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Immunology: Research + Clinic > HC5: Regulation of the complement system in health and disease > Flashcards

HC5: Regulation of the complement system in health and disease Flashcards

HC5

1
Q

In which stages of immune response is the complement involved?

A

All stages, and after it

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2
Q

Complement system is a ….

A

Protein cascade

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3
Q

Stages immune response

A
  • Prevention infection: containment by anatomic barrier
  • Innate phase, recognition and removal by nonspecific effectors
  • Recruitment effectors, PAMP recognition and effector cells and inflammation activation
  • Transport antigen to lymphoid organs > recognition by naive B and T cells and clonal expansion and differentiation.
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4
Q

Central protein in complement

A

C3

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5
Q

Is C3 abundant in blood?

A

Yes, important protein
> all complement proteins are in blood

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6
Q

Complement factors when inactive: how do we call this kind of molecule?

A

Zymogens
> inactive proteases activated through a modification like cleavage
> snowball effect: cleavage leads to activation

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7
Q

How to distinct C3a from C3b and C5a from C5b etc

A

CXa: small part after cleavage
CXb: large part after cleavage

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8
Q

Complement is quick and deathly. Explain with Human B-cells from lymphoma in vitro

A

Human B-cells can be opsonized with anti-CD20 > attack by complement in vitro with human serum
> experiment at 24 degrees otherwise to fast at 37 degrees
> takes less than minute
> some tumor cells not affected in vitro: mutated and escape

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9
Q

Why is it important that the complement reaction is fast?

A

In mainly targets bacteria, which replicate fast, so quick response needed

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10
Q

Complement involves which cells?

A

No cells, only proteins
> an always active defense system in blood

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11
Q

Complement 3x3=9

A
  • 3 ways of activation
  • leads to C3 cleavage
  • 3 main effector functions
  • Ends with C9
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12
Q

Stages of complement action

A
  • Pattern recognition trigger
  • Protease cascade amplification / C3 convertase
  • Inflammation, phagocytosis and membrane attack
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13
Q

3 ways of complement activation

A
  • Lectin pathway
  • Classical pathway
  • Alternative pathway
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14
Q

Complement: innate and aspecific: why

A

Everything gets attacked, and the response of it determines if it gets eliminated

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15
Q

Lectin pathway complement

A
  • Mannose Binding Lectin (MBL) binds mannose rich surface of microbe
  • The MBL-Associated Serine Protease 1 (MASP-1) auto-activates (on MBL)
  • MASP-1 activates MASP-2, also associated with MBL
  • MASP-2 activates complement cascade: cleave C4 to C4a and C4b
  • C4b binds to microbial surface
  • C4b binds C2, which gets cleaved by MASP-2 to C2a and C2b
  • C2a joins C4b > C4b2a
  • C4b2a is an active C3 convertase: cleave C3
  • C3b binds to microbial surface or forms complex to C4b2a3b
  • cleave up to 1000 C3 proteins
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16
Q

Classical pathway complement

A
  • C1q binds Fc tails of antibodies bound to antigen
  • C1q is associated with C1r and C1s, and C1r auto-activates upon binding Ab
  • C1r activates C1s
  • C1s activates complement cascade of C2 and C4
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17
Q

C1q and antibody association

A

Antibodies form a platform
> Fc tail platoform of antibody hexamerisation to bind C1q
> Also by IgM penta and hexamers
> one of the Fab arms does not bind pathogen to form horizontal platform of Fc tails

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18
Q

IgM best complement activator

A

As pentamer, make platform for C1q

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19
Q

Importance hexamerization of the IgG antibodies

A

Specific amino acids involved in platform
> mutations induced: improve or weaken complement response in therapy

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20
Q

Is there a confirmed pattern recognition molecule for the alternative pathway of complement?

A

No

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21
Q

C3 tick-over

A

In alternative pathway, spontaneous autoactivation by C3 hydrolysis to C3(H2O) (C3 is slightly unstable)

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22
Q

Alternative pathway self-amplification loop

A

C3(H2O) binds Factor B (FB)
> Factor D (FD) cleaves FB: [C3(H2O)Bb] (C3 convertase)
> Bb activates more C3 to C3b (and C3b binds to a cell surface)
> C3b binds FB
> FD cleaves FB: [C3bBb] (C3 convertase)
> etc.

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23
Q

Is the self-amplification loop of complement specific for alternative pathway?

A

No, can also be from C3b of classical or lectin pathway
> any C3b activates amplification via AP

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24
Q

Why does C3b bind to cell surface?

A

Thioester bond in C3 normally hidden but exposed in C3b > pressed downwards and outwards > react with surface with covalent bond (not easily removed)

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25
Q

What happens when C3 convertase has made enough C3b and C3a?

A

It changes into a C5 convertase through specificity changes

26
Q

3 effector functions complement

A
  • C3a and C5a (anaphylatoxins) recruit phagocytic cells to site of infection and promote inflammation
  • Phagocytes with receptors for C3b engulf and destroy pathogen: opsonization
  • Lysis: completion complement cascade leads to formation membrane-attack complex (MAC) whcih disrupts cell membrane and causes lysis
27
Q

Lysis complement

A

Formation MAC
> leakage of cell
> cell dies because it cannot survive with little resources

28
Q

MAC formation

A

C5b binds C6 and C7
C5b67 bind membrane via C7
C8 binds to complex and inserts into cell membrane
C9 molecules bind to complex and polymerize to form pore in membrane
» MAC complete: efflux contents of cell

29
Q

Marker for lysis through MACs

A

Calcium influx
> triggers apoptosis

30
Q

Mitochondria marker for lysis

A

No fluorescence when GFP marked> cell dies

31
Q

Order of cell death markers when cell complement lysis

A

Calcium influx, impermeable DNA staining, mitochondria stop fluorescencing

32
Q

Neutrophils react strongly to which anaphylatoxin?

A

C3a

33
Q

Which complement factors boost phagocytosis?

A

Opsonins
> C3b and C4b

34
Q

Why is opsonization so important by complement?

A

Many pathogens can escape lysis through physical barriers

35
Q

How do immune cells recognize complement for phagocytosis (opsonins)

A

Complement receptors
> 4 different complement receptors in total for all functions

36
Q

Simultaneous effects complement

A

Opsonization and lysis can be induced at same time > phagocytosis while MAC formation and effect

37
Q

How do immune cells recognize anaphylatoxins

A

Receptors
> C3aR, C5aR, C5aR2

38
Q

Which immune cells are recruited by anaphylatoxins?

A

Neutrophils
Macrophages
Monocytes
DCs.

39
Q

Other effects anaphylatoxins beside recruitment immune cells?

A
  • Vasodilation by endothelium
  • Cytokine release by immune cells
40
Q

How to deal with unwanted complement to prevent killing and tissue damage

A

Complement regulators are made by human cells which inactivate complement
> alternative pathway results in some complement on all encountered cells, but amplification does not go through because of these regulators

41
Q

Complement regulators: where?

A

Membrane bound or soluble

42
Q

Complement regulator deficiency

A

When one regulator is deficient
> sickness
> all regulators are essential

43
Q

Can you live without complement regulator Factor H (FH)?

A

No

44
Q

Important complement regulators and ligands

A
  • Factor H: C3b by displacing Bb and cofactor for Factor I
  • Factor I: C3b, C4b > protease for both
  • CD59 (last resort): prevent lysis by blocking MAC formation through C8
    » C3 is central: most important regulators act on C3 convertase
45
Q

How do complement regulators work: regulation of C3b

A
  • Faster decay of C3bBb complexes (DAF/CD55)
  • Prevent new FB from binding
  • Act as cofactor for factor I (MCP/CD46)
    » Factor H (FH) and Complement Receptor 1 (CR1/CD35) can do all of above
46
Q

Name some membrane bound complement regulators

A

FH, FI, CD46/MCP, CD55/DAF, CD35/CR1

47
Q

Domains of FH

A

Host surface binding domains and Complement regulation domain

48
Q

Factor I functions

A
  • Degrade C3b and C4b
  • Breakdown C3b to C3dg via iC3b with help of FH and CR1
  • C3dg is recognized by immune system
    » A lot of C3dg can still trigger immune system to kill
    » iC3b and C3dg can still signal complement receptors on immune cells as opsonins
    » but: no activation of amplification system and rest of complement
49
Q

Complement paradox

A
  • Excessive regulation and insufficient activation: cancer and infections
  • Insufficient regulation and excessive activation: autoimmune disease, hemtological diseases, kidney diseases
    » balance important
50
Q

Complement in Alzheimers Disease

A

Can amplify the damage
> damage leads to activation leads to damage: cycle

51
Q

Complement in therapy

A

Can help or interfere therapy

52
Q

Paroxysmal Nocturnal Hemoglobinuria (PNH) and involvement complement

A

Genetic defect in RBC (red blood cell) progenitor
> PIGA mutation: no GPI anchors
> Urine is red after night: hemoglobin in urine
» attacks: in morning because no regular urination
> GPI anchors is way to put proteins on membranes: two complement factors are put on cell via GPI anchors
> No CD55 and CD59 regulators on RBC surface (CR1 and FH have some control though)
> causing hemolysis: intra and extravascular
> one MAC is enough to lyse RBC
> also opsonized by complement for phagocytosis by macrophages in spleen and liver
> removal through urine

53
Q

Treatment PNH

A

RBC transfusion each 120 days

54
Q

CHAPLE syndrome

A

Deficient CD55 gene
> inflammatory bowel
> hyperactivation complement
> protein loss through intestine because damage
> angiopathic, thrombosis, protein-losing enteropathy
> variable and unknown disease
> Low IgG
> Carriers have lower CD55 expression but no symptoms
> Homozygous: no CD55

55
Q

Atypical Hemotlyic Uremic Syndrome (aHUS)

A

Glomeruli of kidneys very sensitive to complement
> network blood vessels for ultrafiltration blood
> a lot of blood and complement passes
> C3b on glomeruli: damage
> Factor H impaired: auto-antibodies against FH, mutation FH or in FH associated proteins
» some C3 mutations: C3 gain of function possible: less regulation
> FH is main protector glomeruli
> Impaired C terminal part of FH: cannot bind to human cells well

56
Q

Homozygous FH deficient patients

A

Cannot live
> Heterozygous: aHUS

57
Q

Complement hemolytic assay

A

Human serum tested with sheep RBCs for complement mediated lysis for classical pathway
> sheep RBCs: also sialic acid: FH can bind

58
Q

Autoimmune hemolytic anemia (AIHA)

A
  • Antibodies against own RBCs: auto-antibodies
  • Mainly IgM or IgG > agglutination of RBCs > thrombi > painful and anemia
  • Autoimmune disease often involve complement
  • Mostly in winter: agglutination of antibodies more when cold: more thrombosis in extremities with these patients: painful
59
Q

Complement inhibition therapy: risks

A

Is a risk, for N. meningitidis infections for example for anti-C5
> side effects of anti-C5: infection young children and eldery with meningococcus

60
Q

Eculizumab

A

For PNH patients
> Inhibit C5 convertase
> No C5a: no phagocyte influx and inflammation
> No C5b: No MAC mediated lysis
> benefit for patients
> side effects easily managed by vaccination and antibiotics

61
Q

Problems eculizumab

A
  • Very expensive life-long treatment
  • C3b deposition is unaffected
  • Opsonophagocytosis intact: extravascilar hemolysis
62
Q

CHAPLE therapy

A

Anti-C5 > eculizumab

Immunology: Research + Clinic (7 decks)

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