⭐ COMPLEMENT SYSTEM —

INTRODUCTION

🌟 What is the complement system?

The complement system is a group of 30+ blood proteins that help the immune system
kill microbes, clear infections, and promote inflammation.

👉
Think of it like:​
extra weapons that your immune system can call for backup.

These proteins normally float around in blood in an inactive form​

(we call this “zymogens,” meaning “sleeping enzymes”).

⭐ 🌟 What does complement do? (The 3

main functions)
Use the mnemonic: OIL

1. Opsonization (O)

💡
Complement marks microbes for easy eating by phagocytes.​
Key protein: C3b (most important opsonin)

2. Inflammation (I)

💡
Some complement fragments cause inflammation.​
Key proteins:

●​ C3a → inflammation​

●​ C4a → weak inflammation​

●​ C5a → strongest chemotactic factor (calls neutrophils)​

3. Lysis (L)
💡
Complement forms a hole in the microbe → kills it.​
The final complex is called:​
MAC (Membrane Attack Complex) = C5b–C9

⭐ 🌟 Why is it called “complement”?

Because it complements (helps) both:

●​ innate immunity (first line defense)​

●​ adaptive immunity (antibodies)​

It bridges innate and adaptive immunity.

⭐ 🌟 What activates the complement

system? (3 pathways)
There are three ways to wake up complement:

1. Classical Pathway

Triggered by antibody + antigen, especially IgM, IgG​

This is the one we explained earlier.

2. Lectin Pathway

Triggered when mannose-binding lectin (MBL) binds to mannose sugars on microbes.

3. Alternative Pathway

Triggered spontaneously on all microbial surfaces (no antibody needed).​

This is always “slightly active,” like a smoke detector always on.

👉
Even though there are 3 ways to start,​
all pathways unite at C3 activation​
and follow a common final pathway → MAC formation.
⭐ 🌟 How is complement controlled?
(very important)
To prevent damage to our own cells, the body uses regulators:

●​ C1 esterase inhibitor → stops classical pathway early​

Deficiency → Hereditary Angioedema​

●​ DAF (CD55) → prevents overactive complement on RBCs​

Deficiency → PNH (Paroxysmal Nocturnal Hemoglobinuria)​

⭐ CLASSICAL PATHWAY
1. What activates the classical pathway?
ONLY when antibodies attach to an antigen.

But not all antibodies → only:

●​ IgM (best activator)​

●​ IgG (specifically IgG1, IgG3)​

Mnemonic: “GM makes Classic cars” → IgG & IgM activate the Classical pathway.

Why?​
Because once they bind antigen, their Fc region becomes exposed → complement
can latch onto it.

⭐ 2. The first complement protein that

responds: C1 complex
C1 is actually three proteins working together:

●​ C1q​
 ●​ C1r​

●​ C1s​

Think of them like:

●​ C1q = “hands” that touch the antibody​

●​ C1r = “switch”​

●​ C1s = “scissors” that cut the next proteins​

How does it begin?

1.​ IgM/IgG binds to antigen​

2.​ Their Fc region changes shape​

3.​ C1q binds to Fc region​

4.​ This activates C1r​

5.​ C1r activates C1s​

Now C1s (the scissors) starts cutting complement proteins.

⭐ 3. What gets cut first? → C4

C1s cuts C4 → C4a + C4b

●​ C4a = anaphylatoxin (causes inflammation, weak)​

●​ C4b = sticks to the microbe surface​

Think: B for “binds”.

So now C4b sits on the pathogen like a “marker sticker.”

 ⭐ 4. Next protein cut: C2
C1s cuts C2 → C2a + C2b

BUT IMPORTANT:

●​ C2a stays attached to C4b​

●​ They form C4b2a​

This is SUPER IMPORTANT:

⭐ ⭐ C4b2a = C3 CONVERTASE
(classical pathway)
This enzyme’s job → cut C3.

⭐ 5. What does C3 convertase do?

It cuts C3 → C3a + C3b

●​ C3a = strong inflammatory signal​

●​ C3b = opsonin (“eats me tag”) AND part of the next enzyme​

Some of the C3b sticks to the C3 convertase.

Now we have:

⭐ ⭐ C4b2a3b = C5 CONVERTASE
This enzyme cuts C5 → C5a + C5b​
and C5b leads directly to MAC formation.

⭐ 6. MAC (Membrane Attack Complex)

C5b sticks to:​
C6 → C7 → C8 → many C9 molecules form a pore

That pore = MAC, which punches holes and kills the microbe.

🎯 LET’S PUT IT ALL TOGETHER —

SUPER SIMPLE FLOW
1. Antigen + IgG/IgM

2. C1 (C1q, C1r, C1s) binds Fc

3. C1s cuts C4 → C4b sticks

4. C1s cuts C2 → C2a joins C4b

5. C4b2a = Classical C3 convertase

6. C3 → C3a (inflammation) + C3b (opsonin)

7. C3b joins → C4b2a3b (C5 convertase)

8. Cuts C5 → C5b → MAC (C5b-9)

9. Microbe dies by lysis

●​ CD59 → prevents MAC formation on our cells

 ⭐ ALTERNATIVE COMPLEMENT
PATHWAY

🌟 1. What activates the alternative pathway?

The beautiful part is:

👉 IT DOES NOT NEED ANTIBODIES​

👉 IT STARTS SPONTANEOUSLY
Meaning: complement is always “slightly on” and ready to attack anything that is NOT a
human cell.

How?

C3 in blood spontaneously breaks into:

●​ C3a​

●​ C3b​

This happens all the time.

But on human cells → C3b is destroyed​

On microbes → C3b stays and starts the pathway.

So microbes accidentally activate complement just by existing.​

This makes it part of innate immunity.

⭐ 2. Steps of the Alternative

Pathway

⭐ STEP 1 — C3 → C3b spontaneously

●​ C3 hydrolyzes and forms C3b​

●​ C3b sticks to microbe surface​

Now the microbe is marked.

⭐ STEP 2 — Factor B binds to C3b

C3b attracts Factor B.

➡️
Think:​

➡️
C3b = “platform”​
Factor B = “worker”​
(But worker is inactive)

⭐ STEP 3 — Factor D cuts Factor B

Factor D is a protease in blood.

It cuts Factor B → into Ba + Bb

●​ Bb remains attached​

●​ C3b + Bb = C3bBb​

This is VERY important:

⭐⭐ C3bBb = ALTERNATIVE C3
CONVERTASE
Its job: cut more C3​
→ Positive feedback loop​
→ Explosive amplification

⭐ STEP 4 — Properdin stabilizes it

Properdin (Factor P) = “protein glue”

It binds to C3bBb and stabilizes it so it can keep working.

Mnemonic:​
P for Properdin, P for Protects the convertase
 ⭐ STEP 5 — More C3 is cut → LOTS of C3b
produced
C3 convertase makes:

●​ more C3a = inflammation​

●​ more C3b = opsonization + helps build next enzyme​

Some of the new C3b sticks to the convertase:

C3bBb + C3b → C3bBbC3b

This is:

⭐⭐ C5 CONVERTASE of alternative
pathway

⭐ STEP 6 — C5 convertase cuts C5

Cuts:

●​ C5a → strong chemoattractant​

●​ C5b → leads to MAC formation​

⭐ STEP 7 — MAC (C5b-9) kills the microbe

Same as in classical pathway:​
C5b → C6 → C7 → C8 → many C9​
→ pore forms​
→ microbe dies
 ⭐ NOW THE WHOLE ALTERNATIVE
PATHWAY IN 6 LINES
1️⃣ C3 → C3b (spontaneous)​
2️⃣ C3b binds microbe​
3️⃣ C3b + Factor B​
4️⃣ Factor D cuts → C3bBb (C3 convertase)​
5️⃣ Properdin stabilizes → amplifies​
6️⃣ More C3b → C3bBbC3b (C5 convertase) → MAC

⭐ LECTIN / MANNOSE PATHWAY

🌟 1. What triggers it?
👉 Mannose sugars on the surface of bacteria, fungi, and some viruses.​
These sugars are NOT present on human cells, so the body uses them as a “foreign
marker.”

A protein in our blood called:

MBL = Mannose Binding Lectin

binds to mannose on microbes.

This is the first step, just like C1 binding to antibodies in the classical pathway.

⭐ 2. MBL is attached to helper

enzymes: MASP-1 & MASP-2
Think:

●​ MBL = the “hands” that grab mannose​

●​ MASP-1 / MASP-2 = the “scissors” (just like C1s in classical pathway)​

MASP = MBL-Associated Serine Protease

⭐ 3. Once MBL binds to mannose →
MASP-2 gets activated
Then MASP-2 starts cutting complement proteins.

Which ones?

👉 C4 and C2
Exactly like the classical pathway.

⭐ 4. C4 → C4a + C4b
●​ C4a = mild inflammation​

●​ C4b = sticks to the microbial surface​

⭐ 5. C2 → C2a + C2b
●​ C2a sticks to C4b​

●​ This forms:​

⭐⭐ C4b2a = C3 CONVERTASE (Lectin

+ Classical)
YES, both pathways converge here.

⭐ 6. C3 convertase cuts C3 → C3a +

C3b
 ●​ C3a = inflammation​

●​ C3b = opsonin, and also helps form C5 convertase​

Some C3b attaches to the convertase:

C4b2a + C3b → C4b2a3b

This is:

⭐⭐ C5 CONVERTASE
⭐ 7. C5 convertase cuts C5 → MAC
(C5b–C9)
●​ C5b recruits C6, C7, C8, many C9​

●​ Forms a pore​

●​ Kills the microbe by lysis​

Exactly same as the other pathways.

🌟 NOW THE WHOLE LECTIN PATHWAY

IN JUST 6 LINES
1️⃣ MBL binds mannose on the microbe​
2️⃣ MASP-1 & MASP-2 get activated​
3️⃣ C4 → C4b, sticks​
4️⃣ C2 → C2a, joins​
5️⃣ C4b2a = C3 convertase​
6️⃣ C3 → C3a + C3b → MAC