Complement Deficiency

Key Points

The complement system plays a role in host defense and inflammation response and is a cascade involving three pathways - classical (CP), alternative (AP), and lectin (LP). Each pathway is initiated by distinct mechanisms. Deficiency of any of the proteins in these pathways may lead to recurrent infections (with encapsulated organisms, in particular) or inappropriate inflammatory responses. Inherited deficiencies are uncommon, but acquired deficiencies, due to a variety of etiologies, are much more common.

Initial evaluation for suspected complement deficiency should include testing for both the CP (CH50) and AP (AH50) pathways but may also include testing for LP (MBL), depending on the clinical circumstance. Results from the initial evaluation guide secondary testing for complement deficiency.

Identifying complement pathway deficiencies – primary and secondary testing

Identifying Complement Pathway Deficiencies – Primary and Secondary Testing

Note:  Refer to the algorithm for a visual representation of the suggested testing sequence

Primary Testing*

Pathway Defect Implicated

Secondary Confirmatory Testing

CH50

AH50

MBL

Low or absent

Normal

Normal

Classical

Complement levels or functions 

  • C1
  • C2
  • C4

C1 esterase - if angioedema present

Low or absent

Low or absent

Normal

Terminal

Complement levels or functions

  • C3
  • C5
  • C6
  • C7
  • C8
  • C9

Factor levels 

  • H
  • I

Normal

Low or absent

Normal

Alternative

Properdin level or function

Factors B and/or D levels 

Normal

Normal

Low or absent

Lectin

Lectin pathway deficiency is likely

*ARUP Tests

Complement Activity Enzyme Immunoassay, Total (CH50) 

Complement Activity, Alternative Pathway (AH50)

Mannose Binding Lectin (MBL) 

Clinical presentation is similar among the various complement component dysfunctions. Refer to tables below for details about each pathway.

Classical pathway – complement pathology related diseases

Classical Pathway – Complement Pathology Related Diseases 

Complement ComponentAssociated disease
C1q, C1r, C1s
Anti C1q antibodies
  • Hypocomplementemia, urticarial vasculitis with feature of glomerulonephritis, arteritis, pulmonary diseases, and ocular inflammation
C1-inh

C1-inh

Nonfunctional
  • Acquired angioedema
C2
C3↓  with NL C4
  • Infections – pyogenic (Haemophilus influenzae, S. pneumoniae, Neisseria spp)
  • Immune complex diseases – acute glomerulonephritis, membranoproliferative glomerulonephritis, SLE
C3↓ with ↓ C4
  • Infections – endocarditis
  • Immune complex diseases – serum sickness, chronic hepatitis (most commonly HBV, HCV)
C3
  • Acute inflammation, malignancy
C4↓ with NL C3
C4↓ with ↑ C3
  • Infections – pyogenic (S. pneumoniae), endocarditis 
  • Immune complex diseases – SLE with glomerulonephritis, serum sickness, chronic hepatitis (most commonly HBV, HCV)

Abbreviations

NL – normal

↓ = decreased

↑ = increased

C1-inh = C1 esterase inhibitor

Terminal pathway – complement pathology related diseases

Terminal Pathway – Complement Pathology Related Diseases 

Complement ComponentAssociated disease
C5-C9
  • Infections – pyogenic (N. meningitidis and N. gonorrhoeae)
  • Immune complex disease – SLE (much less frequent than with C1-C4 deficiencies)
Factor H
  • Infections – pyogenic
  • Immune complex disease – membranoproliferative glomerulonephritis
  • Hemolytic uremic syndrome (HUS)
  • Age-related macular degeneration (association)
Factor I
  • Infections – pyogenic
Alternative pathway – complement pathology related diseases

Alternative Pathway – Complement Pathology Related Diseases 

Complement ComponentAssociated disease
Properdin
Factor B
  • Infections – pyogenic (polysaccharide-coated bacterial infection, especially Neisseria spp and  S. pneumoniae)
Lectin pathway – complement pathology related diseases

Lectin Pathway – Complement Pathology Related Diseases 

Complement Component

Associated disease

MBL

Diagnosis

Indications for Testing

Laboratory Testing

  • Initial testing for suspected complement deficiency
    • Testing for both the classical (CH50) and alternative (AH50) pathways
    • May also include testing for lectin (MBL) pathway depending on the clinical circumstance
  • Further testing based on disease presentation and enzyme activity levels
    • Refer to Key Points and algorithm

Monitoring

  • Circulating immune complexes – may be useful for disease monitoring

Clinical Background

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
  • Classical 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 disorders involving the following
    • Circulating immune complexes (CIC) may form with C1q
  • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Complement Activity Enzyme Immunoassay, Total 0050198
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Initial screening test for suspected complement deficiency in the classical complement pathway

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Refer to Key Points

Complement Activity, Alternative Pathway (AH50) 2005373
Method: Semi-Quantitative Radial Immunodiffusion

Initial screening test for suspected deficiency in the alternative complement pathway

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Refer to Key Points

Mannose Binding Lectin 0051692
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Initial screening for suspected deficiency in the lectin complement pathway

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Refer to Key Points

Anti-C1q Antibody, IgG 2007601
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Assess risk for lupus nephritis and global SLE disease activity

Test result value could be decreased by presence of anti-C1q autoantibodies

 
Complement Component 2 0050148
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when CH50 is low or absent and AH50 is normal and high suspicion remains for complement deficiency

   
Complement Component 3 0050150
Method: Quantitative Immunoturbidimetry

Secondary testing based on initial screening (CH50, AH50) and clinical presentation

C3 is an acute phase reactant and may also be elevated early in inflammation or infection

 
Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

Secondary testing based on initial screening (CH50, AH50) and clinical presentation

   
Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Monitor rheumatologic disease

   
Complement Component 4A 2003180
Method: Radioimmunoassay

Follow-up test for complement activity screening when CH50 is low or absent and AH50 is normal and high suspicion remains for complement deficiency

   
Complement Component 5 0050156
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when CH50 and AH50 are low or absent and high suspicion remains for complement deficiency

   
Complement Component 6 0099072
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when CH50 and AH50 are low or absent and high suspicion remains for complement deficiency

   
Complement Factor B 0051720
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when CH50 is normal and AH50 is low.

   
Complement C3 Nephritic Factor 2009380
Method: Qualitative Immunofixation Electrophoresis 

Marker of nephritis/prediction of glomerular nephritis

   
Complement Factor H (B1H) 2009416
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when both CH50 and AH50 are low or absent.

   
Complement Factor I 2009382
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when both CH50 and AH50 are low or absent.

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Complement Component 3A 2003304
Method: Radioimmunoassay

Follow-up test for complement activity screening when CH50 and AH50 are low or absent and high suspicion remains for complement deficiency

Complement Component 1q, Functional 2008097
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Follow-up test for complement activity screening when CH50 is low or absent and AH50 is normal and high suspicion remains for complement deficiency
Raji Cell Immune Complex Assay 0050302
Method: Quantitative Flow Cytometry
Immune Complex Panel 0050667
Method: Quantitative Flow Cytometry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Panel includes C1Q Binding Assay and Raji Cell Immune Complex Assay

Complement Component 1Q Level 0099130
Method: Radial Immunodiffusion
Aids in diagnosis of C1q deficiency
Complement Component 7 0099073
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when  CH50 and AH50 are low or absent and high suspicion remains for complement deficiency

Complement Component 8 0099074
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when CH50 and AH50 are low or absent and high suspicion remains for complement deficiency

Complement Component 9 0099076
Method: Quantitative Radial Immunodiffusion

Follow-up test for complement activity screening when  CH50 and AH50 are low or absent and high suspicion remains for complement deficiency

Complement Component 1, Functional 0099078
Method: Quantitative Hemolytic Assay

Follow-up test for complement activity screening when CH50 is low or absent and AH50 is normal and high suspicion remains for complement deficiency

Complement Component 6 Functional 0099131
Method: Quantitative Hemolytic Assay
Complement Component 7 Functional 0099121
Method: Quantitative Hemolytic Assay
Complement Component 8 Functional 0099133
Method: Hemolytic Assay
Complement Component 9 Functional 0099120
Method: Quantitative Hemolytic Assay
C1-Esterase Inhibitor 0050140
Method: Quantitative Nephelometry
C1-Esterase Inhibitor Functional 0050141
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
C-1-Esterase Inhibitor Panel 0050139
Method: Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry
Panel includes C1-esterase inhibitor, C1-esterase inhibitor functional, and complement component 4
C1q Binding Assay 0050301
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Detect circulating immune complexes (CIC)

Not a first-line test for determining CIC activity