Complement Deficiency

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

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

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Clinical Background

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)

Complement Factor Abnormalities and Disease Associations
Complement	Level	Associated Diseases
C1q, C1r, C1s	Decreased	Immune complex diseases (eg, SLE) Pyogenic infections
C1-esterase inhibitor	Decreased	Hereditary angioedema
C1-esterase inhibitor	Non-functional	Acquired angioedema
C2	Decreased	Pyogenic infections (especially Streptococcus pneumoniae)
C2	Extremely decreased	Lupus-like disease
C3	Decreased with normal C4	Pyogenic infections (especially Haemophilus influenzae, Streptococcus pneumoniae, Neisseria spp) C3 deficiency, acute glomerulonephritis, membranoproliferative glomerulonephritis
	Decreased with decreased C4	Active SLE, serum sickness, immune complex disease, infective endocarditis, chronic hepatitis
	Increased	Acute inflammation, malignancy
C4	Decreased with normal C3	C4 deficiency, immune complex disease, hereditary angioedema, cryoglobulinemic vasculitis Pyogenic infections (especially Streptococcus pneumoniae)
C4	Decreased with increased C3	Active SLE, serum sickness, immune complex disease, infective endocarditis, chronic hepatitis Pyogenic infections (especially Streptococcus pneumoniae)
C5	Decreased	Pyogenic infections (especially Neisseria meningitidis and Neisseria gonorrhea), SLE
C6, C7, C8	Decreased	Pyogenic infections (disseminated Neisseria meningitidis and Neisseria gonorrhea), SLE (rare)
C9	Decreased	Usually asymptomatic
Factor H	Decreased	Hemolytic uremic syndrome
Factor I	Decreased	Pyogenic infections
Properdin	Decreased	Pyogenic infections (Neisseria spp)
Factor B	Decreased	Pyogenic polysaccharide coated bacterial infection
(Adapted with permission from Haynes and Fauci, 2005, 1928 and Jacobs, et al., 2001, 519)

See Also

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

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

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

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Tests

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

Test name: Complement Activity Enzyme Immunoassay, Total

ARUP #: 0050198

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Screen for functional activity of entire classical complement sequence (C1-C9)

Limitations:

Does not quantitate individual components

Follow-up:

If test result abnormal, order tests for specific complement component suspected

Test name: Complement Component 2

ARUP #: 0050148

Methodology: Radial Immunodiffusion

Use:

Detect most common genetic deficiency of complete or heterozygous state

Determine C2 levels in patients with pneumococcal infections or lupus-like syndrome (nephritis, arthritis and rashes)

Limitations:

Follow-up:

Test name: Complement Component 3

ARUP #: 0050150

Methodology: Immunoturbidimetric

Use:

As an acute phase reactant, C3 may be elevated early in inflammation or infection

Determine levels of complement components in patients with clinical symptoms: recurrent infection by pyogenic bacteria

Test name: Complement Component 4

ARUP #: 0050155

Methodology: Immunoturbidimetric

Use:

Detect consumption of complement by antigen-antibody complexes or by homozygous or heterozygous deficiency of C4

Determine C4 levels in patients with lupus-like disorders (arthritis, nephritis, rashes)

Limitations:

Follow-up:

Test name: Complement Components 3 & 4

ARUP #: 0050149

Methodology: Immunoturbidimetric

Use:

Determine whether classical pathway (C3, C4) or alternate pathway (C3) has been activated

Limitations:

Follow-up:

Test name: Complement Component 5

ARUP #: 0050156

Methodology: Radial Immunodiffusion

Use:

Determine levels of C5 in patients with systemic Neisseria spp infections:
- Recurrent N. meningitidis or N. gonorrhoeae infections
- Systemic gonorrhea with arthritis

Limitations:

Follow-up:

Test name: Complement Component 6

ARUP #: 0099072

Methodology: Radial Immunodiffusion

Use:

Determine levels of C6 in patients with pyogenic infections (especially in Neisseria spp infections)

Test name: Mannose Binding Lectin

ARUP #: 0051692

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

May be assistive in cases of serious bacterial and/or fungal infections when other abnormalities are not detected

Test name: C1Q Binding Assay

ARUP #: 0050301

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Not a first line test for determining circulating immune complex (CIC) activity

Detect complement binding immune complexes

Limitations:

Circulating immune complexes (CIC) may be found without any evident pathology, and positive results do not necessarily implicate the immune complex in a disease process

This test is a sensitive, but non-specific test; use in conjunction with more specific testing in patients with suspected vasculitis

Follow-up:

Suggest ordering complement component 4, complement component 3, C1q binding and Raji cell assays to assess complement binding immune complexes and triggering of the classic complement pathway

Test name: Complement Factor B

ARUP #: 0051720

Methodology: Radio Immunodifussion

Use:

Determine whether classical pathway (C3, C4) or alternate pathway (C3) has been activated

Additional Tests Available

Test name: Raji Cell Immune Complex Assay

ARUP #: 0050302

Methodology: Flow Cytometry

Comments:

Test name: Immune Complex Panel

ARUP #: 0050667

Methodology: Flow Cytometry/Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Complement Component 1Q Level

ARUP #: 0099130

Methodology: Radial Immunodiffusion

Comments:

Test name: Complement Component 7 Level

ARUP #: 0099073

Methodology: Radial Immunodiffusion

Comments:

Test name: Complement Component 8 Level

ARUP #: 0099074

Methodology: Radial Immunodiffusion

Comments:

Test name: Complement Component 9 Level

ARUP #: 0099076

Methodology: Radial Immunodiffusion

Comments:

Test name: Complement Component 8 Functional

ARUP #: 0099133

Methodology: Hemolytic Assay

Comments:

Test name: Complement Component 7 Functional

ARUP #: 0099121

Methodology: Hemolytic Assay

Comments:

Test name: Complement Component 6 Functional

ARUP #: 0099131

Methodology: Quantitative Hemolytic Assay

Comments:

Test name: Complement Component 9 Functional

ARUP #: 0099120

Methodology: Quantitative Hemolytic Assay

Comments:

Test name: C1-Esterase Inhibitor

ARUP #: 0050140

Methodology: Nephelometry

Comments: Refer to Hereditary Angioedema topic

Test name: C1-Esterase Inhibitor Functional

ARUP #: 0050141

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Refer to Hereditary Angioedema topic

Test name: C-1-Esterase Inhibitor Panel

ARUP #: 0050139

Methodology: Immunoturbidimetric/Enzyme-Linked Immunosorbent Assay/Nephelometry

Comments: Refer to Hereditary Angioedema topic

Test name: Complement Component 1, Functional

ARUP #: 0099078

Methodology: Hemolytic Assay

Comments:

Additional Information

Many complement components are heat labile

References

Cited References

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.

Jacobs DS et al. eds. Complement C3, Serum and Complement C4, Serum. Laboratory Test Handbook with Key Word Index, 5th ed. Hudson, OH: Lexi-Comp, 2001. pp. 519-520.

General References

Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician. 2003;68(10):2001-2008.

Frank MM. Complement deficiencies. Pediatr Clin North Am. 2000;47(6):1339-1354.

Immune Deficiency Foundation (Accessed 30 May 2008)

Kishore U, Reid KB. C1q: structure, function, and receptors. Immunopharmacology. 2000;49(1-2):159-170.

Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171(3):715-727.

Picard C, Puel A, Bustamante J, Ku CL, Casanova JL. Primary immunodeficiencies associated with pneumococcal disease. Curr Opin Allergy Clin Immunol. 2003;3(6):451-459.

Sjoholm AG, Jonsson G, Braconier JH, Sturfelt G, Truedsson L. Complement deficiency and disease: an update. Mol Immunol. 2006;43(1-2):78-85.

Turner MW. The role of mannose-binding lectin in health and disease. Mol Immunol. 2003;40(7):423-429.

Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058-1066.

Walport MJ. Complement. Second of two parts. N Engl J Med. 2001;344(15):1140-1144.

Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004;113(4):585-593.

Medical Reviewers

Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah

Tebo, Anne E., Ph.D. Assistant Medical Director, Immunology at ARUP Laboratories; Clinical Assistant Professor, Clinical Pathology, University of Utah

Comprehensive Review: July 2008
Last Update: July 2008