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ICB > Complement > Flashcards

Complement Flashcards

1
Q

Complement

A
  • innate immune killing mechanism of blood
  • pre-formed effector exploited by adaptive system
  • intrinsic antibacterial killing mechanism of blood
  • free bacteria in blood are unusual because they engage a key immediate innate response
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2
Q

Complement and humoral defense

A

historically cell free serum was observed to kill many bacteria

  • important features: facilitates by antibody but does not require specific antibody
  • some bacteria are resistant
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3
Q

Complement Naming

A
  • C1-C9 are classical complement components
  • B, H, D, I are regulatory factors (accessory factors)
  • when complement factors are cleaved the products get a letter appended (C3 becomes C3a and C3b)
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4
Q

Alternative complement pathway

A
  • complement component C3 present at high concentration in serum
  • C3 is a central protein
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5
Q

C3

A
  • has a sequence of residues forming an internal covalent cysteine-glutamine thioester bond (unstable but shielded from water)
  • at some small frequency the thioester is hydrolysed
  • hydrolysis generates a conformational change (water leaks in and hydrolyses the bond)
  • C3(H2O) binds a circulating serine protease zymogen, factor B
  • C2(H2O)B is cleaved by another serine protease factor D generating C3(H2O)Bb and Ba
  • Ba floats away
  • C3(H2O)Bb is able to cleave other C3 molecules (convertase serine protease enzyme)
  • ** see notes ***
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6
Q

C3 Cleavage

A
  • critical event in complement activation
  • C3 is cleaved into C3a and C3b
  • C3a is a signalling molecule: it drives smooth muscle contraction, macrophage recruitment, mast cell degranulation, vascular permeabilization
  • in C3b the thioester bond is exposed and reactive - reacts with water or with local hydroxyl or amine groups
  • if C3b reacts to a group on the bacterial surface it recruits B, D factors
  • a factor is proinflammatory and C3b is a structural component carrying the bond
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7
Q

Bacterial Reaction

A
  • biological surfaces react with the thioester of C3b and Bb (active convertase)
  • bound to the microbe surface
  • amplification of C3b bound to the bacterium surface
  • C3b is an opsonin : surface becomes covered with C3b and are recognised as foreign by phagocytes and targeted for phagocytosis
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8
Q

Higher order complexes

A
  • at high concentrations of C3 there is competition for binding to factor B
  • multiple C3 bind to a single factor B
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9
Q

C5

A
  • cleaved and activated by C3bBbC3b
  • splits into C5a and C5b
  • C5a is a signalling molecule and potent inflammatory signal to dendrites
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10
Q

C5 fragments

A
  • each C5 fragment has a function
  • C5a is an anaphylotxoin but more potent than C3a
  • signals to immature dendritic cells to enhance production of antibacterial helper T cells
  • C5b nucleates the membrane attack complex (C5b,C6,C7,C8,C9)
  • C9 multimerizes to form a pore in biological membranes directly lysing foreign bodies
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11
Q

MAC Formation

A
  • C5b binds C6 and C7
  • C7 has membrane affinity and recruits C8
  • C8 inserts into the cell membrane
  • C9 molecule binds and polymerises to the complex (pore forms)
  • 10-16 molecules of C9 bind to form the pore
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12
Q

Phagocytosis

A
  • via macrophages requires recognition by phagocytic receptors
  • C3b is an opsonin
  • C3b bound on microbial surfaces is recognised by C3R, a phagocytic receptor, to drive uptake of labeled microbes
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13
Q

Classical complement Pathway

A
  • role for antibody
  • alternative pathway (initiated by spontaneous C3 hydrolysis) is 80-90% of successful complement activation
  • classical pathway affords a mechanism for complement to be activated by specific antibodies (not so common)
  • example of adaptive immunity using innate immune mechanisms to promote microbial killing (antibody recruitment of complement system)
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14
Q

Antibodies

A
  • mainly IgG
  • bind a bacterium in serum
  • variable region binds antigen and constant region (Fc region) is bound by other recognition proteins of the immune system such as C1
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15
Q

C1

A
  • C1 is a complex containing 5 peptides (C1qC1r2C1s2)
  • C1q binds Fc constant antibody region
  • C1r and C1s are serine protease zymogens
  • C1q binding to Fc activates C1r activity : C1r cleaves and activates C1s
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16
Q

C4

A
  • C1s cleaves C4
  • C4 is like C3 : contains a thioester bond (C4b) that is revealed by cleavage
  • C4 cannot have spontaneous cleavage like C3
  • C4a is an anaphylotoxin : C4b binds microbial surfaces (like the C3b reaction with hydroxyl groups of bacterial surfaces)
  • triggers inflammatory signalling pathways
  • C4b binds C2 and cleaves by C1s to form C4bC2a
  • C4bC2a is a C3 convertase (serine protease) just like C3bBb
  • bacterium is opsonized with C3b and lysed
17
Q

General Mechanisms of Classical Pathways

A
  • generalise to other circulating receptors
  • example is the mannose binding lectin pathway
  • MBL binds mannose and recruits MASP1 and MASP2 (MBL associated serine proteases like C1r/s)
  • MASP1/2 cleave and activate C4 then C2 as in the classical pathway
  • therefore: circulating receptors utilise/recruit complement systems
18
Q

Effector Cassette

A
  • detection mechanisms funnel into a consistent effector cassette
  • antibody activates C1 and then C4bC2a
  • MBL activates MASP1/2 and then C4bC2a
  • C3 spontaneous activation
  • all funnel into C3 activation and opsonization/phagocytosis or the C5 activated membrane attack complex
19
Q

Host Control of Complement

A
  • C3a is a signalling molecule driving smooth muscle contraction, macrophage recruitment, etc, etc
  • in C3b the thioester bond is exposed and reactive reacting with water or with local hydroxyl/amine groups
  • host cells are covered in these groups and anaphylotoxins such as C3a, C4a, C5a have symptoms of septic shock
  • control pathways prevent overactivity and host targeting
20
Q

Complement Regulatory Factors

A
  • H, I, P, CD46
  • H binds glycosaminoglycans (surface of host cells) and recruits factor I
  • CD46 is a TM protein produced in host cells recruiting factor I
  • I is a serine protease cleaving and inactvating C3b and C4b preventing opsonization and killing the amplification step of complement activation (terminates the process of host cell complement activation)
  • P is an activating factor binding biological surfaces and increasing the half life of C3bBb (released by neutrophils)
  • enhance stability of complement activating systems
21
Q

Complement Deficiencies

A
  • people who lack C1q or C2 have autoimmune disease (failure to clear complexes of cell debris with antibodies)
  • people who lack C3 are susceptible to infections with pyogenic bacteria (gram negative as MAC is good at targeting gram negative bacteria)
  • people who lack MAC components (C5-C9) are similar
22
Q

Bacterial Evasion

A

General mechanisms disrupting general immune recognition

  • polysaccharide capsules
  • inhibition of antibody binding

Complement specific effects

  • mimickry of host cell surfaces
  • hiding inside host cells
23
Q

Polysaccharide Capsule

A
  • escape from complement
  • layer is slimy forming diffusion barrier
  • impairs complement mediated killing in several ways
  • capsule excludes efficient diffusion of C3 to bacterial surface - so that activated C3 is mostly exposed to capsule (not the membrane)
  • MAC can’t get to membrane making opsonisation less efficient
  • because C5 convertase is bound at capsule surface, efficiency of membrane attack is severely diminished
  • diffusion within the capsule is inefficient : distance between activated C3 convertase complexes is high reducing amplification of effectiveness
  • capsule inhibits phagocytosis by increasing effective size of bacterium
24
Q

Capsular Targets

A
  • capsules can still be targets for Abs and complements
  • capsular polysaccharides are recognized as non host due to antibodies
  • diversity of capsules indicates selective pressure of bacteria
25
Q

Streptococcus pyogenes

A
  • mimics the host
  • uses more targeted mechanisms
  • capsule : glycosaminoglycan binds host factor H to impair complement activation
  • M protein recruits factor H
  • ultimate goal is to recruit endogenous protective mechanism
26
Q

Neisseria meningitidis

A
  • uses mimickry and interference
  • LPS is sialylated to recruit factor H and facilitate interaction with C3
  • secretes factors that bind and degrades C3
  • impairment and degradation of complement amplification
27
Q

Staphylococcus aureus

A
  • uses many mechanisms
  • Efb: secreted to bind and inhibit C3
  • Protein A: binds Fc and inhibits C1q binding (inhibition of classical complement system)
  • SdrE: TM protein binding C4BP to recruit H

ICB (15 decks)

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