Immunology > Complement System & Deficiency > Flashcards

Complement System & Deficiency Flashcards

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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
**Which type of disease does need measurement of complements C3, C4?**
**Where complement activation is occuring**
26
**Diseases associated with hypocomplementaemia OR** **Disease associated with low complement levels OR** **Diseases where we need to measure complement levels**
* **SLE (Systemic Lupus Erythematosus)** * **Mesangiocapillary GN** * **Chronic infections (e.g. endocarditis. quartan malaria)**
27
**Depletion of C3, C4 \>\>\> suggests what?**
**Immunologically driven disease**
28
**Complement deficiencies: Inheritance**
**Most are AR (Autosomal Recessive)** Except Properdin deficiency (X-linked recessive)
29
**C1q deficiency \>\>\> results**
**SLE (Systemic Lupus Erythematosus)** (in \>90% patients)
30
**A risk factor (complement-cascade related) for SLE?**
**Inherited C1q deficiency** (we can find low complement levels: C3, C4 here in SLE)
31
**C1q, C1r, C1s, C2, C4 deficiency (classical pathway components) \>\>\> results?**
**Immune complex diseases** * **SLE (Systemic Lupus Erythematosus)** * **HSP (Henoch schonlein purpura)**
32
**What is C1- inhibitor?**
**Multi-functional serine proteinase inhiitor**
33
**Role of C1 esterase (= C1 inhibitor)**
* **Regulator of classic complement pathway** * **Inhibitor of _"*kallikrein"*_ \>\>\> kallikrein can't release bradykinin \>\>\> low bradykinin**
34
**Result of C1 inhibitor (= C1 esterase) deficiency**
* **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)** ## Footnote **​**
35
**Drug-induced angioedema \>\> underlying mechanism**
**_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
**Drug-induced angioedema \>\>** **properties of bradykinin**
* 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
**Drug-induced angioedema \>\> drug causes**
* **ACE inhibitor *(most important)*** * **Moxonidine** * *(ARB is NOOOTTT a cause; Ref: Pastest)*
38
**Hereditary angioedema: Inheritance**
**Autosomal dominant (AD)**
39
**Hereditary angioedema: Genetic defect**
**Mutation in C1 inhibitor gene**
40
**Hereditary angioedema \>\>\> findings**
* **During attack \> Low plasma levels of C1-inhibitor protein (in 85% cases)** * **Low C2, C4 persistantly (Even in between attacks)** ## Footnote ​(For hereditary angioedema or angioneurotic oedema)
41
Hereditary/Acquired angioedema Vs D/D
**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
**The most common type of genetic and acquired angioedema**
* **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
**Hereditary angioedema: Features**
* **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) **v*_isceral oedema \>\>\> abdominal pain_*** * **NO urticaria** (usually)
44
**Hereditary angioedema: triggering stimuli**
* **Instrumentation (e.g. dental work)** * **Menstruation** * **Viral illness** * **Some medications** * Ref: Pastest
45
**Hereditary angioedema \>\>\> Screening tool/test**
**Serum C4 level** (persistantly low, even in between attacks)
46
**Hereditary angioedema \>\>\> investigation during an attack**
**C1-Inhibitor level (= C1 esterase level)** **(Low levels of C1-inhibitor protein indicate hereditary angioedema)**
47
**Hereditary angioedema \>\>\> investigation in between attacks**
**C4 level** **(Best screening tool)** **Persistantly Low C4 indicates \>\>\> hereditary angioedema**
48
**Hereditary angioedema: Treatment**
**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
**Drug-induced angioedema: Treatment**
* **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
**C3 deficiency \>\>\> results**
* **​Recurrent bacterial infections** * **Pneumococcus** * **Haemophilus** * **​​Lipodystrophy**
51
**C4 deficiency \>\> common association**
**SLE**
52
**C5 deficiency \>\>\> results**
* **Disseminated meningococcal infection** * **Seborrhoeic dermatitis** * **Leiner disease** * **Recurrent diarrhoea** * **Wasting** _*\*\*\* DSLR Wasting*_
53
**Final common pathway (MAC) OR C5-9 deficiency \>\>\> results**
**Recurrent Neisseria Spp infection**
54
**Neisseria meningitidis infection \>\>\> complement deficiency?**
**C5 to 9 (MAC = membrane attack complex)** **Final common pathway**
55
**Disseminated meningococcal infection \>\>\> complement deficiency?**
**C5**
56
**Recurrent dirrhoea \>\> possible complement deficiency**
**C5**
57
**Wasting \>\> possible complement deficiency**
**C5**
58
**Seborrhoeic dermatitis \>\> possible complement deficiency**
**C5**
59
**Leiner disease \>\> possible complement deficiency**
**C5**
60
**Lipodystrophy \>\> possible complement deficiency**
**C3**
61
**Recurrent bacterial infection \>\> possible complement deficiency**
**C3**
62
**SLE \>\> possible complement deficiency**
* **C1q** (inherited) * **C4** * **C3** (maybe also)
63
**HSP (Henoch-Scholein purpura) \>\> possible complement deficiency**
**Classical pathway complements (C1qrs, C2, C4)**
Immunology
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