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STEP Physiology > I4 > Flashcards

I4 Flashcards

1
Q

What is the complement cascade?

A

a series of enzymatic cleavages of complement proteins that ultimately leads to covalent binding of opsonins to the surface of the foreign material

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2
Q

What are the three components of the complement pathway?

A
  1. classical pathway (acquired)2. alternative pathway (innate)3. lectin pathway (innate)
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3
Q

What are the three functions of the complement cascade?

A

(1) opsonization of pathogens , making them more likely to be taken up and destroyed by a phagocyte, (2) recruitment of inflammatory and innate cells (primarily phagocytes)- anaphylatoxins, and (3) direct killing of pathogens via the membrane attack complex, or MAC.

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4
Q

In what order do the three components of the complement cascade typically act?

A

First to lastAlternative, lectin, classical

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5
Q

What is the most important product of the complement cascade?

A

complement component C3b, which is the primary opsonin created by these pathways

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6
Q

What are anaphylatoxins?

A

inflammatory mediators that activate vascular endothelium and recruit phagocytes to the inflammatory site. This is one of three end products of the complement cascade. What re the other two?

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7
Q

How is the complement cascade different from anitbody-mediated opsonization?

A

Complement proteins like C3b are permanent because they are COVELANTLY bound to the surface of pathogens, permanently marking hem for destruction

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8
Q

How does the membrane attack complex lyse bacterial pathogens?

A

by forming membrane pores

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9
Q

T or F. The proteins of the complement system are produced all the time in the body

A

T. Doesn’t matter if there is an infection or not

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10
Q

Where are complement system proteins produced in the body? Are they produced in their active form?

A

in the liver secreted in theirinactive, or zymogen form. Therefore, they are always available in the circulation and in extravascular fluids throughout the body.

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11
Q

What are the two versions of the C3 convertase enzymes that are responsible for cleaving component C3?

A

C3bBb and C4bC2a

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12
Q

When is C3bBb generated/activated to act?

A

generated following activation of the alternative pathway.

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13
Q

When is C4bC2a generated/activated to act?

A

following activation of the classical pathway or lectin pathway. The enzyme (C4bC2a) is usually referred to as the C3 convertase of the classical pathway (even thought the lectin pathway makes it too).

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14
Q

What are the primary functions of the C3b production?

A

(1) C3b is a component of the C5 convertase, and is therefore needed for the eventual formation of the membrane attack complex, and (2) C3b (and its breakdown products) are the opsonins that are permanently deposited on the surface of pathogens, targeting them for uptake and destruction by phagocytes.

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15
Q

T or F. The alternative pathway is a purely innate mechanism that does not require any product of an acquired immune response.

A

T.

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16
Q

Remember: All of the complement proteins are made constitutively and are always available in the circulation and in extravascular fluids throughout the body. These proteins are also constantly “turned-over” at a low rate.

A

Remember: All of the complement proteins are made constitutively and are always available in the circulation and in extravascular fluids throughout the body. These proteins are also constantly “turned-over” at a low rate.

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17
Q

The “turn-over” of C3 proteins results in the formation of what two protein fragments?

A

(1) the small fragment, C3a, which is an anaphylatoxin, and (2) C3b that has an exposed thioester bond that will cause it to bind covalently to the next thing it comes in contact with (unless the thioester bond is hydrolyzed first, which happens quickly).

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18
Q

What happens if the C3b binds to a pathogen (such as a bacterium)?

A

it becomes a ligand for factor B binding

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19
Q

What happens once factor B binds to C3b?

A

Once factor B has bound to C3b, it undergoes a conformation change that makes it susceptible to cleavage by factor D

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20
Q

What does cleavage of the factor B: C3b complex by factor D cause?

A

This cleavage results in formation of C3bBb, better known as the C3 convertase of the alternative pathway

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21
Q

What happens if the thirster bond on C3b binds to a host cell instead of a pathogen?

A

complement control proteins prevent activation of the complement pathway.

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22
Q

What happens once C3bBb forms?

A

Once C3bBb is formed, it becomes an active enzyme that can cleave many copies of C3 to C3b and C3a. Please keep in mind that each new copy of C3b is a new ligand for factor B binding. Therefore, this is an accelerating reaction because each of the primary products of the reaction, C3b, can be converted into an enzyme that catalyzes a reaction that produces more of that some primary product.

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23
Q

How is C5 convertase made?

A

C3bBb is also a ligand for C3b binding. The resulting product is C3b(2)Bb, better known as the C5 convertase enzyme. This enzyme initiates a sequence that results in formation of the membrane attack complex.

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24
Q

What is the first step in the formation of the MAC?

A

When a copy of C3 convertase (in this case the C3bBb of the alternative pathway) is bound by a copy of C3b, the resulting product (C3b2Bb) is the C5 convertase enzyme.

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25
Q

What does activated C5 convertase enzyme do?

A

Once this enzyme is formed, it will cleave any C5 proteins it engages with, resulting in a large fragment (C5b, the 1st component of the MAC) and a small fragment (C5a) that is a potent anaphylatoxin. In fact, C5a is a very important chemotactic factor for neutrophils.

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26
Q

MAC complex: What happens once C5b is generated?

A

it binds to one copy of C6 and one copy of C7 to form the C5b,6,7 complex.

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27
Q

What does the C5b,6,7 complex do?

A

This complex then inserts into membranes (outer envelope of bacteria, for instance). Once embedded in the membrane, C5b,6,7 becomes a ligand for C8 binding, and then 10-16 molecules of C9 bind to that complex forming a pore in the membrane. These pores cause osmotic disintegrity of the bacteria that results in its death.

28
Q

Important note on the lectin pathway of the complement pathway.Bacterial outer envelope (surface) glycoproteins and glycolipids have terminal mannose residues that are unique to bacteria (mammals do not make these structures).

A

Bacterial outer envelope (surface) glycoproteins and glycolipids have terminal mannose residues that are unique to bacteria (mammals do not make these structures).

29
Q

Lectin pathway: What protein binds to exposed mannose residues on the surface of bacteria?

A

Mannose binding protein (MBP)

30
Q

What happens once MBP binds to mannose not he surface of a bacteria?

A

Once bound, the MBP undergoes conformational changes that result in it becoming a ligand for binding by mannan-binding lectin-associated serum proteases, or MASP proteins (MASP-1 and MASP-2).

31
Q

What happens once MASP molecules bind to MBP?

A

Once MASP proteins bind to MBP, they become enzymatically active and are able to cleave copies of complement components C2 (to create a large fragment called C2a and a small fragment called C2b) as well as C4 (to create a large fragment named C4b and a small fragment called C4a).

32
Q

What happens when when C4b becomes bound by C2a?

A

the product is the C3 convertase of the classical pathway (C4bC2a). This enzyme can cleave many copies of C3.

33
Q

T or F. The classical pathway of complement activation involves antibodies, most of which are produced as a component of an acquired immune response.

A

T

34
Q

How is the classical pathway initiated?

A

This pathway is initiated when complement component C1 binds to antibody that is bound to its cognate antigen (like a bacterial surface structure). C1 has affinity for a region of the Fc portion of some antibody isotypes that becomes available for binding when the antibody is bound to its cognate determinant.

35
Q

Describe the composition of a C1 complement component.

A

Each C1 molecule is composed of six identical C1q “stalks” and 1 copy each of the serine proteases C1r and C1s.

36
Q

What happens to the structure of a C1 complement component when it binds to an antibody attached to a pathogen?

A

When a copy of C1 binds to antigen-engaged antibody(s), the C1r protein becomes enzymatically active and cleaves C1s. Once C1s is cleaved, it becomes enzymatically active and is able to cleave C2 and C4 proteins, initiating the classical complement cascade.know that C1 cleaves both C4 and C2, and the results of these cleavage events are the production of the C3 convertase of the classical cascade [C4bC2a] and anaphylatoxin [C4a]). C2b is not considered an anaphylatoxin, which is probably why the designation was changed to C2b.

37
Q

What does it mean for antibody isotypes to “fix” complement?

A

these antibodies have C1 binding sites in their Fc regions.

38
Q

What is the order of antibodies ability to fix complement?

A
  1. IgM (best) and IgG32. IgG13. IgG2, IgA1, IgA2Cannot fix (i.e. no C1 binding in the Fc region of the antibody): IgG4, IgD, and IgE
39
Q

Is why IgM such as efficient activator of the classical cascade?

A

Each secreted copy of IgM is a pentameric structure. When it binds to a multivalent antigen, the C1 binding site becomes available on multiple copies of the IgM Fc regions. This allows for the C1q stalks to bind to several of these Fc ligands simultaneously, causing a conformational change to C1 that initiates cleavage of C1s.In contrast, more than one copy of the monomeric antibody isotypes is required for activation of C1. Ask how many.

40
Q

Describe the initial steps of the classical cascade.

A

C1 has affinity for the Fc regions of some antibody isotypes (like IgM) when the antibody is engaged with its cognate antigenic determinant. When C1 binds to one copy of IgM or multiple copies of the other isotypes, C1r becomes active and cleaves C1s. Activated C1s cleaves C2 and C4, resulting in formation of the large fragments C2a and C4b, respectively. C4b binds to the pathogen surface, and is a ligand for C2a binding. The product of this binding is a copy of C4bC2a, which is the C3 convertase of the classical pathway. This complex can now cleave many copies of C3 to create the membrane-binding large fragment (C3b) and a small anaphylatoxin fragment (C3a).

41
Q

How is the C5 convertase of the alternative pathway made?

A

generated when a copy of C3b binds to the C3 convertase of the alternative pathway (C3bBb) to form C3b2Bb.

42
Q

How is the C5 convertase of the alternative pathway made?

A

formed when C3b binds to the C3 convertase of the classical pathway (C4bC2a) to form C4b2a3b.

43
Q

Note on interconnectedness of the three pathways.

A

It does not matter what the source of C3b is, it will be a ligand for factor B. Therefore, when either the lectin or classical pathway is activated, resulting in C3b deposition, those C3b molecules can be bound by factor B and converted into a copy of the C3 convertase of the alternative pathway. In an immunocompetent person, the alternative pathway always amplifies the other two pathways.

44
Q

What is an innate mechanism for activation of the classical pathway?

A

During septic bacterial infections, a protein known as C-reactive protein is produced in the liver and released into the circulation. CRP binds to phosphocholine residues that are found on the surface of bacteria (but not host cells). When CRP is bound to phosphocholine, it mimics an IgM molecule and becomes a ligand for C1 binding. When C1 binds, the classical pathway becomes active.

45
Q

What is the basis of opsonization?

A

Phagocytes such, as macrophages and neutrophils, express an array of complement receptors that allow them to recognize materials that have been opsonized with complement component C3b (or its various breakdown products).

46
Q

What is complement receptor 2 (or CR2)?

A

CR2 serves as a co-receptor for the B cell receptor. When it is engaged, it increases the signaling that results from B cell receptor binding to cognate antigen, decreasing the amount of costimulation signal needed from helper T cellsIn other words, when a foreign antigen that is recognized by a B cell is also labeled with complement opsonins, that is a pretty good sign that the antigen was derived from a pathogen because the complement cascade must have been initiated.

47
Q

Complement is an important component of the immune response because some bacterial pathogens have “learned” how to evade the immune responses that were designed to clear them. What are some of these mechanisms?

A

Bacterial pathogens that produce a capsule are almost impossible for phagocytes to recognize. The capsule encloses all other surface structures on the bacteria, and there are no phagocyte receptors that recognize capsular material.However, because phagocytes have complement receptors, they can recognize an encapsulated bacterium that has been labeled with C3b. When phagocytes recognize C3b, they phagocytize the material that C3b is bound to and destroy It.Phagocytes also have Fc receptors for IgGs and IgAs (there are no Fc receptors for IgM… important to remember). Antibodies also serve as opsonins because if a phagocyte recognizes antibody-”labeled” material, it phagocytizes the material and destroys it.

48
Q

What is the complement specificity of CR1?

A

C3b, C4bi (breakdown of C4b)

49
Q

What cell types express CR1?

A

erythrocytes, macrophages, monocytes, PMN leukocytes, B cells, FDCs

50
Q

Why do erythrocytes express CR1?

A

Small immune complexes, which consist of antigen that is bound by either antibodies, C3b, or both are not efficiently taken up by phagocytes. If they are allowed to build up in the circulation, they can cause vasculitis and kidney dysfunction. One of the important roles of erythrocytes is the transport of small immune complexes to the liver and spleen (blood filters that have many resident macrophages). Macrophages in these tissues remove these immune complexes from the RBCs and destroy them.

51
Q

Why must the complement pathways be tightly regulated?

A

The complement cascade is a positive feedback loop that continues to amplify itself (in the absence of regulation) until complement components are depleted.

52
Q

What are the ways in which the complement pathway is regulated?

A

(1) passive regulation and (2) active regulation.It is important to note that in an immunocompetent individual, these proteins are produced constitutively (meaning all of the time) and should always be available to regulate the complement cascade.

53
Q

What is the basis of passive regulation?

A

Passive regulation is the result of the rapid hydrolysis of the thioester bonds that are made available on the large fragments of C2, C3, C4, C5, and Bb following their cleavage. They must bind to something before they are hydrolyzed, or they become inert.

54
Q

What is the basis of active regulation?

A

Active regulation depends on the activity of several regulatory proteins, some of which are soluble, while the others are embedded on the surface of host cells.

55
Q

What is C1 inhibitor (C1INH) and how does with work?

A

an active regulation soluble/plasma proteinThis regulatory protein binds to activated C1r:C1s, forcing them to dissociate from C1q. This halts the cleavage of C2 and C4 proteins by that particular copy of C1, thus dampening the complement cascade.

56
Q

Inherited deficiency of functional C1INH results in what?

A

the overproduction of anaphylatoxins, resulting is a serious illness that is characterized by systemic edema. The name of this syndrome is hereditary angioneuotic edema, or HANE, and treatment is via replacement therapy (monthly injection of C1INH).

57
Q

What is C4 binding protein and how does with work?

A

an active regulation soluble/plasma proteinbinds to the C4b component of the classical pathway C3 convertase, causing a displacement of the C2a fragment and making the C4b fragment susceptible to cleavage by factor I, permanently disabling that copy of the C3 convertase enzyme.

58
Q

What is Factor H and how does with work?

A

binds to C3b, making it susceptible to cleavage by factor I. Once C3b is cleaved to form iC3b , it can no longer serve as a template for factor B binding (it is still important though!!- think C3 and C4 receptors), so that copy of C3b can never become part of a functional C3 convertase of the alternative pathway. Cleavage of the C3b component of the C5 convertase enzyme also deactivates that copy of C5 convertase.

59
Q

What is Factor I and how does with work?

A

the protease that cleaves C4b once C2a has been dissociated from it by C4-binding protein and it cleaves C3b that has been bound by factor H.essentially shuts down the C3 convertases

60
Q

What does deficiency of factor I cause?

A

Deficiency of factor I allows extended C3 convertase activity and for more production of C3 convertase of the alternative and classical pathways. Ultimately, this leads to depletion of C3, preventing activation of the complement cascades when they are really needed. Additionally, factor I deficiency prevents the formation of an important opsonin of complement, referred to as iC3b.

61
Q

What is Decay accelerating factor (DAF)?

A

a host cell membrane bound complement pathway regulation factorhas ability to dissociate C3 convertase enzymes. It is a critical complement control protein. You will also need to know that DAF is also designated as CD55

62
Q

What is MCP?

A

a host cell membrane bound complement pathway regulation factorshort for membrane co-factor protein, another membrane-bound protein on host cells. When MCP binds to either C3b or C4b, they become susceptible to cleavage by factor I. Therefore, this protein is important for shutting down C3 convertase activity.

63
Q

What is CR1?

A

complement receptor 1, is another membrane-bound protein that binds to C3b and C4b, making them susceptible to factor I cleavage.

64
Q

What is CD59, or protectin?

A

a protein that is found on the surface of host cells. This protein prevents membrane attack complex formation on host cells by binding to the C5b,6,7,8 complex and preventing C9 from binding to the complex.This protects host cells from MAC-mediated damage. There may be some extracellular pathogens that have adapted by producing a homolog of CD59, but most pathogens have no way to prevent MAC formation.

65
Q

What genetic disease results from the inability to produce a phosphoinositol glycolipid tail that anchors decay accelerating factor and CD59 (or protectin) into the membrane of host cells?.

A

paroxymal noctural hemoglobulinuria. These patients suffer periodic episodes of intravascular erythrocyte lysis

66
Q

What does factor P do?

A

stabilizes alternative C3 convertase

STEP Physiology (68 decks)

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