[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Immunology](https://durgical.com/en/immunology/) › [Immunodeficiencies](https://durgical.com/en/immunology/#a-immunodeficiency) › Complement deficiencies and hereditary angioedema

[Immunology](https://durgical.com/en/immunology/) · [Immunodeficiencies](https://durgical.com/en/immunology/#a-immunodeficiency)

# Complement deficiencies and hereditary angioedema

- Topic

Missing complement proteins cause repeated Neisseria or capsule infections, lupus-like disease, or episodes of deep swelling.

Updated 2026-11-01

## Key points

- C5–C9 (membrane attack complex) deficiency: recurrent Neisseria meningitidis and N. gonorrhoeae infections.
- C1q, C2, C4 deficiency: lupus-like disease (poor immune complex clearance); C2 is the most common inherited complement deficiency in people of European descent.
- C3 deficiency: severe recurrent pyogenic infections with encapsulated bacteria and immune complex glomerulonephritis.
- Hereditary angioedema: C1 inhibitor deficiency (SERPING1, autosomal dominant); excess bradykinin; non-itchy swelling without hives; low C4 even between attacks.
- Decay-accelerating factor (CD55) and CD59 loss on red cells: paroxysmal nocturnal hemoglobinuria (acquired PIGA mutation), with hemolysis and thrombosis.
- C5 inhibitors (eculizumab, ravulizumab) raise the risk of meningococcal disease: meningococcal vaccination is part of their use.

## What it is

Complement is a cascade of blood proteins that tags microbes, attracts phagocytes, punches holes in bacteria and clears immune complexes. What goes wrong depends on the missing piece: early classical components fail to clear immune complexes, C3 fails to opsonize, the membrane attack complex fails to kill Neisseria, and missing regulators let the cascade run unchecked.

## Complement defects: the table to know

| Deficiency | Defect (gene, inheritance) | What is low | Infections and clues | Key test |
| --- | --- | --- | --- | --- |
| Early classical components (C1q, C1r/s, C2, C4) | Several genes; autosomal recessive | Classical pathway activity | Lupus-like disease, immune complex disease; some encapsulated bacterial infections | Low CH50; specific component levels |
| C3 | C3 gene; autosomal recessive | C3 (opsonization, both pathways) | Severe recurrent pneumonia, sepsis and meningitis by encapsulated bacteria; glomerulonephritis | Very low C3; low CH50 and AH50 |
| Terminal components (C5–C9) | C5 to C9 genes; autosomal recessive | Membrane attack complex | Recurrent or unusual-serogroup meningococcal disease; disseminated gonococcal infection | CH50 near zero; AH50 low |
| Properdin and factor D (alternative pathway) | Properdin (CFP) X-linked; factor D autosomal recessive | Alternative pathway activity | Severe, often fatal meningococcal disease in boys | Low AH50 with normal CH50 |
| Hereditary angioedema (C1 inhibitor) | SERPING1 (types I and II) or F12 (normal C1-INH); autosomal dominant | C1 inhibitor level (type I) or function (type II); C4 consumed | No infections: recurrent non-itchy swelling of face, limbs, gut (abdominal pain) and larynx; triggers: trauma, dental work, stress, estrogens; ACE inhibitors worsen it | Low C4; low C1-INH level or function; C1q normal (low in acquired form) |
| Paroxysmal nocturnal hemoglobinuria (CD55, CD59) | Acquired PIGA mutation in a stem cell clone (X-linked gene, not inherited) | GPI-anchored regulators on blood cells | Intravascular hemolysis, dark morning urine, venous thrombosis in unusual sites, cytopenias | Flow cytometry: loss of CD55 and CD59 (FLAER) |

## Clinical notes

- A person with a second episode of meningococcal disease, or one caused by an uncommon serogroup, should be studied for terminal complement deficiency.
- Laryngeal swelling in hereditary angioedema can be fatal; it does not respond reliably to antihistamines, corticosteroids or epinephrine, which helps tell it from allergic angioedema.
- Angioedema caused by ACE inhibitors also works through bradykinin and has no hives.

## In the lab

- CH50 tests the classical pathway from C1 to C9; AH50 tests the alternative pathway.
- C3 and C4 are measured first; C4 is the best screening test for hereditary angioedema.
- Low C3 and C4 also appear when complement is consumed, as in active lupus or some glomerulonephritis.

## Memory aid

Late pieces missing, Neisseria wins; early pieces missing, lupus begins; the brake missing (C1 inhibitor), the tissues swell.

## Test yourself

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

## Which complement deficiency predisposes to recurrent Neisseria infections?

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

## Why do patients with hereditary angioedema swell without hives or itching?

The swelling is caused by bradykinin, not histamine; missing C1 inhibitor lets kallikrein and bradykinin build up.

## Which complement level is the best screening test for hereditary angioedema?

C4, which is low during and usually between attacks because the uncontrolled C1 keeps consuming it.

## Which class of antihypertensive drug can cause or worsen bradykinin-mediated angioedema?

ACE inhibitors, because ACE also breaks down bradykinin.

## Early classical pathway deficiencies (C1q, C2, C4) are linked to which disease?

Systemic lupus erythematosus or lupus-like disease, from poor clearance of immune complexes and apoptotic cells.

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## Related

- [Complement: three pathways, MAC, regulators](https://durgical.com/en/immunology/complement-three-pathways-mac-regulators/)
- [Type III hypersensitivity (immune complexes)](https://durgical.com/en/immunology/type-iii-hypersensitivity/)
- [Immunodeficiency: warning signs and the infection pattern by defect](https://durgical.com/en/immunology/immunodeficiency-warning-signs-and-the-infection-pattern-by-defect/)
- [Secondary immunodeficiency: HIV, malnutrition, drugs, asplenia](https://durgical.com/en/immunology/secondary-immunodeficiency-hiv-malnutrition-drugs-asplenia/)

## Related conditions

- [Bacterial meningitis](https://durgical.com/en/conditions/bacterial-meningitis/)
- [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/)
- [Haemophilus influenzae](https://durgical.com/en/microbiology/haemophilus-influenzae/)

## In Pharmacology

- [ACE inhibitors](https://durgical.com/en/pharmacology/classes/ace-inhibitors/)

[← 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: [Complement](https://medlineplus.gov/ency/article/003456.htm) (MedlinePlus, U.S. National Library of Medicine, 2026); [Hereditary angioedema](https://medlineplus.gov/genetics/condition/hereditary-angioedema/) (MedlinePlus Genetics, U.S. National Library of Medicine, 2026); [Risk Factors for Meningococcal Disease](https://www.cdc.gov/meningococcal/risk-factors/index.html) (Centers for Disease Control and Prevention (CDC), 2026).

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Source: https://durgical.com/en/immunology/complement-deficiencies-and-hereditary-angioedema/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/immunology/complement-deficiencies-and-hereditary-angioedema/