Complement deficiencies !

Inherited lack of a complement protein: missing late parts cause repeated meningococcal infections; missing early parts cause lupus-like disease.

Updated 2026-11-01

Structures involved

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Why it happens

What it is

A group of mostly inherited primary immunodeficiencies in which one complement protein is missing or does not work. Missing early classical components (C1q, C4, C2) mainly cause lupus-like autoimmunity, missing C3 causes severe pyogenic infections from infancy, and missing terminal components (C5–C9) or properdin cause recurrent Neisseria infections; hereditary angioedema has its own page.

Who gets it

Rare overall; together they account for only a small share of primary immunodeficiencies. C2 deficiency is the most common in people of European ancestry (about 1 in 20,000). Terminal component deficiencies are found in a meaningful fraction of people with recurrent or familial meningococcal disease, and are more frequent in some populations (for example C6 deficiency in people of African ancestry). No Colombian prevalence data exist; cases are usually recognised after a second meningococcal episode or a lupus-like illness in a child.

Causes

Autosomal recessive variants in genes for individual complement proteins (C1q, C2, C4, C3, C5–C9, factors B, D, H and I)
X-linked recessive properdin deficiency (affects boys)
Partial (heterozygous) deficiency of C4 is common and usually silent
Acquired low complement: consumption in active lupus or glomerulonephritis, liver failure, malnutrition, and treatment with complement-inhibiting monoclonal antibodies

Risk factors

Parental consanguinity or a sibling with the same deficiency
Family history of meningococcal disease or early-onset lupus
Living in or travelling to areas with high meningococcal transmission, or crowded settings (dormitories, military barracks)
Lack of meningococcal and pneumococcal vaccination

Pathophysiology

Complement is activated by three pathways (classical, lectin, alternative) that converge on C3. Cleavage of C3 coats bacteria with C3b for phagocytosis and starts the terminal pathway, in which C5b–C9 assemble the membrane attack complex that lyses thin-walled Gram-negative bacteria such as Neisseria. Without the terminal components, Neisseria survive in the blood and meninges. Without C3, opsonisation of encapsulated bacteria fails and infections are severe from early life. Early classical components also clear immune complexes and apoptotic cells; when they are missing, nuclear self-antigens persist and drive lupus-like autoimmunity. Deficiency of regulators (factor H or I) lets the alternative pathway run unchecked, consuming C3 and damaging the glomerular endothelium.

Classification

Early classical pathway (C1q, C1r/s, C4, C2): lupus-like disease, also pyogenic infections
C3 and alternative pathway activators (factor B, D): severe recurrent pyogenic infections, glomerulonephritis
Terminal pathway (C5–C9) and properdin: recurrent invasive Neisseria infections
Regulators (factor H, factor I, CD46): atypical haemolytic uraemic syndrome, C3 glomerulopathy, secondary C3 consumption
Lectin pathway (MBL): common and usually not a cause of immunodeficiency by itself

Symptoms and signs

Two or more episodes of meningococcal meningitis or sepsis, often in adolescence and with less common serogroups (terminal or properdin deficiency)
Disseminated gonococcal infection (fever, skin pustules, arthritis)
Recurrent pneumonia, otitis, bacteraemia with Streptococcus pneumoniae or Haemophilus influenzae from infancy (C3 deficiency)
Lupus-like disease beginning in childhood: photosensitive rash, oral ulcers, arthritis, kidney involvement (C1q, C4 deficiency)
Blood or protein in the urine, oedema and high blood pressure (glomerulonephritis)
Many people with partial or C2 deficiency have no symptoms

Diagnosis

Clinical: Suspect it after a second meningococcal infection, a first episode with an uncommon serogroup, meningococcal disease in a family, or lupus in a young child (especially a boy or a prepubertal child). Test when the patient is well, because acute infection and active lupus lower complement levels.
Tests: CH50 (classical pathway) and AH50 (alternative pathway) haemolytic assays as screening: a value near zero suggests a complete deficiency of one component; a low CH50 with normal AH50 points to C1, C2 or C4; low AH50 with normal CH50 to factor B, D or properdin; both low to C3 or C5–C9. Then measure individual components (C3, C4 and the suspected protein) and confirm with genetic testing. Urinalysis, renal function and autoantibodies (ANA, anti-dsDNA) when lupus or kidney disease is suspected. Blood cultures and lumbar puncture during acute infection.
Imaging: Not needed for diagnosis; chest radiography for pneumonia and renal ultrasound when kidney disease is present.

Differential diagnosis

Asplenia or hyposplenism (also predisposes to encapsulated bacteria)
Antibody deficiencies such as common variable immunodeficiency or X-linked agammaglobulinaemia
Acquired complement consumption (active lupus, post-infectious or membranoproliferative glomerulonephritis)
Treatment with complement inhibitors for paroxysmal nocturnal haemoglobinuria or atypical HUS
Hereditary angioedema (C1 inhibitor deficiency; swelling without infections)

Goal of treatment

Treat each infection fast, prevent the next one with full vaccination and, when indicated, antibiotic prophylaxis, and detect and control autoimmune or kidney disease early.

Treatment

Acute: Emergency treatment of suspected meningococcal disease: immediate intravenous third-generation cephalosporin, fluid resuscitation and intensive care for shock; prophylaxis for close contacts.
Medical: Vaccination against Neisseria meningitidis (conjugate ACWY and serogroup B vaccines, with boosters), Streptococcus pneumoniae and Haemophilus influenzae type b; antibody responses may be checked afterwards.
Medical: Long-term antibiotic prophylaxis (for example a penicillin) for people with recurrent infections, decided by the specialist.
Medical: Lupus-like disease treated as SLE: hydroxychloroquine, glucocorticoids and immunosuppressants for organ involvement; C1q deficiency has been corrected by haematopoietic stem cell transplantation in severe cases.
Medical: For factor H or I deficiency with atypical HUS or C3 glomerulopathy: complement-inhibiting monoclonal antibodies under specialist care (with meningococcal vaccination first).
Follow-up: Patient and family education to seek care at the first fever with rash; screening of siblings; carry a medical alert card.

Complications

Meningococcal sepsis with shock, limb loss or death
Hearing loss and neurological sequelae after meningitis
Bronchiectasis after recurrent pneumonia (C3 deficiency)
Lupus nephritis and other organ damage
Membranoproliferative glomerulonephritis, C3 glomerulopathy, atypical HUS and kidney failure

Prognosis

With vaccination and prompt treatment of infections, most people with terminal component deficiency live normally; each meningococcal episode tends to be less lethal than in people with normal complement, but recurrences are frequent. C1q and C4 deficiency carry the highest risk of lupus (most affected people) and their outlook depends on kidney and nervous system involvement. C3 deficiency has the most severe infectious course.

Prevention

Meningococcal (ACWY and B), pneumococcal and Hib vaccination of affected people and of anyone starting complement-inhibitor therapy
Testing of siblings of an affected person
Early medical attention for any fever, especially with rash

Test yourself

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

Recurrent Neisseria meningitidis infections suggest deficiency of which complement components?

The terminal components C5–C9 (membrane attack complex) or properdin.

Which complement deficiencies are most strongly associated with systemic lupus erythematosus?

Early classical pathway components: C1q (highest risk), C4 and C2.

What is the best screening test for a suspected complement deficiency?

Total haemolytic complement (CH50), together with AH50 for the alternative pathway; a near-zero value suggests a complete deficiency.

Which deficiency causes the most severe recurrent pyogenic infections from infancy?

C3 deficiency, because C3 is the convergence point needed for opsonisation and for the terminal pathway.

Which vaccines must patients receive before starting a complement inhibitor?

Meningococcal vaccines against serogroups A, C, W, Y and B, because the drug creates an acquired terminal complement deficiency.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Complement deficiencies (Immune Deficiency Foundation, 2024); Complement component 2 deficiency (MedlinePlus Genetics (U.S. National Library of Medicine), 2024); Risk Factors for Meningococcal Disease (Centers for Disease Control and Prevention (CDC), 2024).

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Kidneys highlighted on the Durgical 3D model