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Immunity Week 1 > ICL 3.3: Complement Diseases > Flashcards

ICL 3.3: Complement Diseases Flashcards

1
Q

what are the three consequences of the complement system?

A
  1. chemotaxis/inflammation
  2. opsonization/phagocytosis/immune response = pathogen killing/housekeeping
  3. MAC formation = lysis
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2
Q

what is the initiating molecule of the lectin pathway?

A

MBL

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3
Q

what’s the initiating molecule of the classical pathway?

A

C1q

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4
Q

what contributes to action of the alternative pathway of complement?

A

spontaneous hydrolysis of C3 or C3b from the other pathways

lack of regulation also contributes to activation of the alternative pathway of complement

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5
Q

deficiency of which complement proteins leads to SLE?

A

C1q
C1r/s
C4
C2

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6
Q

deficiency of which complement proteins leads to encapsulated bacterial infections?

A

C1q
C1r/s
C4
C2

defective opsonization

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7
Q

what is SLE?

A

systemic lupus erythematosus

defective elimination of immune complexes

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8
Q

what does a MBL deficiency cause?

A

increased susceptibility to bacteria infections

especially in infants

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9
Q

what does factor D deficiency cause?

A

meningococcal and encapsulated bacterial infections

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10
Q

deficiency of which complement proteins leads to meningococcal infections?

A

C5, C6, C7, C8 or C9

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11
Q

what does deficiency in C3 cause?

A

susceptible to all pyogenic infections

SLE

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12
Q

do our dead/dying cells activate complement?

A

yes!

when a cell starts to undergo apoptosis, they down regulate complement regulatory proteins on the cell surface

they down regulate them just enough to allow for sufficient opsonization so that the cells can be phogocytosed but not enough so that MAC gets generated or else you’d get autoimmune disease

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13
Q

deficiency of early components of classical pathway (C1q, C1r/s, C4, C2), as well as autoantibodies against complement proteins predisposes us to…?

A
  1. autoimmune disease due to increase of dangerous autoantigens.

autoimmune diseases are triggered because the dead/dying cells can’t be removed and they transition into necrotic cells that release dangerous antigens into our blood

  1. immune complex diseases
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14
Q

what is SLE caused by?

A

antibodies against multiple autoantigens – most common is anti-dsDNA

deficiency of initial CP proteins (C1q,r,s; C4, C2) also predisposes to SLE (as well as autoantibodies against C1q)

SLE is the most prevalent immune complex disease

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15
Q

is SLE more common in men or women?

A

women

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16
Q

what are the two most common symptoms of SLE?

A
  1. glomerulonephritis

2. arthritis

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17
Q

what are the symptoms of SLE?

A
  1. glomerulonephritis
  2. arthritis
  3. vasculitis
  4. butterfly rash
  5. small immune complexes get trapped or formed in tissues (e.g. kidney, sinovial tissue and joints) –> activation of complement –> tissue injury to kidney or joints
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18
Q

which complement protein is the most abundant?

A

C3

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19
Q

what does C3 do?

A

plays an important role in the clearing of infections as it is involved in cytolysis, increased vasopermeability, opsonization, clearance of immune complexes and facilitation of B cell proliferation and differentiation

20
Q

what happens when there’s a C3 deficiency?

A

C3 plays an important role in the clearing of infections

so individuals lacking C3 are highly susceptible to all pyogenic infections (recurrent, systemic)

they also frequently suffer from immune complex-related disorders, such as glomerulonephritis and SLE

this disorder is hella rare, there’s only 23 families with it

21
Q

what causes C3 deficiency?

A

mutations in the C3 gene which lead to absence/markedly reduced levels, or dysfunction of the protein

22
Q

what does CD59 do?

A

it’s regulatory protein that inhibits the actions of C8 and C9

this means that MAC can’t form

23
Q

what can lead to increased susceptibility to Neisseria?

A

aka meningitis and gonorrhea

genetic deficiency in C5, C6, C7, C8, C9, and factor D, and properdin leads to increased susceptibility to Neisseria

this can lead to DISSEMINATION of gonococcal infection –> septic arthritis –> meningitis

24
Q

C1-INH deficiency causes which disease?

A

hereditary angioedema (HAE)

25
Q

properdin deficiency causes which disease?

A

meningococcal infection

26
Q

factor I deficiency causes which diseases?

A
  1. susceptible to all pyogenic bacterial infections (~C3 deficiency)
  2. atypical hemolytic uremic syndrome (aHUS)
27
Q

factor H deficiency causes which diseases?

A
  1. aHUS

2. membranoproliferative glomerulonephritis

28
Q

CD59 and CD55 (DAF) deficiency causes which disease?

A

Paroxysmal nocturnal hemoglobunuria (PNH)

29
Q

what does C1INH stand for? what does it do?

A

C1 inhibitor

C1INH dissociates C1r and C1s from the active C1 complex

30
Q

what is HAE?

A

hereditary angioneurotic endema

it’s a C1INH deficiency – C1INH restricts how long C1 stays active

C1NH deficiency leads to activation of serine proteases that are normally inhibited by C1INH

this results in chronic spontaneous complement activation and excess cleavage of C4 and C2

C2a is further cleaved into C2 kinin

lack of inhibition of a related plasma protease, bradykinin, also occurs which only increases the swelling more

31
Q

what are the symptoms of HAE?

A

extensive and reoccurring edema – dangerous if swelling occurs near trachea

recurrent attacks of skin, laryngeal and intestinal edema

edema in the GI tract = severe abdominal pain and vomiting and diarrhea

patients are NOT susceptible to infection because the alternate pathway is still intact

32
Q

how do you treat HAE?

A

replace C1INH

medicine: CINRYZE

33
Q

HAE is the deficiency of what?

A

C1INH

34
Q

what is PNH?

A

PNH = paroxysmal nocturnal hemoglobinuria

increased intravascular hemolytic anemia and increased incidence of deep vein thrombosis

RBCs and platelets have increased sensitivity to complement-mediated lysis

35
Q

what causes PNH?

A

somatic mutation in PIGA gene in a hematopoietic stem cell clone

this leads to a deficiency in gpi-anchored proteins, including complement regulators like DAF (CD55), CD59 (MAC inhibitor)

36
Q

what is the hallmark symptom of PNH?

A

super dark urine in the morning

37
Q

what test do you do for PNH? what will the results be?

A

HAM test = acid serum lysis test

PNH RBCs will lyse way more than normal RBCs

during the night, pH drops and the coverts of the alternative pathway are more stable and since the mutated PNH RBCs lack regulation, they become more susceptible to complement mediated lysis during the night time

38
Q

how do you cure PNH?

A

BM transplant is the only cure

39
Q

how do you treat PNH?

A

Eculizumab = anti-C5 antibody

it inhibits C5 activation

if you block C5, you can’t form MAC and then you won’t lyse the RBCs

patients should be concomitantly vaccinated with the meningococcal vaccine as well as vaccines to prevent Strep pneumoniae and Haemophilus influenza type b

40
Q

what is HUS?

A

diarrhea-associated form of HUS

caused by toxins from bacterial infections like e. coli

not hereditary

41
Q

what is aHUS?

A

the non-diarrhea form = atypical

caused by congenital mutations in factor H, factor I, CD46 (MCP), factor B, C3

C3 deposits indicate complement activation in the kidney

lack of cell surface protection by factor H –> endothelial cell damage, microthrombosis, hemolysis, kidney failure –> uremia, anemia, fatigue

42
Q

what is the prognosis for aHUS?

A

pretty poor

50% mortality

43
Q

what is the treatment for aHUS?

A
  1. kidney transplant
  2. plasma exchange to elevate factor H levels
  3. Eculizumab (anti-C5 antibody)
44
Q

how does the complement system remove immune complexes?

A

ICs are produced wherever there is an antibody response to a soluble antigen

these are normally eliminated when complement receptor CR1 on RBCs binds to IC via bound C3b

however, certain pathological situations just generate too many ICs!!!!

and no matter how hard complement is working, it can’t get rid of them fast enough

45
Q

what happens during autoimmune hemolytic anemia?

A

there are auto-antibodies against RBCs which are IgM or IgG

this causes hemolysis of RBCs that is complement mediated or Fcγ receptor mediated

46
Q

what is the CH50 assay?

A

tells you the general CP activity

classical pathway-mediated hemolysis of IgG-coated sheep RBCs due to complement activity in the patient serum

sheep RBCs have high content of sialic acid (protected from the alternative pathway by factor H) Antibodies will trigger the classical pathway only

measures combined activity of: any complement component or regulator that influences classical pathway activity

47
Q

what is the AP50 assay?

A

tells you the general activity of the alternative pathway

alternative pathway-mediated hemolysis of rabbit RBCs

rabbit RBCs have low content of sialic acid (not efficiently protected from the alternative pathway by factor H); no membrane-bound regulators. Only AP will activate (no antibodies present)

measures combined activity of: any complement component or regulator that influences alternative pathway activity

Immunity Week 1 (14 decks)

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