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-C8
  • Recurrent bacterial infections – C2-C8, mannose-binding lectin (MBL), properdin
  • Systemic lupus erythematosus (SLE) – C2-C4
  • Atypical hemolytic uremic syndrome (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

• Circulating immune complexes – may be useful for disease monitoring

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

Epidemiology

• Prevalence – 2% of immunodeficiency disorders relate to complement deficiency
  • Homozygous complement deficiencies – C2 most common (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, 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, C6, C7, C8, C9
• Pathways converge into a final terminal pathway
• Classic pathway
  • Activated by antigen antibody complexes and aggregated immunoglobulins that activate all components
    • First component, C1, consists of three proteins – C1q, C1r, C1s
    • Next components are C2, C3, C4
  • Congenital deficiencies of early classic pathway components, particularly C2 or C4, 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 (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, certain types of glomerulonephritis)
    • Assays for CIC
      • Designed to detect antigen-nonspecific CIC
      • Target C1q and its ability to bind immunoglobulins
      • Include Raji cell, C1q binding, and conglutinin
• MBL pathway
  • 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 A and factor B 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, 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
    • In some cases, leads to lysis of target cells

Clinical Presentation

• Associated with frequent, recurrent disseminated infections
  • Streptococcus pneumoniae – C1, C2, C3, C4, factor A and B
  • Neisseria meningitidis – C5, C6, C7, C8
  • Neisseria gonorrhea – C5, C6, C7, C8
• 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 – systemic lupus erythematosus (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-C4 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)
  MBL	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

• Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, Kobrynski LJ, Levinson AI, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94 (5 Suppl 1) :S1-63.PubMed
• Chen M, Daha MR, Kallenberg CG. The complement system in systemic autoimmune disease. J Autoimmun. 2010; 34 (3) :J276-J286.PubMed
• Haynes BF and Fauci AS. Introduction to the Immune System. In Kasper D et al. eds. Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005. pp. 1907-1930.
• Immune Deficiency Foundation. [Accessed: 27 Apr 2009] 
• Lipsker D, Hauptmann G. Cutaneous manifestations of complement deficiencies. Lupus. 2010; 19 (9) :1096-1106.PubMed
• Mayilyan KR. Complement genetics, deficiencies, and disease associations. Protein Cell. 2012; 3 (7) :487-496.PubMed
• Nilsson B, Ekdahl KN. Complement diagnostics: concepts, indications, and practical guidelines. Clin Dev Immunol. 2012; 2012 :962702-.PubMed
• Pettigrew HD, Teuber SS, Gershwin ME. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009; 1173 :108-123.PubMed
• Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004; 113 (4) :585-593.PubMed

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