Complement system explained: three pathways, one ending
The complement system has three ways in and one way out. Compare how the classical, lectin and alternative pathways start, then follow the shared steps that all three produce.
Compare how the classical, lectin and alternative complement pathways are initiated and name the shared effector functions of C3b (opsonisation), C3a and C5a (inflammation) and the membrane attack complex (lysis).
The short version
- Classical starts with C1q on antibody, lectin with mannose-binding lectin on sugars, alternative with spontaneous C3 tick-over.
- Classical and lectin share one C3 convertase, made of C4b and C2a.
- All three pathways converge on C3, and then do the same three jobs.
- C3b opsonises, C3a and C5a cause inflammation, and C5b to C9 form the membrane attack complex that lyses the cell.
- Two of the three pathways, lectin and alternative, need no antibody.
The case: what burst the red cells so fast?
A patient is given the wrong blood type. Soon after the transfusion starts: fever, back pain and dark red urine. No new antibody could have been made in that time, so the antibodies were already there.[5][6][7][9]
What actually burst the red cells so fast is the complement system. This lesson compares how the three complement pathways start and what they all do once they merge.
What the complement system is: a plasma cascade
Complement is a set of plasma proteins that sit inactive until something triggers them.[1][3]
In the early steps, each activated enzyme cleaves the next protein, so one trigger is amplified into a cascade.[1]
The useful way to learn the complement system is by its shape: three different ways in, one shared middle at C3, and three shared jobs at the end.
The three pathways differ mainly in how they start. All three converge on C3.[1][3]
Classical pathway: C1q on antibody
The recognition molecule of the classical pathway is C1q. It binds the Fc region of IgM or IgG that is already stuck to an antigen. One IgM is enough, but IgG needs several molecules close together.[1][3]
In other words, the classical pathway is mainly triggered by antibody that is already bound to its target. It is the antibody-linked arm of complement.
Bound C1q wakes up C1r and C1s, which cleave C4 and C2. The fragments C4b and C2a join to form the classical C3 convertase, C4b2a (newer sources call the C2 fragment C2b and write C4b2b).[1][3]
Lectin pathway: mannose-binding lectin, no antibody
Mannose-binding lectin binds mannose sugars on microbial surfaces, with no antibody needed.[1][3]
It activates enzymes called MASP-1 and MASP-2, which also cleave C4 and C2. So the lectin pathway makes the same C3 convertase as the classical pathway, C4b2a.[1][3]
The difference is the trigger. Here a sugar pattern on the microbe is recognised directly, so the lectin pathway needs no antibody against that microbe.[1][3]
Alternative pathway: tick-over and the amplification loop
In plasma, C3 is always slowly hydrolysing on its own. This is called tick-over, and it leads to a small, steady supply of C3b.[1][3]
If C3b lands on a microbe's surface, factor B binds it and factor D cleaves factor B, making C3bBb. Properdin stabilises it, and it cuts more C3: an amplification loop.[1][2][3]
Human cells carry protective proteins, such as DAF and CD59, that restrain complement. Many microbes do not.[1][4]
The shared steps: opsonisation, inflammation and lysis
A C3 convertase cleaves C3 into C3a and C3b. C3b coats the microbe as an opsonin, so phagocytes engulf it more readily.[1][3]
C3b also joins the convertase to make a C5 convertase, which cleaves C5 into C5a and C5b.[1][3]
C3a and C5a are anaphylatoxins: they trigger mast cell degranulation, and C5a also draws neutrophils in.[2][3]
C5b then recruits C6, C7, C8 and C9, forming the membrane attack complex (MAC), a pore that lyses the cell.[1][2]
So there are three jobs: opsonisation by C3b, inflammation by C3a and C5a, and lysis by the membrane attack complex.[1][2][3]
| Pathway | What starts it | What it makes |
|---|---|---|
| Classical | C1q on IgM or IgG bound to antigen; C1r and C1s cleave C4 and C2 | C4b2a, the C3 convertase |
| Lectin | Mannose-binding lectin on mannose sugars; MASP-1 and MASP-2 cleave C4 and C2 | C4b2a, the same C3 convertase |
| Alternative | Spontaneous C3 tick-over; factor B and factor D; properdin stabilises | C3bBb, with an amplification loop |
| Product | Job |
|---|---|
| C3b | Opsonisation: phagocytes engulf the coated microbe |
| C3a and C5a | Inflammation: mast cell degranulation; C5a also draws in neutrophils |
| C5b to C9 (MAC) | Lysis: a pore in the membrane |
Back to the patient: the wrong blood type
The patient's plasma already holds IgM against the donor's blood group. It binds the donor red cells and activates the classical pathway, and the membrane attack complex bursts them.[5][6][8]
Practice question
Original · USMLE styleA laboratory technician mixes fresh serum from a healthy adult who has never met a particular bacterial strain with that strain. The bacterial surface is rich in mannose. Within 30 minutes, C3b is deposited on the bacteria, although the serum contains no antibody against the strain. When excess free mannose is added to the serum before the bacteria, C3b deposition is prevented.
Common questions
What are the three complement pathways?
The classical, lectin and alternative pathways. They differ mainly in how they start, and all three converge on C3.
What starts the classical, lectin and alternative pathways?
The classical pathway starts with C1q on IgM or IgG bound to antigen. The lectin pathway starts with mannose-binding lectin on mannose sugars. The alternative pathway starts with spontaneous C3 tick-over.
What do all three complement pathways have in common?
They all make a C3 convertase, and then do the same three jobs: C3b opsonises, C3a and C5a cause inflammation, and the membrane attack complex lyses the cell.
What is the membrane attack complex?
C5b recruits C6, C7, C8 and C9 to form a pore, the membrane attack complex, which lyses the cell.
Which complement pathways need no antibody?
The lectin and alternative pathways. Mannose-binding lectin binds mannose sugars on microbial surfaces, and the alternative pathway starts with spontaneous C3 tick-over, so neither needs antibody. Only the classical pathway starts with C1q on antibody.
Transcript
Read the full narration, by chapter709 words
0:00The case: the wrong blood type and burst red cells
A patient is given the wrong blood type. Soon after the transfusion starts: fever, back pain, and dark red urine. No new antibody could have been made in that time. The antibodies were already there. So what actually burst the red cells so fast?
0:18Complement: a plasma cascade with three ways in
Today: compare how the three complement pathways start, and what they all do once they merge. Complement is a set of plasma proteins that sit inactive until something triggers them. Each activated protein cleaves the next, so one trigger is amplified into a cascade. The three pathways differ only in how they start. All three converge on C three.
0:42Classical pathway: C1q on IgM or IgG, C4b2a
First, the classical pathway. The recognition molecule is C one q. C one q binds the Fc region of IgM or IgG that is already stuck to an antigen. One IgM is enough, but IgG needs several close together. That wakes up C one r and C one s, which cleave C four and C two. The fragments C four b and C two a join to form the classical C three convertase. Second, the lectin pathway.
1:14Lectin pathway: mannose-binding lectin, MASPs, the same convertase
Mannose-binding lectin binds mannose sugars on microbial surfaces, with no antibody needed. It activates enzymes called MASP one and two, which also cleave C four and C two. So the lectin pathway makes the same C three convertase as the classical one.
1:35Alternative pathway: tick-over, factor B and D, properdin
Third, the alternative pathway. In plasma, C three is always slowly breaking down on its own, called tick-over, and that produces a little C three b. If C three b lands on a microbe's surface, factor B binds it and factor D cleaves factor B, making C three b B b. Properdin stabilises it, and it cuts more C three, an amplification loop. Human cells carry protective proteins, such as DAF and CD59, that restrain complement. Many microbes do not.
2:12The shared steps: C3b, C3a, C5a and the membrane attack complex
Now the shared steps. AC three convertase cleaves C three into C three a and C three b. C three b coats the microbe as an opsonin, so phagocytes engulf it more readily. C three b also joins the convertase to make a C five convertase, which cleaves C five into C five a and C five b. C three a and C five a are anaphylatoxins: they trigger mast cell degranulation, and C five a also draws neutrophils in. C five b then recruits C six, seven, eight and nine, forming the membrane attack complex, a pore that lyses the cell. So: opsonisation by C three b, inflammation by C three a and C five a, lysis by the membrane attack complex.
3:06Back to the patient: IgM, classical pathway, lysis
That is the wrong blood type. The patient's plasma already holds IgM against the donor's blood group. It binds the donor red cells, activates the classical pathway, and the membrane attack complex bursts them.
3:21Your turn: a practice question
Your turn. A technician mixes fresh serum from a healthy adult, who has never met a particular bacterial strain, with that strain. The strain's surface is rich in mannose. Within 30 minutes, C three b is deposited on the bacteria, although the serum contains no antibody against the strain. Adding excess free mannose to the serum beforehand prevents the deposition. Which of the following most likely recognised the bacterial surface and started this? A, C one q. B, factor B. C, mannose-binding lectin. D, factor D. E, IgM. Pause here and decide.
4:05The pause, then each option ruled out
A is out: C one q mainly recognises antibody bound to antigen, and free mannose would not block it. B is out: factor B is part of the alternative convertase, and it does not recognise sugars. D is out: factor D only cleaves factor B in the alternative pathway, and does not recognise sugars. E is out: the serum had no antibody against this strain.
4:37The answer
So the answer is C. Mannose-binding lectin binds mannose, free mannose competes with it, and the lectin pathway needs no antibody.
4:47Recap pocket card and next lesson
Three things to keep. One: classical starts with C one q on antibody, lectin with mannose-binding lectin on sugars, alternative with spontaneous C three. Two: classical and lectin share one C three convertase, made of C four b and C two a. Three: C three b opsonises, C three a and C five a inflame, and C five to nine lyse. Next, complement deficiencies: what goes wrong when a component is missing.
Sources
Numbers in the text, e.g. [1], point here- Complement System Part I. Front Immunol 2015. europepmc.org/article/PMC/PMC4451739
- Complement System Part II: Role in Immunity. Front Immunol 2015. europepmc.org/article/PMC/PMC4443744
- Complement system. Wikipedia. en.wikipedia.org/wiki/Complement_system
- Complement in kidney disease review, 2026 (DAF and CD59). europepmc.org/article/PMC/PMC13078055
- Hemolytic transfusion reaction. Wikipedia. en.wikipedia.org/wiki/Hemolytic_transfusion_reaction
- Acute hemolytic transfusion reaction. Wikipedia. en.wikipedia.org/wiki/Acute_hemolytic_transfusion_reaction
- Transfusion case report, 2018 (timing of back pain). europepmc.org/article/PMC/PMC6035818
- Transfusion case report, 2025 (anti-A and anti-B isoagglutinins are mainly IgM). europepmc.org/article/PMC/PMC12615022
- Acute intravascular haemolysis case report (tea-coloured urine, fever). europepmc.org/article/PMC/PMC13600969
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): lying man, blood bag, antibody, syringe. NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain: red blood cell (442), complement C1 complex (85), bacteria (790), macrophage (307), neutrophil (379). Mast cell degranulation icon by Sebastian-Reinig via bioicons.com, CC BY 4.0. The complement proteins, convertase brackets, scissors, membrane attack complex, IgM ring, mannose sugars, tubes, clock, cards and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-IMM-001.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01MHC I vs MHC II: how antigen presentation works5:03
- EP 02T-cell activation: the two-signal model4:58
- EP 03Th1, Th2, Th17 and Treg: helper T-cell subsets5:13
- EP 04Antibody isotypes and class switching5:13
- EP 05Central vs peripheral tolerance: how lymphocytes learn self-tolerance5:26
- EP 06Complement system explained: three pathways, one ending5:24
- EP 07Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor5:15
- EP 08Hypersensitivity types I to IV: the four effectors5:20
- EP 09B-cell vs T-cell immunodeficiency: predict the infections5:24
- EP 10Hyper IgM syndrome: CD40 ligand and class switching5:19
- EP 11Chronic granulomatous disease: NADPH oxidase and the respiratory burst5:20
- EP 12Leukocyte adhesion deficiency: CD18 and neutrophil extravasation5:01
- EP 13Transplant rejection explained: hyperacute, acute, chronic and GVHD5:51
- EP 14Vaccine types explained: live, inactivated, conjugate and mRNA5:41