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Licensed Unlicensed Requires Authentication Published by De Gruyter June 12, 2015

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

Maddalena Alessandra Wu and Roberto Castelli EMAIL logo


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.

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:


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

©2016 by De Gruyter

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