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[Immunology](https://durgical.com/en/immunology/) · [Innate immunity](https://durgical.com/en/immunology/#a-innate)

# Complement: three pathways, MAC, regulators

- Process

A cascade of blood proteins that coats microbes for eating, calls in white cells and punches holes in some bacteria.

Updated 2026-11-01

## Key points

- All three pathways converge on C3; C3b is the main opsonin.
- C5a is the key neutrophil chemoattractant; C3a and C5a are anaphylatoxins.
- Deficiency of C5 to C9 predisposes to recurrent Neisseria infections.
- C1 inhibitor deficiency causes hereditary angioedema (bradykinin, no urticaria).
- Early classical deficiency (C1q, C2, C4) is associated with lupus.
- Loss of CD55 and CD59 on red cells causes paroxysmal nocturnal hemoglobinuria.

## What it is

Complement is a group of plasma proteins, made mostly by the liver, that activate one another in a cascade. Three pathways (classical, lectin and alternative) converge on cleaving C3. The products tag microbes for phagocytosis (C3b), attract and activate inflammatory cells (C3a, C5a) and build the membrane attack complex (C5b-C9) that lyses thin-walled bacteria such as Neisseria.

## Function

- Opsonization: C3b (and iC3b) coat microbes so phagocytes can bind them.
- Inflammation: C3a and C5a are anaphylatoxins that degranulate mast cells; C5a strongly attracts neutrophils.
- Lysis: the membrane attack complex kills gram-negative bacteria, especially Neisseria.
- Clearance of immune complexes and apoptotic cells, which protects against autoimmunity.

## Step by step

- Classical pathway: C1q binds IgM or IgG attached to an antigen; C1 cleaves C4 and C2.
- Lectin pathway: mannose-binding lectin binds microbial sugars; its proteases (MASPs) also cleave C4 and C2.
- Both form the C3 convertase C4b2a.
- Alternative pathway: C3 hydrolyzes slowly on its own; on microbial surfaces factor B, factor D and properdin form the C3 convertase C3bBb.
- C3 convertase splits C3 into C3a (inflammation) and C3b (opsonin, and part of C5 convertase).
- C5 convertase splits C5 into C5a (neutrophil chemotaxis, anaphylatoxin) and C5b.
- C5b joins C6, C7, C8 and several C9 to form the membrane attack complex, a pore that lyses the cell.

## Complement defects to know

| Defect | Consequence |
| --- | --- |
| C3 deficiency | Severe, recurrent pyogenic infections by encapsulated bacteria; immune-complex disease |
| C1 esterase inhibitor deficiency (hereditary angioedema) | Episodes of swelling without hives, from excess bradykinin; low C4 between attacks |
| [Early classical components (C1q, C2, C4)](https://durgical.com/en/conditions/systemic-lupus-erythematosus/) | Lupus-like disease from poor clearance of immune complexes |
| Terminal components (C5 to C9) | Recurrent Neisseria infections (meningococcal disease, disseminated gonorrhea) |
| [CD55 (DAF) and CD59 missing on red cells](https://durgical.com/en/conditions/paroxysmal-nocturnal-haemoglobinuria/) | Paroxysmal nocturnal hemoglobinuria: complement-mediated hemolysis |

## Markers

- C3
- C4
- CH50
- C1q
- C5a
- C5b-C9 (MAC)
- CD55 (DAF)
- CD59
- C1-INH
- Factor H

## In the lab

- C3 and C4 are measured in blood; both fall when complement is consumed, as in active lupus nephritis.
- CH50 tests the whole classical pathway; a very low result suggests a missing component.
- In hereditary angioedema, C4 is typically low and C1 inhibitor level or function is reduced.

## Memory aid

C3b sticks (coats the microbe), C5a shouts (calls the neutrophils) and C5b-9 drills (makes the hole).

## Test yourself

Think of the answer, then tap the question to see it.

## Where do the three complement pathways converge?

At the cleavage of C3 by a C3 convertase (C4b2a in the classical and lectin pathways, C3bBb in the alternative pathway).

## A young adult has a second episode of meningococcal meningitis. Which complement defect is suspected?

A deficiency of the terminal components C5 to C9, which form the membrane attack complex.

## Which complement fragment is the most important chemoattractant for neutrophils?

C5a.

## Why does hereditary angioedema cause swelling without hives?

Lack of functional C1 inhibitor allows excess bradykinin, which increases vascular permeability; histamine is not the main mediator, so urticaria and itching are absent.

## Which two red-cell proteins are missing in paroxysmal nocturnal hemoglobinuria?

CD55 (decay-accelerating factor) and CD59, both anchored by GPI; without them complement lyses red cells.

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## Related

- [Innate immunity (overview, barriers)](https://durgical.com/en/immunology/innate-immunity/)
- [Phagocytosis and the respiratory burst](https://durgical.com/en/immunology/phagocytosis-and-the-respiratory-burst/)
- [Antibody structure and isotypes (IgG, IgA, IgM, IgE, IgD)](https://durgical.com/en/immunology/antibody-structure-and-isotypes/)
- [Acute inflammation: vascular and cellular events](https://durgical.com/en/immunology/acute-inflammation-vascular-and-cellular-events/)
- [Complement deficiencies and hereditary angioedema](https://durgical.com/en/immunology/complement-deficiencies-and-hereditary-angioedema/)
- [Type III hypersensitivity (immune complexes)](https://durgical.com/en/immunology/type-iii-hypersensitivity/)

## Related conditions

- [Systemic lupus erythematosus](https://durgical.com/en/conditions/systemic-lupus-erythematosus/)

## Microorganisms

- [Neisseria meningitidis](https://durgical.com/en/microbiology/neisseria-meningitidis/)
- [Neisseria gonorrhoeae](https://durgical.com/en/microbiology/neisseria-gonorrhoeae/)
- [Streptococcus pneumoniae](https://durgical.com/en/microbiology/streptococcus-pneumoniae/)

[← All of immunology](https://durgical.com/en/immunology/)

Educational content on the immune system; not a treatment or individual vaccination guide and no substitute for a health professional's advice. No doses are given.

Sources: [17.2 Chemical Defenses](https://openstax.org/books/microbiology/pages/17-2-chemical-defenses) (OpenStax (Microbiology), 2016); [17.4 Pathogen Recognition and Phagocytosis](https://openstax.org/books/microbiology/pages/17-4-pathogen-recognition-and-phagocytosis) (OpenStax (Microbiology), 2016); [Hereditary angioedema](https://medlineplus.gov/genetics/condition/hereditary-angioedema/) (MedlinePlus Genetics, U.S. National Library of Medicine, 2024).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/immunology/complement-three-pathways-mac-regulators/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/immunology/complement-three-pathways-mac-regulators/