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.

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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Microorganisms

In Pharmacology

ACE inhibitors

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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 (MedlinePlus, U.S. National Library of Medicine, 2026); Hereditary angioedema (MedlinePlus Genetics, U.S. National Library of Medicine, 2026); Risk Factors for Meningococcal Disease (Centers for Disease Control and Prevention (CDC), 2026).

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