Internal Medicine

Complement deficiency


Complement system is a humoral recognition and effector system comprised of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation.

  • Rare (1-7%) primary immunodeficiency syndrome
Relative distribution of the primary immunodeficiencies according to a more traditional classification. | Stiehm ER, editor. Immunologic disorders in infants and children. 5th ed. Philadelphia: Elsevier, Inc.; 2004


Early complement deficiencies (C1-C4):

  • Increased risk of severe, recurrent pyogenic sinus and respiratory tract infections
  • Increased risk of SLE
  • C2 deficiency (M/C complement deficiency)

Terminal complement deficiencies (C5–C9):

  • Increased susceptibility to recurrent Neisseria bacteremia

Complement regulatory protein deficiencies:

  • C1 esterase inhibitor deficiency
    • Causes hereditary angioedema due to unregulated activation of kallikrein → ↑  bradykinin.
    • Characterized by ↓ C4 levels
    • ACE inhibitors contraindicated
  • Paroxysmal nocturnal hemoglobinuria
    • A defect in the PIGA gene preventing the formation of anchors for complement inhibitors, such as decay-accelerating factor (DAF/CD55) and membrane inhibitor of reactive lysis (MIRL/CD59)
    • Causes complement-mediated lysis of RBCs
(2020) Inherited Innate Immunodeficiencies (Immunology) Flashcards | Memorang. Retrieved February 07, 2020, from


Bacteriology of microorganisms involved in complement deficiencies. | Audemard-Verger, A., Descloux, E., Ponard, D., Deroux, A., Fantin, B., Fieschi, C., … Bienvenu, B. (2016). Infections Revealing Complement Deficiency in Adults: A French Nationwide Study Enrolling 41 Patients. Medicine, 95(19), e3548–e3548.


Complement pathways:

  • Early complement pathway:
    • Classical pathway: C1qrs, C2, and C4
    • Lectin-binding pathway: Mannose-binding lectin (MBL)
    • Alternative pathway: C3, factor B and properdin
  • Terminal pathway: C5, C6, C7, C8, and C9
A Variety Of. (2018) Introduction to immunology | McMaster Pathophysiology Review. Retrieved May 14, 2018, from
Schematic representing the activation of the complement cascade. The fragments released into solution are indicated in blue. The key fluid-phase regulators are indicated in green. | Ab, antibody; CRP, C-reactive protein; SAP, serum amyloid P component; PTX3, pentraxin 3; C1 inh, C1 inhibitor; α2-M, α2-macroglobulin; C4BP, C4b-binding protein; FHL-1, factor H-like protein-1; FHR-1, factor H-related molecule-1. | Ram, S., Lewis, L. A., & Rice, P. A. (2010). Infections of people with complement deficiencies and patients who have undergone splenectomy. Clinical Microbiology Reviews, 23(4), 740–780.
  • C4b, C3b → Opsonization
  • C3a, C5a → Inflammation

Clinical features

Recurrent infections:

Clinical manifestations of infections. | Audemard-Verger, A., Descloux, E., Ponard, D., Deroux, A., Fantin, B., Fieschi, C., … Bienvenu, B. (2016). Infections Revealing Complement Deficiency in Adults: A French Nationwide Study Enrolling 41 Patients. Medicine, 95(19), e3548–e3548.

Other manifestations:

  • Auto-immune disorders
  • Glomerulonephritis
  • Joint problems (manifestation)
  • Lung function (MBL variant alleles)
  • Angioedema
  • Dermatomyositis
  • Vasculitis
  • Anaphylactoid purpura
SLE patients with a homozygous deficiency of early components for the classical pathway of complement activation: Severe cutaneous lesions are common clinical presentations in SLE patients with a complete complement deficiency. (A) A homozygous C1q-deficient male child with cutaneous infection (upper panel) and with discoid lupus erythematosus and scarring lesions on face when he was 22 years old (lower panel). (B) A male child with discoid lupus at 16-month old with homozygous C1r-deficiency. This patient experienced generalized seizures, developed a scissoring gait with toe walking, spasticity and weakness of the legs. At 18 years old, he was diagnosed with class IV lupus nephritis and progressed to end-stage renal disease. (C) A complete C4-deficient girl at 3 years old with butterfly rash and cheilitis (upper panel), and osteomyelitis of the femur at 10 years old (lower panel). This patient died at age 12 because of pulmonary infection and cardiovascular failure. (D) A homozygous C2-deficient young woman with acute cutaneous lupus erythematosus. The upper panel shows the butterfly rash, and the lower panel shows photosensitive lesions on sun-exposed areas | Lintner, K. E., Wu, Y. L., Yang, Y., Spencer, C. H., Hauptmann, G., Hebert, L. A., … Yu, C. Y. (2016). Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Frontiers in immunology, 7, 36. doi:10.3389/fimmu.2016.00036


Complement function tests:

C4 (C) FB (A) C3 CH50 Conditions
 · PSGN, C3 NeF AA
 ·  · HAE, C4D
 ·  ·  · TCPD
 · /↓ SLE
  • (C): Classic pathway
  • (A): Alternate pathway
  • PSGN: Post-streptococcal glomerulonephritis
  • C3 NeF AA: C3 Nephritic factor autoantibody
  • C4D: Complement 4 deficiency
  • TCPD: Terminal complement pathway deficiency

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