrolytic enzymes, oxygen radicals, prostaglandins (aid to destroy foreign antigen)

cells are directed to source of antigen concentration; PMN migrate from bld vessel to tissues and tend to aggregate

causes oxidative burst; increased production of hydrolytic enzymes, PMN chemotactic factor, platelet activating factors, IL-1, and toxin oxygen metabolites

C3b, C4b

increased T cell activation, may produce fever and lead to increase in acute phase reactants (inflammatory response)

inactivates C3a and C5a to localize and control their effects (AKA inactivates C3a and C5a anaphylatoxin activity)

specific receptors on erythrocytes, PMNs, monocytes, and mq

binding facilitates phagocytosis and clearance of foreign substances or cellular debris ; attaches C3 products to antigen to enhance B cell response

1. activated on large scale gram neg septicemia
2. activated by tissue necrosis (MI)
3. lysis of RBC occurs

large amt of C3a and C5a generated, leading to OMN aggregation and clotting (leads to damaged pulm capillaries and pulm edema)

cause complement activation and deposition of MACs on cell surfaces, increased damage to heart tissue

increased susceptibility to infection and delayed clearance of immune complexes

C2 deficiency

more prone to recurrent streptococcal and staphylococcal infections and decrease Factor B

pneumonia, sepsis, meningococcal disease in infarcts; risk of cancer, lupus

develop severe, recurrent life-threatening infections with encapsulated bacteria; glomerulonephritis

increased susceptibility to Neisseria infections

RBCs are deficient in DAF (subject to lysis by bystander effect once complement has been triggered)

insertion of C9 into membrane by binding to C5b-8 complex, inhibiting formation

DAF and CD59

recurrent attacks of swelling that affect extremities, skin, GI, and mucosal surfaces caused by lack of C1-INH

localized swelling

1. type I: decrease of C1-INH protein
2. type II: normal C1-INH but function decreased

hemolytic anemia, low platelet count, and acute renal failure due to Shiga Toxin

occurs because complement dysreg caused by genetic polymorphisms

diseases involving glomeruli because C3 deposits into kidneys from mutation of C3, Factor B, Factor H, or Factor I

C3, factor B, factor H, factor I

leads to uncontrolled cleavage of C3 and uncontrolled deposition of C3 on the kidneys