Complement Deficiency - Complement Activity

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

Epidemiology

• Prevalence – 2% of immunodeficiency disorders are related to complement deficiency

Pathophysiology

• The 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 synthesized by cells in gut columnar epithelium
• C4 and C2 produced by macrophages in primary organs
• Hepatic parenchymal cells synthesize C3
• Fetal lung, liver and intestine produce C5
• Complement activation can occur via three different pathways
  • Classical, mannose binding and alternative pathways
    • C3 cleavage by each pathway leads to activation of C5-9
    • All 3 pathways converge in the final terminal pathway
  • Classical pathway
    • Consists of antigen antibody complexes and aggregated immunoglobulins; all components are activated
    • First component is C1 which consists of 3 proteins, C1q, C1r, C1s
    • Next components are C4, C2 and C3
    • Congenital deficiencies of early classical pathway components, particularly C2 or C4, often present with lupus-like or other autoimmune disorders involving
      • 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 (RA) and certain types of glomerulonephritis
      • May be useful for disease monitoring
      • Assays for CIC
        • Designed to detect antigen-nonspecific CIC
        • Target C1q and its ability to bind Ig
        • Include Raji cell, C1q binding and conglutinin
  • Mannose binding pathway
    • Mannose binding lectin binds to microbes with terminal mannose group
    • Triggers complement activation which results in opsonization
    • MBL-associated serine proteases 1 and 2 activate C4, C2, C3 and terminal pathway
    • Patients who have abnormal levels of mannose binding protein may have recurrent significant infections in the absence of abnormalities in the four major arms of the immune system
  • Alternative pathway
    • Activated by complex polysaccharides and lipopolysaccharides
    • C1, C4 and C2 bypassed; activation begins with factor A (C3b) and factor B (C3PA) which breaks down C3
    • Factor B and factor A (C3b) form C3 convertase alternative pathway
    • Pathway triggered by complex polysaccharides, including endotoxin
    • C3b is a major opsonin along with iC3b
    • Decreased C3 levels and factor B noted in:
      • Neonates
      • Nephrotic syndrome
      • Membranoproliferative nephritis type II
    • Patients present with polysaccharide coated bacterial infections
  • Terminal pathway
    • Activated 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 which binds to surface of target cells and lysis them

Clinical Presentation

• Associated frequently with disseminated recurrent infections
  • Streptococcus pneumoniae
  • Neisseria meningitidis
  • Neisseria gonorrhea
• May present as an autoimmune disease (eg, SLE, nephritis)

Bruton Agammaglobulinemia

Chronic Granulomatous Disease - Neutrophil Oxidative Burst

Hereditary Angioedema

Immunodeficiency, Innate System  

Immunoglobulin Disorders  

Leukocyte Adhesion Deficiency  

Neutrophil Dysfunction

T-Cell Deficiency Disorders, Inherited

Diagnosis

• Indications for testing – recurrent pyogenic infections; recurrent angioedema; cryoglobulinemic vasculitis
• Laboratory testing
  • Complement enzyme activity and concentration testing is based on disease presentation
  • Initial screening may involve complement activity enzyme immunoassay – if decreased, order further testing
  • Most common deficiencies in C3 and C4
  • If initial presentation is angioedema, order C-1 esterase testing

Indications for Ordering

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.
Test Name and Number	Comments
Raji Cell Immune Complex Assay 0050302 Method: Flow Cytometry
Immune Complex Panel 0050667 Method: Flow Cytometry/Enzyme-Linked Immunosorbent Assay
Complement Component 1Q Level 0099130 Method: Radial Immunodiffusion
Complement Component 7 Level 0099073 Method: Radial Immunodiffusion
Complement Component 8 Level 0099074 Method: Radial Immunodiffusion
Complement Component 9 Level 0099076 Method: Radial Immunodiffusion
Complement Component 8 Functional 0099133 Method: Hemolytic Assay
Complement Component 7 Functional 0099121 Method: Hemolytic Assay
Complement Component 6 Functional 0099131 Method: Quantitative Hemolytic Assay
Complement Component 9 Functional 0099120 Method: Quantitative Hemolytic Assay
C1-Esterase Inhibitor 0050140 Method: Nephelometry	Refer to Hereditary Angioedema topic
C1-Esterase Inhibitor Functional 0050141 Method: Enzyme-Linked Immunosorbent Assay	Refer to Hereditary Angioedema topic
C-1-Esterase Inhibitor Panel 0050139 Method: Immunoturbidimetric/Enzyme-Linked Immunosorbent Assay/Nephelometry	Refer to Hereditary Angioedema topic
Complement Component 1, Functional 0099078 Method: Hemolytic Assay