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Complement 3 Deficiency

Complement 3 (C3) is a central component of the complement system. It is a major opsonin, hence Complement 3 deficiency predisposes the patient to serious infections by pyogenic bacteria. Deficiency of C3 also results in autoimmune-like diseases. Specific therapy is not available, but vaccination for meningococcal and pneumococcal diseases is advised as a preventative measure.


Presentation

The complement pathways are important parts of the immune system with roles in the fight against pathogens, inflammation, and autoimmune diseases. The complement system has three branches: the classical pathway is activated by interactions between antibodies and the early protein components of the classical branch; the alternative pathway is independent of antibodies; the third pathway is activated by lectins. All three branches result in the activation of complement 3 (C3) factor by proteolysis. Deposition of C3 products triggers the formation of the membrane attack complex (MAC) from the late components of the complement system. The membrane attack complex executes the killing function of the complement pathways. Deficiencies of the complement system could also lead to autoimmune diseases, such as systemic lupus erythematosus (SLE), and renal diseases.

Complement deficiency may be acquired, but in most cases is inherited. Deficiencies of complement components, particularly of C3, are rare [1]. Defects of the early components (C1-C4) are often associated with autoimmune conditions [2], whereas shortages in late protein components lead to recurrent infections. Complement 3 is a central component of the pathways and a principal opsonin; its deficiency predisposes to infections with encapsulated bacteria, such as Neisseria meningitides. Autoimmune diseases are also present in a considerable proportion of patients who have decreased concentrations (usually less than 1% of the normal values) of C3.

History is an important part of evaluating the patient as recurrent infections are common, but specific physical signs are lacking in complement deficiencies. Recognition of pneumococcal and meningococcal infections is crucial. Recurrent otitis media and Bordetella pertussis pneumonia were reported in patients with complement 3 deficiency [3] [4]. In one described case, an infant with Leiner’s disease, which is usually associated with C5 deficiency, was found to have a decreased level of C3 [5].

Early reports found evidence for recurrent infections in homozygous patients with C3 mutations [6] [7]. Patients with complement 3 deficiency were also described with SLE-like conditions [8] [9]. Some patients also developed glomerulonephritis. A more recent study, summarizing the phenotypic effects of C3 deficiencies based on 37 cases in 29 families, found that the overwhelming majority had recurrent infections, often with Neisseria meningitides, and that rheumatic and renal diseases each occurred in about a quarter of the patients [10]. More than half of the patients with autoimmune diseases also had recurrent infections.

Recurrent Bacterial Infection
  • Severe recurrent bacterial infections occur in patients with homozygous C3 deficiency and in those patients with low levels of C3 secondary to the absence of C3b activator.[mayomedicallaboratories.com]
  • Deficiencies or defects in specific complement components have been linked to specific disorders; the following are examples: Deficiency in C1, C2, C3, MBL, MASP-2, factor H, factor I, or complement receptor 2 (CR2): Susceptibility to recurrent bacterial[merckmanuals.com]
  • At least 17 mutations in the C3 gene have been found to cause C3 deficiency, a rare condition characterized by recurrent bacterial infections beginning in childhood.[ghr.nlm.nih.gov]
  • C2 deficiency is also associated with recurrent bacterial infection and an increased risk of cardiovascular disease.[patient.info]
Malnutrition
  • […] that are lower than the normal may occur with: lupus cirrhosis with severe liver damage or liver failure glomerulonephritis, a type of kidney disease hereditary angioedema, which is episodic swelling of the face, hands, feet, and some internal organs malnutrition[healthline.com]
  • […] infections (usually bacterial ) Autoimmune diseases, including SLE and vasculitis Hereditary angioedema Acquired angioedema Various types of kidney disease , including: glomerulonephritis, lupus nephritis, membranous nephritis, IgA nephropathy, aHUS Malnutrition[labtestsonline.org.au]
  • […] lupus and rheumatoid arthritis Hereditary angioedema Acquired angioedema Various types of kidney disease, including glomerulonephritis, lupus nephritis, membranous nephritis, and IgA nephropathy as well as kidney transplant rejection Cirrhosis Hepatitis Malnutrition[labtestsonline.org]
  • Common causes include malnutrition, HIV/AIDS, malignancy, immune suppressive drugs, and toxin exposure. Malignancy can directly suppress B-cell function, as is seen in chronic lymphocytic leukemia and lymphomas.[worldallergy.org]
Recurrent Otitis Media
  • Recurrent otitis media and Bordetella pertussis pneumonia were reported in patients with complement 3 deficiency.[symptoma.com]
  • Scarred tympanic membranes or chronic perforation due to recurrent otitis media is commonly seen in patients with antibody deficiencies.[worldallergy.org]
Pertussis
  • Recurrent otitis media and Bordetella pertussis pneumonia were reported in patients with complement 3 deficiency.[symptoma.com]
Meningism
  • Other tests may include computed tomography of the head and lumbar puncture in cases of suspected meningitis. Patients with C3 deficiency should be checked for manifestations of autoimmune diseases.[symptoma.com]
  • A 4-year-old girl was admitted for meningitis. She had had repeated attacks of pneumococcal meningitis and otitis media at the age of 3 years. Analysis of cerebrospinal fluid showed that this meningitis was due to pneumococcal infection.[link.springer.com]
  • Meningitis — An inflammation of the lining surrounding the brain and spinal cord.[medical-dictionary.thefreedictionary.com]
  • […] suggested testing sequence. a ARUP tests : Complement Activity Enzyme Immunoassay, Total ; Complement Activity, Alternative Pathway (AH50) ; Mannose Binding Lectin Diagnosis Indications for Testing Recurrent pyogenic infections (especially meningococcal meningitis[arupconsult.com]
  • […] total complement tests for people with a family history of complement deficiency and those who have symptoms of: RA hemolytic uremic syndrome (HUS) kidney disease SLE myasthenia gravis, a neuromuscular disorder an infectious disease, such as bacterial meningitis[healthline.com]
Ataxia
  • […] deficiency Hyper IgM syndrome ( 1 2 3 4 5 ) Wiskott–Aldrich syndrome Hyper-IgE syndrome Other Common variable immunodeficiency ICF syndrome T cell deficiency ( T ) thymic hypoplasia : hypoparathyroid ( Di George's syndrome ) euparathyroid ( Nezelof syndrome Ataxia-telangiectasia[en.wikipedia.org]
  • Ocular telangiectasia in association with cerebellar ataxia is the hallmark of ataxia telangiectasia, which leads to progressive combined immunodeficiency. Chronic inflammatory arthritis is seen in antibody and complement deficiencies.[worldallergy.org]
Cerebellar Ataxia
  • Ocular telangiectasia in association with cerebellar ataxia is the hallmark of ataxia telangiectasia, which leads to progressive combined immunodeficiency. Chronic inflammatory arthritis is seen in antibody and complement deficiencies.[worldallergy.org]

Workup

Laboratory examination of the hemolytic activity of the complement system is the cornerstone for testing the function of the classical complement pathway. One CH50 unit is the dilution or volume of serum that causes the hemolysis of 50% of sheep erythrocytes coated with antibodies [11]. An analogous value can be determined for the alternative pathway. When both pathways are dysfunctional, it is likely that the C3 or other common components of the pathways are affected.

The levels of individual components of the complement cascades can be determined by using the enzyme-linked immunosorbent assay (ELISA) technique. A recent study using dried blood spot samples, routinely collected from newborns, and reverse phase protein microarrays successfully identified patients deficient in C3 [12] [13]. This approach is well suited for large-scale screening of neonates and has a potential for future use.

Other tests may include computed tomography of the head and lumbar puncture in cases of suspected meningitis. Patients with C3 deficiency should be checked for manifestations of autoimmune diseases.

Lymphocytopenia
  • Idiopathic CD4 lymphocytopenia Complement deficiency C1-inhibitor ( Angioedema / Hereditary angioedema ) Complement 2 deficiency / Complement 4 deficiency MBL deficiency Properdin deficiency Complement 3 deficiency Terminal complement pathway deficiency[en.wikipedia.org]
Streptococcus Pneumoniae
  • ., Neisseria meningitidis and Streptococcus pneumoniae) is crucial for preventing infections in complement deficiencies.[en.wikipedia.org]
  • 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 MBL testing[arupconsult.com]
  • Complement testing may be used to: Help diagnose the cause of recurrent microbial infections (such as Streptococcus pneumoniae, Neisseria meningitides, Neisseria gonorrhea ), angioedema, or inflammation Help diagnose and monitor the activity and treatment[labtestsonline.org]
  • In primary immunodeficiency, C2 deficiency is found in young children who have recurrent infections, primarily upper respiratory infections with Streptococcus pneumoniae or similar organisms.[primaryimmune.org]
  • Infections with Haemophilus influenzae, Streptococcus pneumoniae and other encapsulated bacterial organisms are most common.[worldallergy.org]
Bordetella Pertussis
  • Recurrent otitis media and Bordetella pertussis pneumonia were reported in patients with complement 3 deficiency.[symptoma.com]

Treatment

  • Treatment of anemia Treatment depends on the cause of the anaemia. If the anaemia is due to a lack of iron, eating iron-rich food or iron supplements may be given.[news-medical.net]
  • Prophylactic treatments include attenuated androgens and C1 inhibitor.[primaryimmune.org]
  • Alternative treatment There is no alternative treatment for complement problems. Prognosis Since complement deficiencies include a wide range of disorders, the prognoses can also vary widely. Some patients remain healthy their entire life.[medical-dictionary.thefreedictionary.com]
  • Bork-K; Barnstedt-SE Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema ARCHIVES-OF-INTERNAL-MEDICINE.[malattierare.regione.veneto.it]
  • A doctor can use a complement test to monitor the progress of a person undergoing treatment for an autoimmune disease such as systemic lupus (SLE) or rheumatoid arthritis (RA).[healthline.com]

Prognosis

  • Prognosis Since complement deficiencies include a wide range of disorders, the prognoses can also vary widely. Some patients remain healthy their entire life.[medical-dictionary.thefreedictionary.com]
  • Deficiencies of the components of the MAC (C5-C9) tend to lead to less severe infections and have a better prognosis with careful management.[patient.info]
  • In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. {ECO:0000269 PubMed:18796626, ECO:0000269 PubMed:20513133}.[genecards.org]
  • […] genetic cause cannot be identified in the majority of patients with clinical features of CVID, there are an increasing number of identificable conditions that can be linked to newly identified genetic disorders that have implications for the long term prognosis[worldallergy.org]
  • In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease.[uniprot.org]

Etiology

  • Etiology and clinical course of missed spine fractures. J Trauma 1987;27:980-6. [ PUBMED ] 12. Platzer P, Hauswirth N, Jaindl M, Chatwani S, Vecsei V, Gaebler C. Delayed or missed diagnosis of cervical spine injuries.[ijoonline.com]
  • Inherited deficiencies are uncommon, while acquired deficiencies, due to a variety of etiologies, are much more common.[arupconsult.com]
  • The diagnosis should be directed toward primary and secondary etiologies that are consistent with the clinical presentation and pattern of infections.[worldallergy.org]

Epidemiology

  • Ross SC, Densen P: Complement deficiency states and infection: epidemiology, pathogenesis, and consequences of neisserial and other infections in an immune deficiency. Medicine 1984;63:243-273 2.[mayomedicallaboratories.com]
  • Genatlas disease for C3 Gene glomerulonephritis,pyogenic recurrent infections,lupus systemic syndrome Relevant External Links for C3 Genetic Association Database (GAD) C3 Human Genome Epidemiology (HuGE) Navigator C3 Atlas of Genetics and Cytogenetics[genecards.org]
  • […] also include MBL testing, depending on clinical presentation Further testing based on disease presentation and initial testing – refer to Key Points and algorithm Monitoring Circulating immune complexes – may be useful for disease monitoring Background Epidemiology[arupconsult.com]
  • Epidemiology Complement deficiencies are rare.[patient.info]
  • Epidemiology Frequency International Complement deficiencies are relatively rare worldwide, and estimates of prevalence are based on results from screening high-risk populations.[emedicine.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • Frank MM: Complement in the pathophysiology of human disease. N Engl J Med 1987;316:1525-1530[mayomedicallaboratories.com]
  • H00941 先天性第XII因子欠乏症 パスウェイ hsa04610 補体と凝固カスケード 病因遺伝子 F12 [HSA: 2161 ] [KO: K01328 ] リンク ICD-11: 3B15 ICD-10: D68.2 OMIM: 234000 文献 PMID: 20022081 著者 Stavrou E, Schmaier AH タイトル Factor XII: what does it contribute to our understanding of the physiology and pathophysiology[genome.jp]
  • Caccia S, Suffritti C and Cicardi M (2014) Pathophysiology of hereditary angioedema. Pediatric Allergy, Immunology, and Pulmonology 27: 159–163. Carroll MC (2004) The complement system in regulation of adaptive immunity.[els.net]
  • 100 Factor H 100 FHR1 (FHR3) 100 (5% Caucasians) Factor 1 50 Thrombomodulin (CD141) 10 CD46/MCP 50 CD55/DAF CR2 (CD21) Rare CR3 (CD18/CD11b) 1/million Genetics Autosomal recessive – most complement deficiency disorders X-linked – properdin deficiency Pathophysiology[arupconsult.com]
  • In summary, the complement system takes part in both specific and non-specific resistance and generates a number of products of biological and pathophysiological significance (Table 4).[microbiologybook.org]

Prevention

  • Specific therapy is not available, but vaccination for meningococcal and pneumococcal diseases is advised as a preventative measure.[symptoma.com]
  • ., Neisseria meningitidis and Streptococcus pneumoniae) is crucial for preventing infections in complement deficiencies.[en.wikipedia.org]
  • For the same reason that we brush our teeth daily to prevent cavities, we need to take care of the pipes’ condition. ProtectPipe Home Microbe -solution is a preventive and ecological solution for pipe maintenance.[protectpipe.fi]
  • The genetic changes that cause C3 deficiency lead to an altered version of the C3 protein or prevent cells from producing any of this protein.[ghr.nlm.nih.gov]
  • Prevention There is currently no way to prevent complement deficiencies. Resources Organizations Immune Deficiency Foundation. 25 W. Chesapeake Ave., Suite 206, Towson, MD 21204. (800) 296-4433. .[medical-dictionary.thefreedictionary.com]

References

Article

  1. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110-117.
  2. Bryan AR, Wu EY. Complement deficiencies in systemic lupus erythematosus. Curr Allergy Asthma Rep. 2014;14(7):448.
  3. Botto M, Fong KY, So AK, et al. Homozygous hereditary C3 deficiency due to a partial gene deletion. Proc Natl Acad Sci U S A. 1992;89(11):4957-4961.
  4. Kurvers RA, Westra D, van Heijst AF, Walk TL, Warris A, van de Kar NC. Severe infantile Bordetella pertussis pneumonia in monozygotic twins with a congenital C3 deficiency. Eur J Pediatr. 2014;173(12):1591-1594.
  5. Sonea MJ, Moroz BE, Reece ER. Leiner's disease associated with diminished third component of complement. Pediatr Dermatol. 1987;4(2):105-107.
  6. Pussell BA, Bourke E, Nayef M, Morris S, Peters DK. Complement deficiency and nephritis. A report of a family. Lancet. 1980;1(8170):675-677.
  7. Alper CA, Colten HR, Rosen FS, Rabson AR, Macnab GM, Gear JS. Homozygous deficiency of C3 in a patient with repeated infections. Lancet. 1972;2(7788):1179-1181.
  8. Sano Y, Nishimukai H, Kitamura H, et al. Hereditary deficiency of the third component of complement in two sisters with systemic lupus erythematosus-like symptoms. Arthritis Rheum. 1981;24(10):1255-1260.
  9. Nilsson UR, Nilsson B, Storm KE, Sjölin-Forsberg G, Hällgren R. Hereditary dysfunction of the third component of complement associated with a systemic lupus erythematosus-like syndrome and meningococcal meningitis. Arthritis Rheum. 1992;35(5):580-586.
  10. Okura Y, Kobayashi I, Yamada M, et al. Clinical characteristics and genotype-phenotype correlations in C3 deficiency. J Allergy Clin Immunol. 2016;137(2):640-644.e1.
  11. Costabile M. Measuring the 50% haemolytic complement (CH50) activity of serum. J Vis Exp.2010;(37). pii:1923.
  12. Janzi M, Sjöberg R, Wan J, et al. Screening for C3 deficiency in newborns using microarrays. PLoS One.2009;4(4):e5321.
  13. Paweletz CP, Charboneau L, Bichsel VE, et al. Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene.2001;20(16):1981-1989.

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Last updated: 2019-07-11 20:43