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Immunology (By: Ben + Dustin) > Lecture 3 (Dustin) - Complement System and Acute Phase Reaction > Flashcards

Lecture 3 (Dustin) - Complement System and Acute Phase Reaction Flashcards

1
Q

What are the 3 pathways to complement activation?

A
  1. Classical Pathway: induced by antigen:antibody complexes
    2: Mannose-binding Lectin Pathway: Lectin binds to Mannose/carbs on bacterial surface
    3: Alternative pathway: spontaneous hydrolyzation of C3 into C3a and C3b. (lecturer says it’s medically the most important pathway)
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2
Q

What are the 3 main effects of complement activation?

A
  1. Recruitment of inflammatory cells
  2. Opsonization of pathogens
  3. Killing of pathogens (via membrane attack complex)
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3
Q

Is the complement system mainly effective against extracellular or intracellular pathogens?

A

Extracellular (bacteria, fungi, protozoa)

It belongs to humoral system, complement proteins floating through bloodstream and lymph

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4
Q

Is the complement system part of innate or acquired immunity? How ancient is it?

A

Innate immunity, and it’s very ancient / highly conserved

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5
Q

In what form do elements of the complement system circulate?

A

In inactive/proenzyme form. They activate each other and initiating a cascade of reactions via serine protease rxns. Each active component activates the next one -> amplification

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6
Q

Which part of the complement system takes part in opsonization?

A

C3b fragment

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7
Q

Which parts of the complement system stimulate inflammatory cells?

A

C3a and C5a. Release chemoattractants for inflammatory cells. Also triggers degranulation of granulocytes/mast cells. With mast cells -> histamine -> increase blood vessel permeability, chemotactic attraction of phagocytes, etc.

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8
Q

Which parts of the complement system form the membrane attack complex (MAC)?

A

C5b, C6, C7, C8, C9

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9
Q

Of the C3 fragments, which is the bigger one?

What enzyme performs the cleavage?

A

C3b is bigger, C3a is smaller

C3 convertase cleaves C3

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10
Q

What is the first step of the classical complement activation pathway?

A

C1 binds to the antigen:antibody complex

IgM type antibody most effectively binds to C1, but IgG3 and IgG1 can also do this

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11
Q

What part of C1 binds to antibodies? In what order

A

C1q binds to IgM or IgG

C1r and C1s are proteolytic (have enzyme activity). After C1q binds, C1r and C1s can bind too.

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12
Q

What does C1s do?

A

It has two substrates:
1. converts C4 into C4b and C4a

  1. converts C2 to C2b and C2a
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13
Q

What, most importantly, do the fragments of C2 and C4 do?

A

C2b + C4b = Classical C3 convertase

Converts C3 -> C3a and C3b (the central functioning molecules of complement system)

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14
Q

How does mannose-binding lectin (MBL) lead to complement activation?

A

Bacteria have a lot of carbs, and mannose-binding lectin is functionally similar to C1q that binds to bacterial carbs instead of antibody:antigen complexes. Then it binds to MASP1 and MASP2 (mannose-binding serine protease). This leads to same effect of C2bC4b (C3 convertase)

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15
Q

How does the alternative pathway to complement activation occur?

A

Because we have so much C3 in our blood (almost as much as IgG), a small fraction of it spontaneously hydrolyzes into C3b and C3a. C3b will bind to pathogens it encounters, and then it also binds factors Bb and D, making an alternative C3 convertase (causing amplification loop, pos feedback)

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16
Q

In which gene region are all the elements of C3 convertases located?

A

MHC III gene region

The MHC region is one of the most important genetic regions of the genome, highly conserved

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17
Q

What takes place in the enzymatic shift towards late events of complement activation?

A

Complexes shift specificy from C3 to C5 (begins C5 convertase activity)

The two C5 convertases are:
C4b2a3b
C3bBb3b

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18
Q

What does C5b do?

A

Binds C6, which binds C7, that binds C8, then a lot of C9s… these form the Membrane Attack Complex (MAC). These can poke a hole in the membrane of pathogens.

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19
Q

What type of bond do C3b fragments make when they opsonize pathogens?

A

(Strong) Covalent bonds: thioester

Sticks with them for as long as they live, helps macrophages with complement receptors to eat them

20
Q

What are some local inflammatory cytokines that are related to C3a/C5a release?

A

IL-1, IL-6, TNF-alpha

21
Q

How long does it take for complement activation to occur?

A

Microseconds, very fast

22
Q

What crucial role does the complement system have for B cells?

A

C3d-binding with Complement Receptor 2 (CR2) is essential for B cell activation (will be mentioned later in lecture on B lymphocytes) - this is a role of complement in the adaptive immune system

23
Q

What is the role of complement receptor 1 (CR1)?

A

CR1 on macrophages binds to the C3b fragment on opsonized pathogens, helps them to phagocytose

24
Q

What portion of IgG or IgM can C3b bind?

A

The Fc portion

25
Q

Why would complement receptors eliminate immune complexes? Seems contradictory

A

Complement prevents immune complexes of antibodies and antigens from becoming huge aggregates, which could be a circulation problem. Complement makes them more soluble.

26
Q

What role do erythrocytes play with the complement system?

A

Erythrocytes have CR1 receptors and can carry immune complexes of C3b, antibody, and antigen to areas with macrophages, such as the liver or spleen

27
Q

What are the 3 levels at which the complement system is regulated?

A
  1. Inhibition of C1 (initiation control)
  2. Regulation of C3 convertase
  3. Regulation of MAC
28
Q

How does C1 inhibitor work?

What disease occurs without C1 inhibitor?

A

Dissociates C1r and C1s. C1s can then not cut C2 and C4.

No C1 inhibitor -> hereditary angioedema (he calls it HANO)

29
Q

What are some things that displace C2b from C4b, thereby inhibiting C3 convertase?

A

DAF, MCP, and CR1

MCP also acts as cofactor for Factor I-mediated proteolytic cleavage of C3b

30
Q

What inhibits the complement system at the level of the membrane attack complex?

A

CD59 inhibits Poly-C9 assembly (final step)

31
Q

What might occur with poor membrane attack complex function?

A

Recurrent Neisseria infections

32
Q

What is the aim of the acute-phase reaction?

A

To eliminate the injury and start the process of repair

(Was not clear at all in the lecture, but acute phase rxn inhibits and localizes inflammation, and decrease its consequences)

33
Q

In the case of local inflammation, how long does it take for:

  1. vasodilation?
  2. increased capillary permeability (plasma exudation)?
  3. inflammatory cells to arrive / extravasation?
A
  1. vasodilation: minutes
  2. increased cap permeability: minutes
  3. inflammatory cells arrive: can take hours
34
Q

6 “inputs” that are used to initiate the EARLY acute phase rxn

A 
PAF (platelet activating factor
TXA2
MCP (monocyte chemoattractant protein)
TGF beta
IL-1
Complement fragments: C3a, C4a, C5a
35
Q

In the middle “alarm” stage of the acute phase rxn, what types of cells secrete cytokine signals?

A

All over body: Macrophages, T cells, endothelial cells, even fibroblasts and keratinocytes

36
Q

What is the most important cytokine to know for the middle “alarm” stage of the acute phase rxn? What are some others?

A

IL-6 is the most important

Also note IL-1, TNF alpha, IFN gamma

37
Q

What is the major target of IL-6 and other inflammatory cytokines? What is the minor target?

A

Major target is the liver (producer of acute phase proteins)

Minor target is the hypothalamic-pituitary-adrenal gland axis

38
Q

What is the effect of IL-6 on the hypothalamic-pituitary-adrenal axis?

A

It’s stimulatory/stress inducing, so it stimulates the hypothalamus to produce CRF, the pituitary gland to produce ACTH, and the adrenal glands to produce cortisol.

Cortisol is an important endogenous anti-inflammatory molecule (note: the acute phase reaction silences systemic inflammation)

It also causes the hypothalamus to induce fever and decreased appetite

39
Q

Acute phase proteins: what are the protease inhibitors?

A

alpha 2 macroglobulin

alpha 1 antitrypsin

40
Q

Acute phase proteins: which complement elements are produced?

A

C3, factor B, C1inhibitor

41
Q

Acute phase proteins: which coagulation factors are produced?

A

fibrinogen - probably the others too but they aren’t mentioned on slide

42
Q

Acute phase proteins: what are the opsonins?

A

C3, CRP (C reactive protein), mannose binding lectin, SAA (serum amyloid A), SAP (serum amyloid protein)

43
Q

Acute phase proteins: what are the radical catchers/ removers?

A

Ceruloplasmine (ferroxidase enzyme), Albumin, SAA,

44
Q

During acute phase reaction, about how much is the increase in concentration of CRP and SAA?

A

100-1000x

these are good biomarkers of acute phase rxn, especially CRP. increase in concentration occurs very quickly too

45
Q

Which proteins are marked by decreased concentration during the acute phase rxn?

A

Transferrin, fibronectin, and albumin

Immunology (By: Ben + Dustin) (12 decks)

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