Indications for Testing

• Recurrent pyogenic infections, recurrent angioedema, cryoglobulinemic vasculitis

Laboratory Testing

• Initial testing – total complement activity enzyme immunoassay
  • CH50, APH50 – if decreased, order further testing
• Further testing based on disease presentation
  • Most common deficiencies – C2, C5-8
  • Recurrent bacterial infections – C2-8, MLB, properdin
  • SLE– C2-C4
  • Atypical HUS – C3, factors B, H and I
  • Membranoproliferative glomerulonephritis – C3, factors H and I
• If initial presentation is angioedema, order C1-esterase testing, C2 and C4

• CIC – may be useful for disease monitoring

The complement system provides an innate defense mechanism against pathogenic organisms.

Epidemiology

• Prevalence – 2% of immunodeficiency disorders are related to complement deficiency
  • Homozygous complement deficiencies – most common is C2 (1/10,000–1/30,000)

Pathophysiology

• Complement system consists of plasma enzymes, regulatory proteins, and proteins activated in cascading fashion, resulting in cell lysis
• In humans, most active complement components are synthesized early in fetal life
  • C1 produced by cells in gut columnar epithelium
  • C4 and C2 produced by macrophages in primary organs
  • C3 produced by hepatic parenchymal cells
  • C5 produced in fetal lung, liver and intestine
• Complement activation can occur via three different pathways – classic, mannose-binding lectin (MBL), and alternative
  • C3 cleavage by each pathway leads to activation of C5-9
• Pathways converge into a final terminal pathway
• Classic pathway
  • Activated by antigen antibody complexes and aggregated immunoglobulins that activate all components
    • First component is C1, which consists of three proteins – C1q, C1r, and C1s
    • Next components are C4, C2 and C3
  • Congenital deficiencies of early classic pathway components, particularly C2 or C4, are often present with lupus-like or other autoimmune disorder involving the following
    • Arthritis
    • Nephritis
    • Rashes
    • Pneumococcal infections
  • Circulating immune complexes (CIC) may form with C1q
    • Elevated in autoimmune disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis and certain types of glomerulonephritis
    • Assays for CIC
      • Designed to detect antigen-nonspecific CIC
      • Targets C1q and its ability to bind immunoglobulins
      • Includes Raji cell, C1q binding, and conglutinin
• MBL pathway
  • MBL binds to microbes with terminal mannose group
    • Triggers complement activation that results in opsonization
  • MBL-associated serine proteases 1 and 2 activate C4, C2, C3 and terminal pathway
  • Patients with abnormal levels of MBL may have recurring significant infections even in the absence of abnormalities in the four major arms of the immune system
• Alternative pathway
  • Activated by complex polysaccharides, lipopolysaccharides and cobra venom
  • C1, C4 and C2 bypassed; activation begins with factor A (C3b) and factor B (C3PA) that break down C3
    • Factor B and factor A form C3 convertase alternative pathway, which is stabilized by properdin
    • Pathway triggered by complex polysaccharides, including endotoxin or lipopolysaccharide
  • C3b is a major opsonin
  • Decreased C3 levels and factor B noted in the following
    • Neonates
    • Nephrotic syndrome
    • Membranoproliferative glomerulonephritis type II
  • Patients present with polysaccharide-coated bacterial infections
• Terminal pathway
  • Activates when any one of the other pathways is activated
  • C3 cleavage results in activation of C5, C6, C7, C8 and C9
    • C3a and C5a function as anaphylotoxins
    • C5a is a major attractant for neutrophils and macrophages
  • Results in membrane attack complex that binds to surface of target cells and, in some cases, leads to lysis of target cells

Clinical Presentation

• Associated with frequent, recurrent disseminated infections
  • Streptococcus pneumoniae – C1, C2, C4, C3, factor A and B
  • Neisseria meningitidis – C5-8
  • Neisseria gonorrhea – C5-8
• May present as an autoimmune disease (eg, SLE, nephritis)
• Complement factor abnormalities and disease associations

  Complement Factor Abnormalities and Disease Associations
  Complement	Level	Associated diseases
  C1q, C1r, C1s	Decreased	Infections – encapsulated bacteria (septicemia, meningitis) Immune complex disease – SLE with glomerulonephritis (risk highest with C1q deficiency)
  C1-esterase inhibitor	Decreased	Hereditary angioedema
  	Non-functional	Acquired angioedema
  C2	Decreased	Infections – pyogenic (Streptococcus pneumoniae), septicemia Immune complex disease – SLE-like, glomerulonephritis Cardiovascular disease
  C3	Decreased with normal C4	Infections – pyogenic (Haemophilus influenzae, S. pneumoniae, Neisseria spp) Immune complex diseases – acute glomerulonephritis, membranoproliferative glomerulonephritis, SLE
  	Decreased with decreased C4	Infections – endocarditis Immune complex diseases – serum sickness, chronic hepatitis (most commonly HBV, HCV)
  	Increased	Acute inflammation, malignancy
  C4	Decreased with normal C3	Infections – encapsulated bacteria (S. pneumoniae) Immune complex disease – cryoglobulinemic vasculitis Hereditary angioedema
  	Decreased with increased C3	Infections – pyogenic (S. pneumoniae), endocarditis Immune complex diseases – SLE with glomerulonephritis, serum sickness, chronic hepatitis (most commonly HBV, HCV)
  C5-C9	Decreased	Infections – pyogenic (N. meningitidis and N. gonorrhoeae) Immune complex disease – SLE (much less frequent than with C1-4 deficiencies)
  Factor H	Decreased	Infections – pyogenic Immune complex disease – membranoproliferative glomerulonephritis Hemolytic uremic syndrome (HUS) Age-related macular degeneration (association)
  Factor I	Decreased	Infections – pyogenic
  Properdin	Decreased	Infections – pyogenic (Neisseria spp and S. pneumoniae)
  Factor B	Decreased	Infections – pyogenic (polysaccharide-coated bacterial infection, especially Neisseria spp and  S. pneumoniae)
  MLB	Decreased	Infections – pyogenic, fungal (yeasts, molds), recurrent respiratory infections in infants Immune complex disease – SLE Cardiovascular disease (increased incidence)

Tests generally appear in the order most useful for common clinical situations

General

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Bruton Agammaglobulinemia
Chronic Granulomatous Disease
Common Variable Immune Deficiency
Hereditary Angioedema
Immunodeficiency, Innate System
Immunoglobulin Disorders
Leukocyte Adhesion Deficiency
Neutrophil Disorders
Severe Combined Immunodeficiencies
T-Cell Deficiency Disorders, Inherited
Thrombotic Microangiopathies