Complement System Disorders

Inherited component deficiencies (mechanism: absent protein)

• Autosomal recessive inheritance for nearly all individual components (C1q/C1r/C1s, C2, C4, C3, C5–C9); heterozygotes are usually clinically silent because roughly half-normal levels suffice for cascade amplification
• X-linked recessive properdin deficiency: the one classic exception — affected patients are essentially all male, and fulminant meningococcemia may be the presenting event
• Ancestry effects: C9 deficiency is the most common inherited complement deficiency in Japanese and Korean populations; C2 deficiency is the most common in populations of European ancestry, and C4 null alleles cluster with certain HLA haplotypes linked to lupus

Inherited regulator defects (mechanism: unopposed activation)

• **Autosomal dominant SERPING1 mutations** cause hereditary angioedema types 1 and 2; family history is present in most but de novo mutation occurs, so its absence does not exclude HAE
• Factor H, factor I, MCP/CD46 mutations and gain-of-function *C3*/factor B variants drive complement-mediated renal disease

Acquired mechanisms

• **Somatic PIGA mutation** in a hematopoietic clone removes GPI-anchored CD55 and CD59 → paroxysmal nocturnal hemoglobinuria, complement-mediated intravascular hemolysis
• Autoantibodies: C3 nephritic factor stabilizes the alternative-pathway convertase; anti-factor H antibodies cause atypical HUS; anti-C1-INH antibodies produce acquired angioedema, classically in older adults with B-cell lymphoproliferative disease or monoclonal gammopathy
• Consumption/loss: SLE flare, post-streptococcal and membranoproliferative GN, endocarditis, cryoglobulinemia, sepsis, plasmapheresis, and protein-losing states

Modifiable risk factors

• Incomplete vaccination — the single most exploitable factor; ACIP designates complement deficiency and complement-inhibitor therapy as indications for both MenACWY and MenB series
• Iatrogenic terminal-pathway blockade with eculizumab or ravulizumab, which creates a functional C5 deficiency and carries a boxed warning for meningococcal sepsis
• Crowding and exposure — dormitories, military barracks, travel to the African meningitis belt or Hajj
• HAE precipitants — ACE inhibitors, estrogen-containing contraceptives, dental/surgical trauma, and psychological stress

• Classical pathway deficiencies (C1q, C1r, C1s, C2, C4): Loss of early complement activation leads to impaired immune complex clearance, resulting in lupus-like autoimmune disease (particularly with C1q deficiency) and increased susceptibility to pyogenic infections; C2 deficiency is the most common classical pathway disorder but paradoxically often asymptomatic
• Alternative pathway defects (Factor D, Factor B, Properdin, C3): Inability to amplify complement cascades, especially critical for opsonization of encapsulated bacteria; Properdin deficiency (X-linked) shows increased Neisseria meningitidis risk; C3 deficiency causes recurrent pyogenic infections and glomerulonephritis
• Terminal complement deficiencies (C5, C6, C7, C8, C9): Specific inability to form the membrane attack complex (MAC); dramatically increases risk of Neisseria species (meningococcus and gonorrhea) with 600-1000 fold increased risk compared to general population; C9 deficiency is usually asymptomatic
• Complement regulatory protein defects (C1-inhibitor, Factor H, Factor I, CD55, CD46): Loss of negative regulation leads to uncontrolled complement activation; causes hereditary angioedema (C1-INH deficiency), post-infectious glomerulonephritis (Factor H mutations), and membranoproliferative glomerulonephritis (Factor I deficiency)
• Acquired complement deficiencies: Consumption occurs in systemic lupus erythematosus (low C3/C4), sepsis, post-infectious glomerulonephritis, and membranoproliferative glomerulonephritis; can develop secondary to infections or malignancies
• Complement-mediated inflammation: Excessive complement activation (particularly C3a and C5a generation) drives inflammation in some regulatory defects, paradoxically causing tissue damage despite "immunodeficiency"

• Recurrent bacterial infections (especially encapsulated bacteria: Streptococcus pneumoniae, Haemophilus influenzae; or Neisseria species: meningococcus, gonorrhea depending on complement defect) presenting with meningitis, bacteremia, or arthritis; usually begins in childhood with classical pathway defects or terminal complement defects
• Meningococcal meningitis as a sentinel infection, particularly in young adults—a key red flag suggesting terminal complement deficiency (C5-C9) or Properdin deficiency; recurrent meningitis is highly unusual and should prompt complement testing
• Systemic lupus erythematosus (SLE)-like syndrome with antinuclear antibodies (ANAs) and low complement levels, most commonly seen with C1q, C4, and C2 deficiencies; presents with rash, arthralgia, and renal disease but may lack typical serologic markers (anti-dsDNA negativity is common)
• Hereditary angioedema (HAE) from C1-inhibitor deficiency: recurrent episodes of nonpitting facial/airway edema without urticaria lasting 24-72 hours, triggered by stress, trauma, or infections; different pathophysiology than allergic angioedema (no mast cell involvement, no urticaria)
• Glomerulonephritis patterns vary by defect: post-infectious GN (Factor H mutations), membranoproliferative GN (C3 deficiency), and lupus nephritis (early pathway defects); may present with hematuria, proteinuria, or progressive renal insufficiency
• Partial lipodystrophy associated with C3 nephritic factor and certain Factor H mutations; presents with selective loss of subcutaneous fat in face, trunk, and proximal extremities often preceding or coinciding with glomerulonephritis

• Complement level quantification (serum C3, C4, C1q, etc.) as initial screening; classical pathway measured by CH50 (total hemolytic complement), alternative pathway by AP50; low levels suggest deficiency or consumption but cannot distinguish between them
• Individual complement protein assays: Specific measurement of suspected deficient proteins (C2, C3, Factor B, Factor H, Factor I, C1-INH); most accurate for diagnosis of specific deficiencies
• Functional assays: CH50 (classical pathway), AP50 (alternative pathway), and CH100 (terminal pathway) assess cascade integrity; a null/abnormal result guides further directed testing
• C1-inhibitor assessment for suspected hereditary angioedema: quantitative (low C1-INH levels) vs. qualitative (normal or elevated levels but dysfunctional protein); check C4 level (typically low during attacks); distinguishes Type 1 (low C1-INH), Type 2 (normal/high C1-INH), and Type 3 (normal C1-INH with F12 mutations)
• Genetic testing: Increasingly available for complement genes; particularly useful for confirming suspected deficiencies and for counseling family members
• Flow cytometry for membrane regulatory proteins (CD55/DAF, CD46/MCP) in suspected membrane-associated defects
• Clinical suspicion triggers: Unexplained meningococcal meningitis (especially recurrent), lupus-like disease with low complement, or unexplained recurrent infections should prompt complement investigation

• Prophylactic antibiotics for terminal complement deficiencies (C5-C9) and Properdin deficiency: penicillin V 250 mg BID orally (or amoxicillin) is standard; excellent evidence for reduced infection risk; continue indefinitely unless vaccination documented
• Meningococcal vaccination (critical for all complement deficiencies, especially terminal pathway): MenACWY (Menhibrix or Menveo) and MenB; revaccinate every 5 years for those with terminal complement deficiency or at risk; educate patient about recurrent risk
• **Pneumococcal and Haemophilus influenzae b (Hib) vaccination** for classical pathway and C3 deficiencies; use conjugate vaccines (PCV13/PPSV23 for pneumococcus) for optimal response
• Complement inhibition therapies (emerging): Eculizumab (C5 monoclonal antibody) approved for post-infectious GN with C3 glomerulonephritis and certain membranoproliferative patterns; pegcetacoplan (C3 inhibitor) for C3 glomerulonephritis; factor H supplementation under investigation
• Hereditary angioedema management:
• Acute attacks: C1-INH replacement (Berinert 20 units/kg IV) or kallikrein inhibitor (ecallantide 30 mg IV or icatibant 30 mg SC); airway involvement requires immediate intervention
• Prophylaxis: C1-INH concentrates, androgens (stanozolol, danazol—increase endogenous C1-INH), or bradykinin receptor antagonist (kallikrein inhibitors); avoid ACE inhibitors and estrogens (precipitate attacks)
• Supportive care for infectious complications: Appropriate antibiotics for identified pathogens; early recognition and aggressive management of systemic infections
• Immune globulin replacement (IVIG) may have role in selective IgA deficiency with complement dysfunction but not standard for isolated complement defects

• Overwhelming sepsis and meningitis in terminal complement deficiencies—particularly with meningococcus—occurring rapidly and with high mortality despite antibiotics if complement deficiency unrecognized; meningococcemia can progress to septic shock and death within hours
• Recurrent Neisseria infections including disseminated gonococcal infection with arthritis-dermatitis syndrome in those with C5-C9 deficiency or Properdin deficiency; unusual presentation should trigger

• **Recurrent or first-episode Neisseria infection in an adolescent is the trigger phrase: the single best next step is a total hemolytic complement (CH50)**, which is absent/near-zero in any terminal-pathway (C5–C9) defect; follow an abnormal CH50 with individual component assays rather than ordering them first
• Angioedema without urticaria or pruritus, unresponsive to epinephrine, antihistamines, and glucocorticoids is bradykinin-mediated by definition — mast cells are not involved. The best screening test is a C4 level, which is low even between attacks; confirm with C1-INH antigenic level and function
• The C1q level is the discriminator: normal C1q with low C4 and low C1-INH = hereditary angioedema; low C1q = acquired C1-INH deficiency, which should prompt a search for lymphoproliferative disease or monoclonal gammopathy in an older adult
• The most tested association: C1q deficiency carries the highest genetic risk of a lupus-like syndrome, because failure of early classical-pathway opsonization impairs clearance of apoptotic debris and immune complexes — the reason early-pathway deficiency causes autoimmunity, while terminal deficiency causes infection
• Distinguish deficiency from consumption: low C3 and C4 in an SLE flare or post-streptococcal glomerulonephritis reflects consumption and normalizes with disease control; persistently absent complement across remission suggests true deficiency
• C3 deficiency is the most severe phenotype because C3 is the convergence point of all three pathways — patients get both encapsulated-organism pyogenic infection and immune-complex glomerulonephritis
• C2 deficiency is the most common inherited defect in Western populations yet is frequently asymptomatic — a favorite distractor when the stem wants a terminal-pathway answer
• Before starting eculizumab or ravulizumab, vaccinate against meningococcus (ACIP recommends both MenACWY and MenB); the drug creates an acquired C5 deficiency and carries a boxed warning for fulminant meningococcal sepsis
• PNH is diagnosed by flow cytometry for CD55/CD59, not the obsolete Ham acid hemolysis or sucrose lysis tests