Complement Deficiency

Primary Authors: Delgado, Julio, MD, MS. Hill, Harry R., MD.

The complement system is a complex system of proteins that play a role in host defense and inflammation response by acting as 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 (using the CH50 method) and AP (using the AH50 method) pathways but may also include testing for the LP pathway (using mannose binding lectin [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	Pathway Defect Implicated	Secondary Confirmatory Testing
Low or absent	Normal	Normal	Classical	Complement levels or functional testing C1 C2 C4 C1 esterase - if angioedema present
Low or absent	Low or absent	Normal	Terminal	Complement levels or functional testing C3 C5 C6 C7 C8 C9 Factor levels H I
Normal	Low or absent	Normal	Alternative	Properdin level or functional testing Factors B and/or D levels
Normal	Normal	Low or absent	Lectin	Lectin pathway deficiency is likely
*ARUP tests Complement Activity Enzyme Immunoassay, Total Complement Activity, Alternative Pathway (AH50) Mannose Binding Lectin

Indications for Testing

Recurrent pyogenic infections (especially meningococcal meningitis, Streptococcus pneumoniae)
Angioedema without urticaria
Autoimmune disorders (eg, cryoglobulinemic vasculitis, renal or ophthalmic disorders)

Laboratory Testing

Initial testing
- Testing for classical (CH50) and alternative (AH50) pathways
- May also include mannose-biding lectin (MBL) testing depending on the clinical presentation
Further testing based on disease presentation and initial testing
- Refer to Key Points and algorithm

Complement Deficiency Testing Algorithm

Read more about Complement Deficiency Testing Algorithm

Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

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

Primary deficiencies of components of complement system – frequencies (Grumach, 2014)

Primary Deficiencies of Components of Complement System – Frequencies
Deficiency	Frequency (cases)
C1q	>40
C1r/s (mostly combined)	<20
C2	1/10,000-20,000
C4 (C4A, C4B)	<30 (homozygous)
C3	10-30
C5	40
C6	>50
C7	>50
C8α-γ/C8β	>50 (mostly C8β)
C9	1/1,000 (Japan), rare
Factor B	<10
Factor D	<10
MBL	5% (Caucasians)
Ficolin 3 (H-ficolin)	<10
MASP-2	<10
C1-inhibitor	1/50,000
C4-binding protein	<10
Properdin	>100
Factor H	>100
FHR1 (FHR3)	>100 (5% Caucasians)
Factor 1	>50
Thrombomodulin (CD141)	>10
CD46/MCP	>50
CD55/DAF	<10
CR2 (CD21)	Rare
CR3 (CD18/CD11b)	1/million

Genetics
- Most disorders are inherited as autosomal recessive disorders
- X-linked – properdin deficiency

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
  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
- Neisseria meningitidis
- Neisseria gonorrhea
May present as an autoimmune disease (eg, SLE, nephritis)
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 Component		Associated Disease
C1q, C1r, C1s C1q – most common	↓	Infections – encapsulated bacteria (septicemia, meningitis) Immune complex disease C1q deficiency – systemic lupus erythematosus (SLE) with prominent bacterial infections C1r deficiency and C1s deficiency – SLE with prominent renal and cutaneous disease
Anti C1q antibodies	↓	Hypocomplementemia, urticarial vasculitis with feature of glomerulonephritis, arteritis, pulmonary diseases, and ocular inflammation
C1-inh	↑	Hereditary angioedema
C1-inh	Nonfunctional	Acquired angioedema
C2	↓	Infections – pyogenic (Streptococcus pneumoniae, Haemophilus influenzae), septicemia Immune complex disease – SLE-like glomerulonephritis, polymyositis, vasculitis Cardiovascular disease
C3	↓ with NL C4	Infections – pyogenic (H. 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	Infections – encapsulated bacteria (S. pneumoniae) Immune complex disease – cryoglobulinemic vasculitis Hereditary angioedema
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 Component		Associated Disease
C5-C9	↓	Infections – pyogenic (N. meningitidis and N. gonorrhoeae) Immune complex disease – systemic lupus erythematosus (much less frequent than with C1-C4 deficiencies)
Factor H	↓	Infections – pyogenic Immune complex disease – membranoproliferative glomerulonephritis Atypical hemolytic uremic syndrome (HUS) Preeclampsia Age-related macular degeneration
Factor I	↓	Infections – pyogenic Immune complex disease – membranoproliferative glomerulonephritis Atypical HUS Preeclampsia
↓ = decreased

Alternative pathway – complement pathology related diseases

Alternative Pathway – Complement Pathology Related Diseases
Complement Component		Associated Disease
Properdin	↓	Infections – pyogenic (Neisseria spp and S. pneumoniae)
Factor B	↓	Atypical hemolytic uremic syndrome
↓ = decreased

Lectin pathway – complement pathology related diseases

Lectin Pathway – Complement Pathology Related Diseases
Complement Component		Associated Disease
MBL	↓	Infections – pyogenic, fungal (yeasts, molds), recurrent respiratory infections in infants Immune complex disease – systemic lupus erythematosus
MASP-2	↓	Infections – pyogenic
Ficolin-3	↓	Infections – pyogenic and severe
↓ = decreased

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.

Complement Activity Enzyme Immunoassay, Total 0050198
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Initial screening for functional ability of the complement system

Tests for defects in the classical complement pathway

Limitations

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Follow-up

Refer to Key Points

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

Recommended Use

Initial screening for functional ability of the complement system

Tests for defects in the alternative complement pathway

Limitations

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Follow-up

Refer to Key Points

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

Recommended Use

Initial screening for functional ability of the complement system

Tests for defects in the lectin pathway

Limitations

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare)

Follow-up

Refer to Key Points

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

Recommended Use

Assess risk for lupus nephritis and global SLE disease activity

Clinical sensitivity/specificity – varies based on disease population and disease state

Analytical sensitivity/specificity – varies based on disease population and disease state as well as testing platform

Limitations

Not all patients with lupus nephritis will be positive for C1q antibodies

C1q antibodies are not specific for lupus

Complement Component 2 0050148
Method: Quantitative Radial Immunodiffusion

Recommended Use

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

Recommended Use

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

Limitations

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

Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

Recommended Use

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

Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Recommended Use

Monitor rheumatologic disease

Complement Component Level 4a 2003180
Method: Radioimmunoassay

Recommended Use

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

Recommended Use

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

Complement Component Level 6 0099072
Method: Quantitative Radial Immunodiffusion

Recommended Use

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

Recommended Use

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

Complement C3 Nephritic Factor 2009380
Method: Qualitative Immunofixation Electrophoresis

Recommended Use

Marker of nephritis/prediction of glomerular nephritis

Complement Factor H Level (B-1H) 2009416
Method: Quantitative Radial Immunodiffusion

Recommended Use

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

Complement Factor I 2009382
Method: Quantitative Radial Immunodiffusion

Recommended Use

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

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Bonilla FA, Bernstein L, Khan DA, Ballas ZK, Chinen J, Frank MM, Kobrynski LJ, Levinson AI, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology. 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): J276-86. PubMed

Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014; 61(2): 110-7. PubMed

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Mayilyan KR. Complement genetics, deficiencies, and disease associations. Protein Cell. 2012; 3(7): 487-96. PubMed

Nilsson B, Ekdahl KN. Complement diagnostics: concepts, indications, and practical guidelines. Clin Dev Immunol. 2012; 2012: 962702. PubMed

Pettigrew D, Teuber SS, Gershwin E. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009; 1173: 108-23. PubMed

Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004; 113(4): 585-93; quiz 594. PubMed