Complement Receptor Deficiency Clinical Presentation

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD   more...
 
Updated: May 27, 2011
 

History

In 1980, Fearon[8] originally identified and determined the molecular structure of the human CR1 receptor on red blood cells. This finding was followed by the discovery of 3 other cellular receptors for C3b and its degradation products: iC3b, C3dg, and C3d.

Genetic and acquired deficiencies of complement receptors were described only recently; they are associated with autoimmune disorders and infections. Deficiencies in CR1 and CR2 are mainly associated with SLE and other autoimmune dysfunctions. No complete deficiency is described, but reduced expression has been reported in humans. Whether they represent an inherited or acquired phenomenon is unclear, but findings tend to support the acquired phenomenon theory. Deficiencies in CR3 and CR4 have been observed in the leukocyte adhesion syndrome, which is inherited in an autosomal recessive fashion. C3aR and C5aR receptor deficiencies have been studied mainly in complement knockout mice and guinea pigs.

Next

Physical

Reduction in the number of complement receptors and immature host defenses in preterm newborns

Host defenses in neonates are not fully developed, and defective chemotaxis is believed to play a role. Neutrophils in preterm newborns have significantly fewer receptors for complement factors C3b (CR1/CD35) and iC3b (CR3) than neonates born at term or in adults. Also, C5aR receptor expression is reduced in preterm neonates.

CR1 and/or CR2 receptor deficiency in SLE and other conditions

SLE in humans is associated with abnormal B-cell functions and circulating autoantibodies probably caused by a dysregulation in B-cell tolerance.

In patients with severe SLE, expression of CR1/CD35 on erythrocytes is reduced to about one half of that of healthy individuals. This finding is correlated with disease activity. CR1 receptors are absent on the glomerular podocytes of patients with proliferative glomerulonephritis.

Mice with a deficiency in CD35/21 develop severe SLE with glomerulonephritis and have high amounts of double-stranded DNA (dsDNA) and antinuclear antibodies.

Fluctuating levels of CR1 are not unique to SLE. Decreased numbers of CR1 receptors on erythrocytes is also reported in other autoimmune disorders or diseases with complement activation, such as lepromatous leprosy, autoimmune hemolytic anemias, juvenile rheumatoid arthritis, and Sjögren syndrome.

Low numbers of CR1 receptors on red blood cells, as well as decreased expression of CR1 on erythrocytes and neutrophils, are also found in patients with AIDS. Their presence is correlated with more advanced disease.

Complement is implicated in the pathogenesis of not only autoimmune disorders but also organ failure due to sepsis, trauma, and burns. Under physiological conditions, regulatory proteins and cellular receptors such as CR1/CD35 prevent uncontrolled activation of complement. In numerous animal models, recombinant soluble CR1 significantly reduced complement-mediated tissue damage and prolonged the survival of heart and kidney transplants in pretreated recipients. Recombinant soluble CR1 is well tolerated in humans, and its therapeutic potential has been evaluated in adults with respiratory distress syndrome and myocardial infarction.

Leukocyte adhesion deficiency and CR3 and/or CR4 receptor deficiency

An autosomal recessive inherited deficiency of the leukocyte beta2 integrin receptor CD11/18 is known as the leukocyte adhesion deficiency syndrome. It is associated with recurrent cutaneous infections and gingivitis. Leukocyte adhesion deficiency I was described in a patient with painful recurrent leg ulcers resembling pyoderma gangrenosum.[9] The syndrome is characterized by absent or reduced expression of leukocyte antigens CR3, LFA1 and CR4, or P150,95 and impaired neutrophil adhesive functions (eg, margination, chemotaxis, iC3b-mediated opsonization, phagocytosis). The defect is heterogeneous in that the severity of the disease parallels the degree of deficiency. The more severe forms are due to defects in gene encoding the common beta chain. Heterozygote individuals do not have a predisposition to infections, and their neutrophilic function is normal.

The following conditions are associated with newborns who are affected: delayed separation of the umbilical cord and secondary omphalitis, severe recurrent Staphylococcus aureus and gram-negative bacterial infections, periodontitis, impaired wound healing, lack of pus formation, and leukocytosis.

C3aR and C5aR receptor deficiency

To the author's knowledge, only animal studies have been performed at this time.

C3a has been implicated in the development of adult respiratory distress syndrome or multisystem failure in patients with toxic shock syndrome. The protective role of receptor C3aR in septic shock has been shown in mice with targeted homozygous gene deficiency for C3aR (C3aR-/-). An increased susceptibility to shock was observed in these mice and associated with increased levels of tumor necrosis factor-alpha and interleukin 6.

C3a and its receptor C3aR also have a pivotal role in the pathogenesis of allergy-induced responses, such as bronchoconstriction in asthma, as demonstrated in guinea pigs with a natural C3aR defect or in genetically engineered C3aR knockout mice.[10]

In C5aR-deficient mice, the inflammatory response is decreased in skin, lung, and peritoneum.

Previous
Next

Causes

Both genetic and acquired factors have been associated with complement receptor deficiencies.

Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Isabelle Thomas, MD  Associate Professor, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School; Chief of Dermatology Service, Veterans Affairs Medical Center of East Orange

Isabelle Thomas, MD is a member of the following medical societies: American Academy of Dermatology and Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

Evan R Farmer, MD  Clinical Professor of Pathology and Dermatology, Department of Pathology, Virginia Commonwealth University School of Medicine

Evan R Farmer, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society of Dermatopathology, and International Society of Dermatology

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD  Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Weaver DJ Jr, Reis ES, Pandey MK, Köhl G, Harris N, Gerard C, et al. C5a receptor-deficient dendritic cells promote induction of Treg and Th17 cells. Eur J Immunol. Mar 2010;40(3):710-21. [Medline].

  2. Fairweather D, Frisancho-Kiss S, Njoku DB, Nyland JF, Kaya Z, Yusung SA, et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J Immunol. Mar 15 2006;176(6):3516-24. [Medline].

  3. Jacobson AC, Weis JJ, Weis JH. Complement receptors 1 and 2 influence the immune environment in a B cell receptor-independent manner. J Immunol. Apr 1 2008;180(7):5057-66. [Medline].

  4. Boos L, Campbell IL, Ames R, Wetsel RA, Barnum SR. Deletion of the complement anaphylatoxin C3a receptor attenuates, whereas ectopic expression of C3a in the brain exacerbates, experimental autoimmune encephalomyelitis. J Immunol. Oct 1 2004;173(7):4708-14. [Medline].

  5. Tone Y, Wada T, Shibata F, Toma T, Hashida Y, Kasahara Y, et al. Somatic revertant mosaicism in a patient with leukocyte adhesion deficiency type 1. Blood. Feb 1 2007;109(3):1182-4. [Medline].

  6. Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. Mar 2009;15(3):306-12. [Medline].

  7. Yashoda-Devi BK, Rakesh N, Devaraju D, Santana N. Leukocyte adhesion deficiency type I--a focus on oral disease in a young child. Med Oral Patol Oral Cir Bucal. Mar 1 2011;16(2):e153-7. [Medline].

  8. Fearon DT. Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte. J Exp Med. Jul 1 1980;152(1):20-30. [Medline].

  9. Nord KM, Pappert AS, Grossman ME. Pyoderma Gangrenosum-like Lesions in Leukocyte Adhesion Deficiency I Treated with Intravenous Immunoglobulin. Pediatr Dermatol. Mar 2011;28(2):156-61. [Medline].

  10. Bautsch W, Hoymann HG, Zhang Q, Meier-Wiedenbach I, Raschke U, Ames RS, et al. Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma. J Immunol. Nov 15 2000;165(10):5401-5. [Medline].

  11. Qasim W, Cavazzana-Calvo M, Davies EG, Davis J, Duval M, Eames G, et al. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency. Pediatrics. Mar 2009;123(3):836-40. [Medline].

  12. Anderson DC, Schmalstieg FC, Arnaout MA, Kohl S, Tosi MF, Dana N, et al. Abnormalities of polymorphonuclear leukocyte function associated with a heritable deficiency of high molecular weight surface glycoproteins (GP138): common relationship to diminished cell adherence. J Clin Invest. Aug 1984;74(2):536-51. [Medline].

  13. Atkinson JP. Complement deficiency. Predisposing factor to autoimmune syndromes. Am J Med. Dec 23 1988;85(6A):45-7. [Medline].

  14. Barrington RA, Zhang M, Zhong X, Jonsson H, Holodick N, Cherukuri A, et al. CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses. J Immunol. Sep 1 2005;175(5):2859-67. [Medline].

  15. Bartholomew WR, Shanahan TC. Complement components and receptors: deficiencies and disease associations. Immunol Ser. 1990;52:33-51. [Medline].

  16. Bowen TJ, Ochs HD, Altman LC, Price TH, Van Epps DE, Brautigan DL, et al. Severe recurrent bacterial infections associated with defective adherence and chemotaxis in two patients with neutrophils deficient in a cell-associated glycoprotein. J Pediatr. Dec 1982;101(6):932-40. [Medline].

  17. Carroll MC. The role of complement in B cell activation and tolerance. Adv Immunol. 2000;74:61-88. [Medline].

  18. Colten HR, Rosen FS. Complement deficiencies. Annu Rev Immunol. 1992;10:809-34. [Medline].

  19. Davies KA. Complement. Baillieres Clin Haematol. Dec 1991;4(4):927-55. [Medline].

  20. Fischer A, Seger R, Durandy A, Grospierre B, Virelizier JL, Le Deist F, et al. Deficiency of the adhesive protein complex lymphocyte function antigen 1, complement receptor type 3, glycoprotein p150,95 in a girl with recurrent bacterial infections. Effects on phagocytic cells and lymphocyte functions. J Clin Invest. Dec 1985;76(6):2385-92. [Medline].

  21. Glovsky MM, Ward PA, Johnson KJ. Complement determinations in human disease. Ann Allergy Asthma Immunol. Dec 2004;93(6):513-22; quiz 523-5, 605. [Medline].

  22. Haas KM, Tedder TF. Role of the CD19 and CD21/35 receptor complex in innate immunity, host defense and autoimmunity. Adv Exp Med Biol. 2005;560:125-39. [Medline].

  23. Harlan JM. Leukocyte adhesion deficiency syndrome: insights into the molecular basis of leukocyte emigration. Clin Immunol Immunopathol. Jun 1993;67(3 Pt 2):S16-24. [Medline].

  24. Holers VM. Phenotypes of complement knockouts. Immunopharmacology. Aug 2000;49(1-2):125-31. [Medline].

  25. Kazatchkine MD, Fearon DT. Deficiencies of human C3 complement receptors type 1 (CR1, CD35) and type 2 (CR2, CD21). Immunodefic Rev. 1990;2(1):17-41. [Medline].

  26. Kazatchkine MD, Jouvin MH, Wilson JG, Fischer E, Fischer A. Human diseases associated with C3 receptor deficiencies. Immunol Lett. Feb 1987;14(3):191-5. [Medline].

  27. Kildsgaard J, Hollmann TJ, Matthews KW, Bian K, Murad F, Wetsel RA. Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock. J Immunol. Nov 15 2000;165(10):5406-9. [Medline].

  28. Kirschfink M. Controlling the complement system in inflammation. Immunopharmacology. Dec 1997;38(1-2):51-62. [Medline].

  29. Köhl J, Gessner JE. On the role of complement and Fc gamma-receptors in the Arthus reaction. Mol Immunol. Sep-Oct 1999;36(13-14):893-903. [Medline].

  30. Morgan BP, Daha M, Meri S, Nicholson-Weller A. Into the third century of complement research. Immunol Today. Dec 2000;21(12):603-5. [Medline].

  31. Moulds JM, Krych M, Holers VM, Liszewski MK, Atkinson JP. Genetics of the complement system and rheumatic diseases. Rheum Dis Clin North Am. Nov 1992;18(4):893-914. [Medline].

  32. Nielsen CH, Fischer EM, Leslie RG. The role of complement in the acquired immune response. Immunology. May 2000;100(1):4-12. [Medline].

  33. Nybo M, Sørensen O, Leslie R, Wang P. Reduced expression of C5a receptors on neutrophils from cord blood. Arch Dis Child Fetal Neonatal Ed. Mar 1998;78(2):F129-32. [Medline].

  34. Perlmutter DH, Colten HR. Molecular basis of complement deficiencies. Immunodefic Rev. 1989;1(2):105-33. [Medline].

  35. Reid RR, Woodcock S, Prodeus AP, Austen J, Kobzik L, Hechtman H, et al. The role of complement receptors CD21/CD35 in positive selection of B-1 cells. Curr Top Microbiol Immunol. 2000;252:57-65. [Medline].

  36. Rhein LM, Perkins M, Gerard NP, Gerard C. FcgammaRIII is protective against Pseudomonas aeruginosa pneumonia. Am J Respir Cell Mol Biol. Apr 2008;38(4):401-6. [Medline].

  37. Rigal D, Andreoni C, Vermot-Desroches C, Rousset F, Souillet G, Robert J. [Physiopathological roles of leukocyte adhesion proteins: LFA-1, CR3, P150-95 in man]. Pediatrie. 1988;43(3):185-90. [Medline].

  38. Smiley JD, Moore SE Jr. Immune-complex vasculitis: role of complement and IgG-Fc receptor functions. Am J Med Sci. Oct 1989;298(4):267-77. [Medline].

  39. Tedder TF, Poe JC, Fujimoto M, Haas KM, Sato S. The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system. Curr Dir Autoimmun. 2005;8:55-90. [Medline].

  40. Webb J, Whaley K. Complement and immune complex diseases. Aust N Z J Med. Apr 1986;16(2):268-78. [Medline].

  41. Whaley K, Schwaeble W. Complement and complement deficiencies. Semin Liver Dis. 1997;17(4):297-310. [Medline].

  42. Wilson JG, Ratnoff WD, Schur PH, Fearon DT. Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus. Arthritis Rheum. Jun 1986;29(6):739-47. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.