Complement Defects

Overview Of The Complement System

• The complement system is a crucial component of innate immunity.
• It consists of multiple proteins circulating as inactive precursors.
• These proteins are primarily synthesised by the liver.
• Once triggered, these proteins activate each other sequentially.
• This sequential activation creates a cascading enzyme reaction.
• The complement system bridges both innate and adaptive immunities.

Pathways Of Complement Activation

• The complement cascade is activated via three main pathways.
• The classical pathway is triggered by antigen-antibody immune complexes.
• Immunoglobulins IgM and IgG activate the classical pathway.
• The alternative pathway is continuously active at low levels.
• It is amplified by bacterial lipopolysaccharides, endotoxins, or yeast cell walls.
• The lectin pathway is activated by mannose-binding lectin binding to microbial surface mannose.
• All three pathways converge at the activation of C3.
• This activation leads to the formation of the membrane attack complex (MAC).

Functions Of Complement

• The complement system causes direct lysis of bacteria, viruses, and tumour cells.
• It facilitates opsonisation, enhancing efficient phagocytosis by macrophages and neutrophils.
• It generates chemotactic mediators like C5a to attract polymorphonuclear leukocytes.
• It promotes immune clearance by removing circulating immune complexes to the spleen and liver.

Primary Complement Deficiencies

• Primary complement deficiencies are rare primary immunodeficiency diseases.
• They lead to an increased susceptibility to infections or autoimmunity.
• Different component deficiencies are associated with specific pathogen susceptibilities.

Early Complement Pathway Deficiencies (C1, C4, C2)

• These deficiencies involve the classical complement pathway.
• C2 deficiency is the most common complement pathway deficiency.
• Patients with early component defects lack sufficient opsonisation capabilities.
• They are highly susceptible to encapsulated bacteria.
• Common pathogens include Streptococcus pneumoniae and Haemophilus influenzae.
• C1q, C4, and C2 deficiencies are strongly associated with systemic lupus erythematosus (SLE).
• Nearly 95% of patients with C1q deficiency develop severe autoimmune disease.

C3 Deficiency

• C3 is the central molecule for all complement activation pathways.
• It is a critical opsonin for the ingestion and killing of bacteria.
• C3 deficiency results in severe, recurrent pyogenic sinus and respiratory infections.
• Patients face severe infections from encapsulated bacteria.
• C3 deficiency is also associated with glomerulonephritis.

Late Complement Pathway Deficiencies (C5-C9)

• These terminal components are responsible for assembling the membrane attack complex.
• The membrane attack complex creates pores in cell membranes to cause osmotic lysis.
• Only Gram-negative bacteria are susceptible to this specific bactericidal effect.
• Deficiency of C5, C6, C7, C8, or C9 severely impairs this lytic capability.
• Patients demonstrate a high risk for recurrent Neisseria infections.
• Approximately 40% of these patients develop neisserial meningitis or septicaemia.

Alternative Pathway Deficiencies

• Properdin (Factor P) stabilises the alternative pathway C3 convertase.
• Properdin deficiency is inherited in an X-linked recessive manner.
• This deficiency strongly predisposes the host to severe meningococcal infections.

Regulatory Protein Deficiencies

• C1 esterase inhibitor (C1 INH) prevents unwarranted autolytic complement activation.
• Deficiency of C1 INH causes hereditary angioedema.
• Hereditary angioedema is an autosomal dominant trait.
• It presents with recurrent episodes of localised oedema.
• Oedema affects the face, trunk, extremities, intestines, and larynx.
• Intestinal oedema manifests as severe colicky abdominal pain.
• Laryngeal oedema can cause life-threatening airway obstruction.
• Decay-accelerating factor (DAF) deficiency leads to complement-mediated haemolysis.
• This condition manifests clinically as paroxysmal nocturnal haemoglobinuria.

Diagnostic Evaluation

Initial Screening Assays

• The CH50 assay screens the entire classical complement pathway from C1 through C9.
• A complete deficiency of any classical component results in a zero or near-zero CH50 value.
• Improper sample handling is the most common cause of an abnormally low CH50 result.
• The AH50 assay assesses the alternative complement pathway.

Specific Immunochemical Assays

• Targeted functional testing should only be pursued when CH50 or AH50 values are severely reduced.
• Measurement of individual serum levels of C3 and C4 is widely available.
• Specific components can be quantified using radial immunodiffusion, ELISA, or nephelometry.
• Flow cytometry and haemolytic assays help detect specific terminal pathway defects.

Management And Prognosis

Infection Prevention And Management

• No specific curative therapy exists for primary complement deficiencies.
• Management relies on aggressive treatment of acute bacterial infections.
• Antibiotic prophylaxis against encapsulated organisms is highly beneficial.
• Meningococcal vaccination is the best protective strategy for terminal complement deficiencies.
• Both the quadrivalent (A, C, Y, W-135) and MenB vaccines must be administered.
• Immunisations against Streptococcus pneumoniae and Haemophilus influenzae are also critical.

Management Of Hereditary Angioedema

• Routine acute episodes are treated with targeted therapies.
• Infusion of synthetic C1 esterase inhibitor is required for acute laryngeal attacks.
• Prophylactic therapy includes attenuated androgens like danazol or stanozolol.
• Tranexamic acid can also provide significant clinical improvement.

Autoimmunity Surveillance

• Close clinical surveillance for systemic lupus erythematosus is required.
• This is particularly important for patients with C1, C2, C4, and C5 deficiencies.

Summary Of Complement Deficiencies