Complement deficiency explained

Complement deficiency
Symptoms:	Recurring infection, rheumatic disease
Causes:	Can be inherited or acquired
Diagnosis:	CH50 measurement, Plasma level
Treatment:	Immunosuppressive therapy

Complement deficiency is an immunodeficiency of absent or suboptimal functioning of one of the complement system proteins.^[1] Because of redundancies in the immune system, many complement disorders are never diagnosed. Some studies estimate that less than 10% are identified.^[2] Hypocomplementemia may be used more generally to refer to decreased complement levels,^[3] while secondary complement disorder means decreased complement levels that are not directly due to a genetic cause but secondary to another medical condition.

Types

• Disorders of the proteins that act to inhibit the complement system (such as C1-inhibitor) can lead to an overactive response, causing conditions such as hereditary angioedema.^[4]
• Disorders of the proteins that act to activate the complement system (such as C3) can lead to an underactive response, causing greater susceptibility to infections.^[5]

Signs and symptoms

The following symptoms (signs) are consistent with complement deficiency in general:^{[6] [7]}

Complications

Vaccinations for encapsulated organisms (e.g., Neisseria meningitidis and Streptococcus pneumoniae) is crucial for preventing infections in complement deficiencies. Among the possible complications are the following:

• Deficiencies of the terminal complement components increases susceptibility to infections by Neisseria.^[8]

Causes

The cause of complement deficiency is genetics (though cases of an acquired nature do exist post infection). The majority of complement deficiencies are inherited as autosomal recessive conditions, while properdin deficiency occurs through X-linked inheritance. MBL deficiency can be inherited by either manner.

Inherited

• Properdin deficiency is an X-linked^[9] disorder that also causes susceptibility to Neisseria infections.
• C1-inhibitor deficiency or hereditary angioedema will have low C4 with normal C1 levels.^[10]

Acquired

Acquired hypocomplementemia may occur in the setting of bone infections (osteomyelitis), infection of the lining of the heart (endocarditis), and cryoglobulinemia. Systemic lupus erythematosus is associated with low C3 and C4.^[11] Membranoproliferative glomerulonephritis usually has low C3.^[12]

Mechanism

The mechanism of complement deficiency consists of:

• C2: In regard to C2 deficiency, about 5 different mutations in the C2 gene are responsible. In turn, immune function decreases and infection opportunities increase. One of the most common mutations deletes 28 DNA nucleotides from the C2 gene. Therefore, no C2 protein which can help make C3-convertase is produced. Ultimately, this delays/decreases immune response.^[13]
• C3: In terms of deficiency of C3, it has been found that 17 mutations in the C3 gene cause problems with C3. This rare condition mutates or prevents C3 protein from forming, lowering the immune system's ability to protect.^[14]
• C4: C4 deficiency is highly associated with systemic lupus erythematosus. Aβ42, a protein involved in Alzheimer's disease, can cause activation of C4 (even in plasma deficient of C1q).^[15] At least one study indicates that the genetic variation of C4 plays a role in schizophrenia.^[16]

Diagnosis

The diagnostic tests used to diagnose a complement deficiency include:^[17]

• CH50 measurement
• Immunochemical methods/test
• C3 deficiency screening
• Mannose-binding lectin (lab study)
• Plasma levels/regulatory proteins (lab study)

Treatment

In terms of management for complement deficiency, immunosuppressive therapy should be used depending on the disease presented. A C1-INH concentrate can be used for angio-oedema (C1-INH deficiency).^[17]

Pneumococcus and Haemophilus infections can be prevented via immunization. Epsilon-aminocaproic acid could be used to treat hereditary C1-INH deficiency, though the possible side effect of intravascular thrombosis should be weighed.

Epidemiology

C2 deficiency has a prevalence of 1 in about 20,000 people in Western countries.^[18]

See also

• Paroxysmal nocturnal hemoglobinuria

Further reading

• Botto . Marina . 1 January 2001 . Links between complement deficiency and apoptosis . Arthritis Research & Therapy . 3 . 4 . 207–210 . 10.1186/ar301 . 1478-6362 . 128896 . 11438036 . free.
• Book: Aghamohammadi, Asghar . Clinical cases in primary immunodeficiency diseases a problem-solving approach . Rezaei . Nima . 2012 . Springer . 9783642317859 . Berlin . en . 21 September 2016.

Notes and References

1. Book: Winkelstein, Jerry A. . Infectious Diseases . 2004 . Lippincott Williams & Wilkins . 978-0-7817-3371-7 . Gorbach . Sherwood L. . 8–13 . The Complement System . Bartlett . John G. . Blacklow . Neil R..
2. Sjöholm . A.G. . Jönsson . G. . Braconier . J.H. . Sturfelt . G. . Truedsson . L. . 2006 . Complement deficiency and disease: An update . Molecular Immunology . 43 . 1–2 . 78–85 . 10.1016/j.molimm.2005.06.025 . 16026838.
3. Book: Rheumatology and Immunology Therapy: A to Z Essentials . 2004 . Springer . 9783540206255 . Moreland . Larry W. . Berlin . 425 . en . 30 August 2016 . https://web.archive.org/web/20230112105022/https://books.google.com/books?id=GiR493YLsgsC&q=hypocomplementemia+definition&pg=PA425 . 12 January 2023 . live.
4. Davis . Alvin E. . Mejia . Pedro . Lu . Fengxin . 1 October 2008 . Biological activities of C1 inhibitor . Molecular Immunology . 45 . 16 . 4057–4063 . 10.1016/j.molimm.2008.06.028 . 0161-5890 . 2626406 . 18674818.
5. Ram . S. . Lewis . L. A. . Rice . P. A. . 7 October 2010 . Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy . Clinical Microbiology Reviews . 23 . 4 . 740–780 . 10.1128/CMR.00048-09 . 0893-8512 . 2952982 . 20930072.
6. Book: Winkelstein, Jerry A. . Oski's Essential Pediatrics . 2004 . Lippincott Williams & Wilkins . 9780781737708 . Crocetti . Michael . 2nd . Philadelphia . 670 . en . Complement Deficiencies . 21 September 2016 . Barone . Michael A. . https://books.google.com/books?id=I3Kh1cNJxyUC&q=complement+deficiency&pg=PA670 . https://web.archive.org/web/20230112105022/https://books.google.com/books?id=I3Kh1cNJxyUC&q=complement+deficiency&pg=PA670 . 12 January 2023 . live.
7. Pettigrew . H. David . Teuber . Suzanne S. . Gershwin . M. Eric . September 2009 . Clinical Significance of Complement Deficiencies . Annals of the New York Academy of Sciences . en . 1173 . 1 . 108–123 . 2009NYASA1173..108P . 10.1111/j.1749-6632.2009.04633.x . 1749-6632 . 19758139 . free.
8. Book: Aghamohammadi, Asghar . Clinical Cases in Primary Immunodeficiency Diseases: A Problem-Solving Approach . Rezaei . Nima . 13 December 2012 . Springer Science & Business Media . 978-3-642-31785-9 . 334 . en . 30 January 2022 . https://web.archive.org/web/20230112105022/https://books.google.com/books?id=IftYOIDjQbcC&q=terminal+complement+components+Neisseria.&pg=PA334 . 12 January 2023 . live.
9. Web site: OMIM Entry - # 312060 - PROPERDIN DEFICIENCY, X-LINKED; CFPD . live . https://web.archive.org/web/20191216171301/http://omim.org/entry/312060 . 16 December 2019 . 21 September 2016 . omim.org.
10. Gower . Richard G . Busse . Paula J . Aygören-Pürsün . Emel . Barakat . Amin J . Caballero . Teresa . Davis-Lorton . Mark . Farkas . Henriette . Hurewitz . David S . Jacobs . Joshua S . Johnston . Douglas T . Lumry . William . Maurer . Marcus . 15 February 2011 . Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies . The World Allergy Organization Journal . 4 . Suppl 2 . S9–S21 . 10.1097/1939-4551-4-S2-S9 . 1939-4551 . 3666183 . 23283143.
11. Web site: Systemic Lupus Erythematosus. Lupus treatment; information Patient . live . https://web.archive.org/web/20190704094650/https://patient.info/doctor/Systemic-lupus-erythematosus-pro . 4 July 2019 . 21 September 2016 . Patient.
12. Web site: Membranoproliferative Glomerulonephritis: Background, Pathophysiology, Etiology . live . https://web.archive.org/web/20191130165809/http://emedicine.medscape.com/article/240056-overview . 30 November 2019 . 21 September 2016 . Medscape.
13. Web site: Reference . Genetics Home . C2 gene . live . https://web.archive.org/web/20180123190642/https://ghr.nlm.nih.gov/gene/C2#conditions . 23 January 2018 . 21 September 2016 . Genetics Home Reference.
14. Web site: Reference . Genetics Home . C3 gene . live . https://web.archive.org/web/20181004154129/https://ghr.nlm.nih.gov/gene/C3#conditions . 4 October 2018 . 21 September 2016 . Genetics Home Reference.
15. Kolev . Martin V . Ruseva . Marieta M . Harris . Claire L . Morgan . B. Paul . Donev . Rossen M . 1 March 2009 . Implication of Complement System and its Regulators in Alzheimer's Disease . Current Neuropharmacology . 7 . 1 . 1–8 . 10.2174/157015909787602805 . 1570-159X . 2724661 . 19721814.
16. Sekar . Aswin . Bialas . Allison R. . de Rivera . Heather . Davis . Avery . Hammond . Timothy R. . Kamitaki . Nolan . Tooley . Katherine . Presumey . Jessy . Baum . Matthew . 2016-02-11 . Schizophrenia risk from complex variation of complement component 4 . Nature . 530 . 7589 . 177–183 . 2016Natur.530..177. . 10.1038/nature16549 . 0028-0836 . 4752392 . 26814963.
17. Web site: Complement Deficiencies Clinical Presentation: History, Physical, Causes . live . https://web.archive.org/web/20180102191532/https://emedicine.medscape.com/article/135478-clinical#showall . 2 January 2018 . 21 September 2016 . emedicine.medscape.com.
18. Web site: Complement Deficiencies. What are complement deficiencies? . live . https://web.archive.org/web/20171231104021/https://patient.info/doctor/complement-deficiencies . 31 December 2017 . 2017-12-31 . patient.info . en-GB.