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Immunology > Complement System & Deficiency > Flashcards

Complement System & Deficiency Flashcards

1
Q

What is complement system?

A

A plasma protein cascade

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2
Q

Complement proteins >>> Functions

A
  • Chemotaxis
  • Opsonisation
  • Cell lysis
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3
Q

What is the ultimate product of complement system, once it is trigerred?

A

MAC (Membrane Attack Complex)

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4
Q

Function of MAC (Membrane Attack Complex)

A

It goes to the pathogen >>> creates pore in the cell membrane >>> exposure of “highly osmolar intracellular milieu’ to extra-cellular fluid >>> osmotic cell lysis

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5
Q

Pathways of complement system

A
  • Classic pathway
  • Alternative pathway
  • Lectin-binding pathway
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6
Q

Describe the complement system

A
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7
Q

What is the common meeting point of all three pathways?

A

All creates C3 convertase >>> that cleaves c3 into >> c3a and c3b

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8
Q

What is the final common pathway of complement cascade?

A

C5b-9 (MAC= Membrane Attack Complex) >>> pore formation >>> osmotic cell lysis

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9
Q

Structure of MAC

A

Rosette-like structure

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10
Q

Describe step-wise classical pathway

A

Antigen-antibody (IgG, IgM) complex activates the pathway >>> C1q binding >>> helps in C1r to C1s activation (activation of C1, qrs complex) >>> It acts upon C4 and C2 >>>

  • C4 breaks into C4a and C4b
  • C2 breaks into C2a and C2b

​>>> formation of C4b,2a (C3 convertase) >>> cleaves C3 into C3a and C3b

  • C3a helps in degradation of mast cells (inflammation)
  • C3b binds to (CBb3b from alternative pathway & C4b2a from classical/lectin pathway) >>> forms C3bBb3b and C3b4b2a >>> they act as C5 convertase >>> cleaves C5 in to C5a & C5b >>> C5b binds to C6,7,8,9 >>> forms C5b,6,7,8,9 (= MAC = Membrane attack complex) >>> MAC causes osmotic cell lysis via pore formation
  • Also, C3b helps in opsonisation
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11
Q

Describe step-wise Lectin pathway

A

Mannose binding lectin (MBL), Ficolins, Collectin-11 >>> Mannose (Sugar residue) on pathogen surface >>> activates mannose associated serine protease (MASP-1 & 2) >>> then, homologus to classical pathway

MASP acts upon C4 and C2 >>>

  • C4 breaks into C4a and C4b
  • C2 breaks into C2a and C2b

​>>> formation of C4b,2a (C3 convertase) >>> cleaves C3 into C3a and C3b

  • C3a helps in degradation of mast cells (inflammation)
  • C3b binds to (CBb3b from alternative pathway & C4b2a from classical pathway) >>> forms C3bBb2b and C3b4b2a >>> they act as C5 convertase >>> cleaves C5 in to C5a & C5b >>> C5b binds to C6,7,8,9 >>> forms C5b,6,7,8,9 (= MAC = Membrane attack complex) >>> MAC causes osmotic cell lysis via pore formation
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12
Q

Describe step-wise alternative pathway

A

It recognises bacterial, fungal cell wall or its associated molecular pattern >>> spontanueous hydrolysis of C3+H2O >>> deposition of C3b+H2O on pathogen surface >>> C3b+H2O binds to factor B >>> C3bB >>> Factor D acts upon B and divides into Ba & Bb >>> C3bBb acts as C3 convertase (with properdin) >>> cleaves C3

>>> into C3a and C3b

  • C3a helps in degradation of mast cells (inflammation)
  • C3b binds to (CBb3b from alternative pathway & C4b2a from classical pathway) >>> forms C3bBb2b and C3b4b2a >>> they act as C5 convertase >>> cleaves C5 in to C5a & C5b >>> C5b binds to C6,7,8,9 >>> forms C5b,6,7,8,9 (= MAC = Membrane attack complex) >>> MAC causes osmotic cell lysis via pore formation
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13
Q

For the complement cascade what are the specific inhibitors & where do they inhibit?

A
  • C1 inhibitor inhibits the activation of C1 complex
  • C4BD, CD46, CR1, DAF, Factor I inhibit C4b2a (C3 convertase of classical and lectin pathway)
  • C1 inhibitor, CR1, DAF, Factor H inhibit C3bBb (C3 convertase) of alternative pathway
  • CD46, CR1, CR2, DAF, Factor H, Factor I, MCP inhibit C3b
  • CD59 (MIRL = Membrane inhibitor of reactive lysis) >>> inhibits MAC (Membrane Attack Complex)
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14
Q

Antibodies to activate complement pathway

A
  • IgG, IgM activate classical pathway
  • IgA can activate alternative pathway
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15
Q

What are the role of those specific inhibitors of complement cascade?

A

They are present in soluble form OR membrane-bound form.

Their role is to naturally protect self cells and tissues from unwanted complement activation

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16
Q

Give an example where specific inhibitor for complement cascade is absent?

A

Paroxysmal noctural Haemoglobinuria (PNH)

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17
Q

What is the defect in PNH (Paroxysmal noctural haemoglobinuria)?

A
  • Post-translational modification
  • Haemolysis: ↓GPI → ↓binding of DAF (CD55) to cell membrane → ↓decay of complements/ ↓complement regulation → ↑sensitivity of cell membranes to complement → MAC (C5b, C-9) attacks red cells → intravascular haemolysis
  • Thrombosis: ↓GPI → ↓binding of MIRL (CD59) → Platelet aggregation → ↑venous thrombosis
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18
Q

When the pathways are activated?

A

During infection (bacterial, viral, fungal)

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19
Q

Which pathway is predominant?

A

Unlikely for any of them

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20
Q

Which pathway is most recently evolved?

A

Classic pathway

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21
Q

Which pathway does require antibody for activation?

A

Classic pathway

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22
Q

How does lectin and alternative pathway get activated?

A

By binding directly to polysaccaride components of cell walls of bacteria and yeasts

In Lectin pathway:

MBL (Mannose binding lectin), Ficolins, Collectin-11 >>> binds with mannose (sugar residues) on pathogen surface

In Alternative pathway:

It recognises bacterial, fungal cell wall OR directly pathogen associated molecular pattern

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23
Q

Progress of complement cascade

A
  • The complement cascade slowly ticks over (never completely inactive) >>> produces ‘small quantities’ of active compliment components
  • Postive feedback loops would be triggered and cause immune complex activation (If it were not important regulatory components)
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24
Q

What are the 3 main effects of ‘biologically active’ 3 complement products?

A
  • Opsonisation (C3b)
  • Chemotaxis and Inflammation (C3a, C5a)
  • Cell lysis (MAC)
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25
Q

Which type of disease does need measurement of complements C3, C4?

A

Where complement activation is occuring

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26
Q

Diseases associated with hypocomplementaemia OR

Disease associated with low complement levels OR

Diseases where we need to measure complement levels

A
  • SLE (Systemic Lupus Erythematosus)
  • Mesangiocapillary GN
  • Chronic infections (e.g. endocarditis. quartan malaria)
27
Q

Depletion of C3, C4 >>> suggests what?

A

Immunologically driven disease

28
Q

Complement deficiencies: Inheritance

A

Most are AR (Autosomal Recessive)

Except Properdin deficiency (X-linked recessive)

29
Q

C1q deficiency >>> results

A

SLE (Systemic Lupus Erythematosus) (in >90% patients)

30
Q

A risk factor (complement-cascade related) for SLE?

A

Inherited C1q deficiency

(we can find low complement levels: C3, C4 here in SLE)

31
Q

C1q, C1r, C1s, C2, C4 deficiency (classical pathway components) >>> results?

A

Immune complex diseases

  • SLE (Systemic Lupus Erythematosus)
  • HSP (Henoch schonlein purpura)
32
Q

What is C1- inhibitor?

A

Multi-functional serine proteinase inhiitor

33
Q

Role of C1 esterase (= C1 inhibitor)

A
  • Regulator of classic complement pathway
  • Inhibitor of “kallikrein” >>> kallikrein can’t release bradykinin >>> low bradykinin
34
Q

Result of C1 inhibitor (= C1 esterase) deficiency

A
  • NO regulation of classic pathway
  • NO inhibition of kallikrein >>> liberation of bradykinin >>> high bradykinin >>> recurrent bradykinin-driven >>> bradykinin mediated vasodilation and increased vascular permeability >>> oedema in tissues, angioedema (called ‘hereditary angioedema’/ angioneurotic oedema)

​

35
Q

Drug-induced angioedema >> underlying mechanism

A

Elevated bradykinin

  • ACE >>> blocks bradykinin; So, ACE inhibitor >>> elevates bradykinin
  • JG complex > pro-renin > renin > converts angiotensinogen to angiotensin I >>> ACE converts angiotensin I to angiotensin II + metabolises bradykinin
    • ACE inhibitor blocks this conversion >>> elevated angiotension I
    • As a feedback >>> Decreased renin
    • Elevated bradykinin (the only cause of angioedema, not any other)
  • Other drugs elevating bradykinin also >>> Moxonidine
  • ARB do NOT cause elevated bradykinin level

​

36
Q

Drug-induced angioedema >>

properties of bradykinin

A
  • Bradykinin is a potent vasoactive peptide
  • It is a potent vasodilator
  • It i_ncreases vascular permeability_
  • It causes pain and contraction of smooth muscle
  • It causes arachidonic acid metabolism
  • After injury >>> Bradykinin B1 receptors are upregulated >>> upregulation of both ‘acute’ and ‘chronic’ inflammation (as same mechanism)
  • In hereditary angioedema >>> an potential therapeutic target can be >>> Bradykinin B2 receptor antagonism
37
Q

Drug-induced angioedema >> drug causes

A
  • ACE inhibitor (most important)
  • Moxonidine
  • (ARB is NOOOTTT a cause; Ref: Pastest)
38
Q

Hereditary angioedema: Inheritance

A

Autosomal dominant (AD)

39
Q

Hereditary angioedema: Genetic defect

A

Mutation in C1 inhibitor gene

40
Q

Hereditary angioedema >>> findings

A
  • During attack > Low plasma levels of C1-inhibitor protein (in 85% cases)
  • Low C2, C4 persistantly (Even in between attacks)

​(For hereditary angioedema or angioneurotic oedema)

41
Q

Hereditary/Acquired angioedema Vs D/D

A

Hereditary angioedema VS Acquired drug-induced angioedema: (Pastest)

  • Hereditary: Childhood onset/young age + NO causative drug
  • Acquired/Drug-induced: Adult/Elderly onset + causative drug
  • Both are due to elevated bradykinin; BUT ACEi does it by blocking ACE enzyme; Hereditary does it by allowing kallikrein to release bradykinin

Angioedema VS Anaphylaxis (Pastest)

  • Anaphylaxis causes urticaria or hypotension and wheeze
  • H.Angioedema or drug-induced angioedema do NOT
  • Anapylaxis is histamin-mediated; Angioedema is bradykinin-mediated

Angioedema VS Latex allergy (Pastest)

  • Latex allergy can cause urticaria
  • Angioedema do NOT cause urticaria
42
Q

The most common type of genetic and acquired angioedema

A
  • Inherited >>> Hereditary angioedema (Angioneurotic oedema)
  • Acquired >>> Drug: ACE inhibitor (if it is running, stop it)
    • Moxonidine
  • (If both 2 drug is taken by the patient >>> prefer ACEi as the cause > than other 2) Ref: Pastest
  • ARB is NOT a cause of angioedema Ref Pastest
43
Q

Hereditary angioedema: Features

A
  • Before Attacks >>> (Maybe) painful macular rash.
  • During attacks >>>
    • Skin >>> Painless, non-pruritic swelling of subcutaneous tissues (= only swelling)
    • Upper airways >>> Painless, non-pruritic swelling of submucosal tissues (= only swelling)
    • Abdominal organs >>> (occasionally) visceral oedema >>> abdominal pain
  • NO urticaria (usually)
44
Q

Hereditary angioedema: triggering stimuli

A
  • Instrumentation (e.g. dental work)
  • Menstruation
  • Viral illness
  • Some medications
  • Ref: Pastest
45
Q

Hereditary angioedema >>> Screening tool/test

A

Serum C4 level (persistantly low, even in between attacks)

46
Q

Hereditary angioedema >>> investigation during an attack

A

C1-Inhibitor level (= C1 esterase level)

(Low levels of C1-inhibitor protein indicate hereditary angioedema)

47
Q

Hereditary angioedema >>> investigation in between attacks

A

C4 level

(Best screening tool)

Persistantly Low C4 indicates >>> hereditary angioedema

48
Q

Hereditary angioedema: Treatment

A

During attack (Acute case) > Immediate Mx

  • 1st line: C1-inhibitor concentrate IV
  • Alternative: Specific bradykinin inhibitor (Icatibant)
  • 2nd line: FFP (Fresh frozen plasma) (only if 1st line & the alternative are NOT available)

In between attack (Prophylaxis)

  • Anabolic steroid: Danazol
49
Q

Drug-induced angioedema: Treatment

A
  • 1st line/ 1st thing to do: STOP the DRUG (do NOT use further in future)
  • C1-inhibitor concentrate IV
  • FFP (Fresh frozen plasma) (only if C1 inhibitor is NOT available)
50
Q

C3 deficiency >>> results

A
  • ​Recurrent bacterial infections
    • Pneumococcus
    • Haemophilus
  • ​​Lipodystrophy
51
Q

C4 deficiency >> common association

A

SLE

52
Q

C5 deficiency >>> results

A
  • Disseminated meningococcal infection
  • Seborrhoeic dermatitis
  • Leiner disease
  • Recurrent diarrhoea
  • Wasting

_*** DSLR Wasting_

53
Q

Final common pathway (MAC) OR C5-9 deficiency >>> results

A

Recurrent Neisseria Spp infection

54
Q

Neisseria meningitidis infection >>> complement deficiency?

A

C5 to 9 (MAC = membrane attack complex)

Final common pathway

55
Q

Disseminated meningococcal infection >>> complement deficiency?

A

C5

56
Q

Recurrent dirrhoea >> possible complement deficiency

A

C5

57
Q

Wasting >> possible complement deficiency

A

C5

58
Q

Seborrhoeic dermatitis >> possible complement deficiency

A

C5

59
Q

Leiner disease >> possible complement deficiency

A

C5

60
Q

Lipodystrophy >> possible complement deficiency

A

C3

61
Q

Recurrent bacterial infection >> possible complement deficiency

A

C3

62
Q

SLE >> possible complement deficiency

A
  • C1q (inherited)
  • C4
  • C3 (maybe also)
63
Q

HSP (Henoch-Scholein purpura) >> possible complement deficiency

A

Classical pathway complements (C1qrs, C2, C4)

Immunology (16 decks)

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