Overview
Complement deficiencies are rare primary immunodeficiencies resulting from inherited absence or dysfunction of complement proteins, regulators, or receptors. They predispose to recurrent bacterial infections, autoimmune disease (particularly systemic lupus erythematosus–like syndromes), and in some cases angioedema. Complement proteins play a central role in innate immunity by opsonisation, chemotaxis, and direct lysis of pathogens via the membrane attack complex (MAC). Overall prevalence is low but varies depending on the specific pathway; deficiencies of terminal components (C5–C9) are strongly associated with recurrent Neisseria infections.
Definition
Complement system: A group of plasma proteins that enhance immune response via opsonisation, inflammation, and cell lysis.
Classical pathway: Activated by antigen–antibody complexes.
Alternative pathway: Antibody-independent activation, triggered by pathogen surfaces.
Membrane attack complex (MAC): Terminal complex (C5b–C9) that creates pores in bacterial membranes, leading to lysis.
Anatomy & Physiology
- Three activation pathways:
- Classical → triggered by IgG/IgM immune complexes.
- Lectin → triggered by mannose-binding lectin binding microbial carbohydrates.
- Alternative → continuous low-grade activation on microbial surfaces.
- Classical → triggered by IgG/IgM immune complexes.
- All pathways converge at C3 convertase → C3b opsonisation, C5 convertase activation → C5b-9 MAC formation.
- Complement also enhances phagocytosis and recruits inflammatory cells (C3a, C5a = anaphylatoxins).
Remember
“C3 is central” → all pathways converge here.
Aetiology and Risk Factors
Aetiology
- Genetic mutations leading to absent or dysfunctional complement proteins.
- Deficiencies may involve early components, central components (C3), terminal components (C5–C9), or regulators (C1 inhibitor, factor H/I).
Risk Factors
- Family history of complement deficiency.
- Consanguinity (rare AR inheritance).
Pathophysiology
- Missing complement protein → impaired opsonisation, chemotaxis, or MAC formation.
- Early classical pathway defects (C1, C2, C4) → defective immune complex clearance → predispose to SLE.
- C3 deficiency → severe, recurrent pyogenic infections (S. pneumoniae, H. influenzae).
- Terminal pathway (C5–C9) deficiency → recurrent Neisseria meningitidis infections.
- Regulatory protein deficiencies:
- C1 inhibitor deficiency → uncontrolled complement activation → hereditary angioedema.
Think
“Early = autoimmunity, Middle = pyogenic infections, Late = Neisseria.”
Clinical Manifestations
- Early complement deficiencies (C1, C2, C4): SLE-like disease, recurrent respiratory infections.
- C3 deficiency: Recurrent severe bacterial infections, sepsis, meningitis, pneumonia.
- C5–C9 (terminal) deficiency: Recurrent Neisseria meningitidis infections (meningitis, sepsis).
- C1 inhibitor deficiency: Angioedema (non-pruritic swelling of skin, airway, gut).
Diagnosis
- Screening test: Total complement activity (CH50) — measures classical pathway.
- AH50: Assesses alternative pathway.
- Specific complement assays: Quantitative C3, C4, C1-INH levels and function.
- Genetic testing: Confirms diagnosis.
Classification
- By site of defect:
- Classical pathway (C1, C2, C4).
- Central (C3).
- Terminal (C5–C9).
- Regulatory (C1-INH, Factor H/I).
Treatment
- Prompt antibiotic therapy for infections.
- Vaccination (especially meningococcal, pneumococcal, Hib).
- Prophylactic antibiotics in recurrent Neisseria.
- C1-INH concentrate or bradykinin inhibitors for hereditary angioedema.
- Genetic counselling.
Remember
Vaccination against Neisseria meningitidis is essential in terminal pathway deficiencies.
Complications & Prognosis
- Early pathway deficiency → recurrent infections + high risk SLE/autoimmunity.
- C3 deficiency → poor prognosis without prophylaxis due to severe recurrent sepsis.
- Terminal pathway deficiency → recurrent but survivable Neisseria infections if recognised and vaccinated.
- Hereditary angioedema → risk of life-threatening airway obstruction.
Complement Deficiency Patterns
| Deficiency | Typical Presentation | Key Pathogens | Associated Conditions |
| C1, C2, C4 | Recurrent infections + SLE-like disease | Pyogenic bacteria | SLE, autoimmune disease |
| C3 | Severe recurrent infections | S. pneumoniae, H. influenzae | Sepsis, meningitis |
| C5–C9 | Recurrent meningitis | Neisseria meningitidis | – |
| C1 inhibitor | Angioedema (non-pruritic, airway risk) | – | Hereditary angioedema |
References
- Walport MJ. Complement. N Engl J Med. 2001;344(14):1058–66.
- Skattum L, van Deuren M, van der Poll T, Truedsson L. Complement deficiency states and associated infections. Mol Immunol. 2011;48(14):1643–55.
- Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110–7.
- Ballow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy Clin Immunol. 2002;109(4):581–91.
- Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020;382(12):1136–48.
Discussion