Home The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity
Article
Licensed
Unlicensed Requires Authentication

The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity

  • Maddalena Alessandra Wu and Roberto Castelli EMAIL logo
Published/Copyright: June 12, 2015
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 54 Issue 2

Abstract

Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation.

Keywords: acquired deficiency of C1-INH; B cell disorder; lymphoproliferative diseases; monoclonal gammopathy of uncertain significance (MGUS); non-Hodgkin lymphoma
Corresponding author: Roberto Castelli, MD, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Luigi Sacco Hospital Milan, Milan, Italy, Phone: +39 2 50319830, Fax: +39 2 50319828, E-mail:

References

1. Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica 2011;96:752–61.10.3324/haematol.2010.036152Search in Google Scholar

2. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med 2005;352:804–15.10.1056/NEJMra041720Search in Google Scholar

3. Smedby KE, Askling J, Mariette X, Baecklund E. Autoimmune and inflammatory disorders and risk of malignant lymphomas – an update. J Intern Med 2008;264:514–27.10.1111/j.1365-2796.2008.02029.xSearch in Google Scholar

4. Hodgson K, Ferrer G, Pereira A, Moreno C, Montserrat E. Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol 2011;154:14–22.10.1111/j.1365-2141.2011.08707.xSearch in Google Scholar

5. Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood 2011;117:6777–85.10.1182/blood-2010-11-297580Search in Google Scholar

6. Cohen AJ, Kessler CM. Acquired inhibitors. Baillieres Clin Haematol 1996;9:331–54.10.1016/S0950-3536(96)80067-9Search in Google Scholar

7. Voisin S, Hamidou M, Lefrançois A, Sigaud M, Mahé B, Trossaërt M. Acquired von Willebrand syndrome associated with monoclonal gammopathy: a single-center study of 36 patients. Medicine (Baltimore) 2011;90:404–11.10.1097/MD.0b013e3182397166Search in Google Scholar PubMed

8. Castelli R, Vismara A, Pavia G, Dagani R, Porro T. Relapsing pure red cell aplasia associated with B-cell chronic lymphocytic leukemia successfully treated by intravenous immunoglobulin concentrate. Ann Ital Med Int 2002;17:47–50.Search in Google Scholar

9. Vlachaki E, Diamantidis MD, Klonizakis P, Haralambidou-Vranitsa S, Ioannidou-Papagiannaki E, Klonizakis I. Pure red cell aplasia and lymphoproliferative disorders: an infrequent association. Sci World J 2012;2012:475313.10.1100/2012/475313Search in Google Scholar PubMed PubMed Central

10. Zhang B, Zheng R, Wang J, Bu D, Zhu X. Epitopes in the linker subdomain region of envoplakin recognized by autoantibodies in paraneoplastic pemphigus patients. J Invest Dermatol 2006;126:832–40.10.1038/sj.jid.5700198Search in Google Scholar PubMed

11. Ramchandren S, Lisak RP. The immunopathogenesis of Guillain-Barré syndrome. Clin Adv Hematol Oncol 2010;8:203–6.Search in Google Scholar

12. Seffo F, Daw HA. Non-Hodgkin lymphoma and Guillain-Barré syndrome: a rare association. Clin Adv Hematol Oncol 2010;8:201–3.Search in Google Scholar

13. Nobile-Orazio E. Neuropathy and monoclonal gammopathy. Handb Clin Neurol 2013;115:443–59.10.1016/B978-0-444-52902-2.00025-4Search in Google Scholar PubMed

14. Castelli R, Gritti G, Cannavò A, Moreo G, Conti G, Reda G, et al. Successful management with intravenous immunoglobulins in alemtuzumab-induced acute inflammatory demyelinating neuropathy: clinical report of three patients. Immunopharmacol Immunotoxicol 2012;34:717–20.10.3109/08923973.2011.644295Search in Google Scholar

15. Cicardi M, Zanichelli A. Acquired angioedema. Allergy Asthma Clin Immunol 2010;6:14.10.1186/1710-1492-6-14Search in Google Scholar

16. Cicardi M, Zanichelli A. The acquired deficiency of C1-inhibitor: lymphoproliferation and angioedema. Curr Mol Med 2010;10:354–60.10.2174/156652410791317066Search in Google Scholar

17. Caldwell JR, Ruddy S, Schur PH, Austen KF. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin. Immunol Immunopathol 1972;1:39–52.10.1016/0090-1229(72)90006-2Search in Google Scholar

18. Jackson J, Sim RB, Whelan A, Feighery C. An IgG autoantibody which inactivates C1-inhibitor. Nature 1986;323:722–4.10.1038/323722a0Search in Google Scholar PubMed

19. Alsenz J, Bork K, Loos M. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med 1987;316:1360–6.10.1056/NEJM198705283162202Search in Google Scholar PubMed

20. Hauptmann G, Petitjean F, Lang JM, Oberling F. Acquired C1 inhibitor deficiency in a case of lymphosarcoma of the spleen. Reversal of complement abnormalities after splenectomy. Clin Exp Immunol 1979;37:523–31.Search in Google Scholar

21. Schreiber AD, Zweiman B, Atkins P, Goldwein F, Pietra G, Atkinson B, et al. Acquired angioedema with lymphoproliferative disorder: association of C1 inhibitor deficiency with cellular abnormality. Blood 1976;48:567–80.10.1182/blood.V48.4.567.567Search in Google Scholar

22. Geha RS, Quinti I, Austen KF, Cicardi M, Sheffer A, Rosen FS. Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N Engl J Med 1985;312:534–40.10.1056/NEJM198502283120902Search in Google Scholar PubMed

23. Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A. Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies. Medicine (Baltimore) 2003;82:274–81.10.1097/01.md.0000085055.63483.09Search in Google Scholar PubMed

24. Cugno M, Bos I, Lubbers Y, Hack CE, Agostoni A. In vitro interaction of C1-inhibitor with thrombin. Blood Coagul Fibrinolysis 2001;4:253–60.10.1097/00001721-200106000-00005Search in Google Scholar PubMed

25. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1 inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 2009;15:69–78.10.1016/j.molmed.2008.12.001Search in Google Scholar PubMed

26. Caccia S, Castelli R, Maiocchi D, Bergamaschini L, Cugno M. Interaction of C1-inhibitor with thrombin on the endothelial surface. Blood Coagul Fibrinolysis 2011;22:571–5.10.1097/MBC.0b013e3283494ba7Search in Google Scholar PubMed

27. Castelli R, Deliliers DL, Zingale LC, Pogliani EM, Cicardi M. Lymphoproliferative disease and acquired C1-inhibitor deficiency. Haematologica 2007;92:716–8.10.3324/haematol.10769Search in Google Scholar PubMed

28. Castelli R, Zanichelli A, Cicardi M, Cugno M. Acquired C1-inhibitor deficiency and lymphoproliferative disorders: a tight relationship. Crit Rev Oncol Hematol 2013;87:323–32.10.1016/j.critrevonc.2013.02.004Search in Google Scholar PubMed

29. Cugno M, Castelli R, Cicardi M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun Rev 2008;8:156–9.10.1016/j.autrev.2008.05.003Search in Google Scholar PubMed

30. Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G, et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005;165:101–5.10.1001/archinte.165.1.101Search in Google Scholar PubMed

31. Dias C, Isenberg DA. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma. Nat Rev Rheumatol 2011;7:360–8.10.1038/nrrheum.2011.62Search in Google Scholar PubMed

32. Jung M, Rice L. Unusual autoimmune nonhematologic complications in chronic lymphocytic leukemia. Clin Lymphoma, Myeloma Leuk 2011;11(Suppl 1):S10–3.10.1016/j.clml.2011.02.005Search in Google Scholar PubMed

33. Guillarte M, Luengo O, Nogueiras C, Labrador-Horrillo M, Muñoz E, López A, et al. Acquired angioedema associated with hereditary angioedema due to C1-inhibitor deficiency. J Investig Allergol Clin Immunol 2008;18:126–30.Search in Google Scholar

34. Healy C, Abuzakouk M, Feighery C, Flint S. Acquired angioedema in non-Hodgkin’s lymphoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e29–32.10.1016/j.tripleo.2006.11.015Search in Google Scholar PubMed

35. Rossi D, Gaidano G. Anaplastic large cell lymphoma and acquired angioedema: a novel association? Ann Ital Med Int 2002;17:143–5.Search in Google Scholar

36. Kaur R, Williams AA, Swift CB, Caldwell JW. Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema. J Asthma Allergy 2014;7:165–7.Search in Google Scholar

37. Gunatilake SS, Wimalaratna H. Angioedema as the first presentation of B-cell non-Hodgkin lymphoma – an unusual case with normal C1 esterase inhibitor level: a case report. BMC Res Notes 2014;7:495.10.1186/1756-0500-7-495Search in Google Scholar PubMed PubMed Central

38. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(Suppl 3):S51–131.10.1016/j.jaci.2004.06.047Search in Google Scholar

39. Spath PJ, Wuthrich B, Matter L, Loos M, Alsenz J. Acquired angioedema and anti-C1-inhibitor autoantibody. Arch Intern Med 1989;149:1213–6.10.1001/archinte.149.5.1213Search in Google Scholar

40. Cicardi M, Bisiani G, Cugno M, Spath P, Agostoni A. Autoimmune C1-inhibitor deficiency: report of eight patients. Am J Med 1993;95:169–75.10.1016/0002-9343(93)90257-PSearch in Google Scholar

41. Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, et al.; HAWK under the patronage of EAACI (European Academy of Allergy and Clinical Immunology). Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 2014;69:602–16.10.1111/all.12380Search in Google Scholar

42. Zanichelli A, Bova M, Coerezza A, Petraroli A, Triggiani M, Cicardi M. Icatibant treatment for acquired C1-inhibitor deficiency: a real-world observational study. Allergy 2012;67:1074–7.10.1111/j.1398-9995.2012.02853.xSearch in Google Scholar

43. Patel NS, Fung SM, Zanichelli A, Cicardi M, Cohn JR. Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency. Allergy Asthma Proc 2013;34:72–7.10.2500/aap.2013.34.3620Search in Google Scholar

44. Lam DH, Levy NB, Nickerson JM, Gruenberg DA, Lansigan F. Acquired angioedema and marginal zone lymphoma. J Clin Oncol 2012;30:e151–3.10.1200/JCO.2011.38.9957Search in Google Scholar

45. Branellec A, Bouillet L, Javaud N, Mekinian A, Boccon-Gibod I, Blanchard-Delaunay C, et al; French National Reference Center for Angioedema (CREAK). Acquired C1-inhibitor deficiency: 7 patients treated with rituximab. J Clin Immunol 2012;32:936–41.10.1007/s10875-012-9691-2Search in Google Scholar

46. Dreyfus DH, Na CR, Randolph CC, Kearney D, Price C, Podell D. Successful rituximab B lymphocyte depletion therapy for angioedema due to acquired C1 inhibitor protein deficiency: association with reduced C1 inhibitor protein autoantibody titers. Isr Med Assoc J 2014;16:315–6.Search in Google Scholar

47. Cugno M, Cicardi M, Agostoni A. Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. J Allergy Clin Immunol 1994;93:870–6.10.1016/0091-6749(94)90380-8Search in Google Scholar

Received: 2015-2-25
Accepted: 2015-5-7
Published Online: 2015-6-12
Published in Print: 2016-2-1

©2016 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Total error vs. measurement uncertainty: the match continues
  4. Review
  5. Application of fatty acid and lipid measurements in neuropsychiatry
  6. Mini Review
  7. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity
  8. Opinion Papers
  9. How to report results of prothrombin and activated partial thromboplastin times
  10. Useful measures and models for analytical quality management in medical laboratories
  11. Total error vs. measurement uncertainty: revolution or evolution?
  12. Genetics and Molecular Diagnostics
  13. Rapid detection of Mmalton α1-antitrypsin deficiency allele by real-time PCR and melting curves in whole blood, serum and dried blood spot samples
  14. General Clinical Chemistry and Laboratory Medicine
  15. Diagnostic and clinical significance of Crohn’s disease-specific pancreatic anti-GP2 and anti-CUZD1 antibodies
  16. Immunoassays for the detection of IgA antibodies to tissue transglutaminase: significance of multiples of the upper limit of normal and inter-assay correlations
  17. Effects of biobanking conditions on six antibiotic substances in human serum assessed by a novel evaluation protocol
  18. Haematology and Coagulation
  19. Measurement of dabigatran, rivaroxaban and apixaban in samples of plasma, serum and urine, under real life conditions. An international study
  20. Reference Values and Biological Variations
  21. Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity
  22. Reference intervals for bone turnover markers in Spanish premenopausal women
  23. Cancer Diagnostics
  24. Citrulline as a biomarker of gastrointestinal toxicity in patients with rectal carcinoma treated with chemoradiation
  25. mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients
  26. Cardiovascular Diseases
  27. TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy
  28. Cardiac troponin I release after a basketball match in elite, amateur and junior players
  29. The role of timely measurement of galectin-3, NT-proBNP, cystatin C and hsTnT in predicting prognosis and heart function after heart transplantation
  30. Infectious Diseases
  31. Neutrophil CD64 combined with PCT, CRP and WBC improves the sensitivity for the early diagnosis of neonatal sepsis
  32. A comparison of three commercial platforms for urinary NGAL in critically ill adults
  33. Diabetes
  34. Liquid citrate acidification introduces significant glucose bias and leads to misclassification of patients with diabetes
  35. Letter to the Editors
  36. A rare and unstable hemoglobin variant, Hb M Dothan β 25/26 (-GTG), detected by the anomalous cytogram on Sysmex XE-2100
  37. Hb Hope [β136Gly→Asp] and Hb Grady [α119_120insGluPheThr] compound heterozygosity in a Mauritanian patient
  38. Falsely elevated ferritin in patients with a high concentration of rheumatoid factor
  39. Susceptibility of commonly used ferritin assays to the classic hook effect
  40. Comparison of the Elecsys calcitonin assay with the Immulite 1000 assay. Describing one case with heterophilic antibody interference
  41. Performance evaluation of low platelet count and platelet clumps detection on Mindray BC-6800 hematology analyzer
  42. Fetal sex discordance between sequencing-based and real-time PCR non-invasive prenatal test due to a vanishing twin
  43. Total HIV-1 DNA detection and quantification in peripheral blood by COBAS®AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0
  44. A replacement for the testosterone “sex gap”
  45. Added value of indirect immunofluorescence intensity of automated antinuclear antibody testing in a secondary hospital setting
https://doi.org/10.1515/cclm-2015-0195
Keywords for this article
acquired deficiency of C1-INH; B cell disorder; lymphoproliferative diseases; monoclonal gammopathy of uncertain significance (MGUS); non-Hodgkin lymphoma

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Total error vs. measurement uncertainty: the match continues
  4. Review
  5. Application of fatty acid and lipid measurements in neuropsychiatry
  6. Mini Review
  7. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity
  8. Opinion Papers
  9. How to report results of prothrombin and activated partial thromboplastin times
  10. Useful measures and models for analytical quality management in medical laboratories
  11. Total error vs. measurement uncertainty: revolution or evolution?
  12. Genetics and Molecular Diagnostics
  13. Rapid detection of Mmalton α1-antitrypsin deficiency allele by real-time PCR and melting curves in whole blood, serum and dried blood spot samples
  14. General Clinical Chemistry and Laboratory Medicine
  15. Diagnostic and clinical significance of Crohn’s disease-specific pancreatic anti-GP2 and anti-CUZD1 antibodies
  16. Immunoassays for the detection of IgA antibodies to tissue transglutaminase: significance of multiples of the upper limit of normal and inter-assay correlations
  17. Effects of biobanking conditions on six antibiotic substances in human serum assessed by a novel evaluation protocol
  18. Haematology and Coagulation
  19. Measurement of dabigatran, rivaroxaban and apixaban in samples of plasma, serum and urine, under real life conditions. An international study
  20. Reference Values and Biological Variations
  21. Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity
  22. Reference intervals for bone turnover markers in Spanish premenopausal women
  23. Cancer Diagnostics
  24. Citrulline as a biomarker of gastrointestinal toxicity in patients with rectal carcinoma treated with chemoradiation
  25. mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients
  26. Cardiovascular Diseases
  27. TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy
  28. Cardiac troponin I release after a basketball match in elite, amateur and junior players
  29. The role of timely measurement of galectin-3, NT-proBNP, cystatin C and hsTnT in predicting prognosis and heart function after heart transplantation
  30. Infectious Diseases
  31. Neutrophil CD64 combined with PCT, CRP and WBC improves the sensitivity for the early diagnosis of neonatal sepsis
  32. A comparison of three commercial platforms for urinary NGAL in critically ill adults
  33. Diabetes
  34. Liquid citrate acidification introduces significant glucose bias and leads to misclassification of patients with diabetes
  35. Letter to the Editors
  36. A rare and unstable hemoglobin variant, Hb M Dothan β 25/26 (-GTG), detected by the anomalous cytogram on Sysmex XE-2100
  37. Hb Hope [β136Gly→Asp] and Hb Grady [α119_120insGluPheThr] compound heterozygosity in a Mauritanian patient
  38. Falsely elevated ferritin in patients with a high concentration of rheumatoid factor
  39. Susceptibility of commonly used ferritin assays to the classic hook effect
  40. Comparison of the Elecsys calcitonin assay with the Immulite 1000 assay. Describing one case with heterophilic antibody interference
  41. Performance evaluation of low platelet count and platelet clumps detection on Mindray BC-6800 hematology analyzer
  42. Fetal sex discordance between sequencing-based and real-time PCR non-invasive prenatal test due to a vanishing twin
  43. Total HIV-1 DNA detection and quantification in peripheral blood by COBAS®AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0
  44. A replacement for the testosterone “sex gap”
  45. Added value of indirect immunofluorescence intensity of automated antinuclear antibody testing in a secondary hospital setting
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 10.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2015-0195/html
Scroll to top button