Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema

Abstract

Acquired angioedema due to C1-inhibitor (C1INH) deficiency (AAE) is caused by secondary C1INH deficiency leading to bradykinin-mediated angioedema episodes. AAE typically presents in adulthood and is associated with B cell lymphoproliferation. Anti-C1INH autoantibodies (antiC1INHAbs) are detectable in a subset of AAE cases and considered a hallmark of the disease. When free antiC1INHAbs and malignant tumors are not detectable, diagnosis relies on the finding of low C1INH levels and/or function, lack of family history and SERPING1 mutations, age at onset and low or undetectable C1q levels, none of which is specific for AAE. We tested the diagnostic value of a novel enzyme-linked immunosorbent assay (ELISA) for the detection of circulating complexes between C1INH and antiC1INHAbs (C1INH-antiC1INHAb) in the serum of 20 European AAE patients characterized on the basis of their complement levels and function. Free antiC1INHAbs were detected in nine of 20 patients [six of immunoglobulin (Ig)G class, two of IgM class and one simultaneously presenting IgG and IgM classes], whereas C1INH-antiC1IN-HAb complexes were found in 18 of 20 of the AAE cases, regardless of the presence or absence of detectable free anti-C1INHAbs. Of note, nine of 20 patients showed negative free antiC1INHabs, but positive C1INH-antiC1INHAb complexes in their first measurement. In the cohort presented, IgM-class C1INH-antiC1INHAb are specifically and strongly associated with low C1q serum levels. Detection of C1INH-antiC1-INHAbs provides an added value for AAE diagnosis, especially in those cases in whom no free anti-C1INH antibodies are detected. The link between IgM-class C1INH-antiC1INHAb complexes and C1q consumption could have further implications for the development of autoimmune manifestations in AAE.

Angioedema Without Wheals: Challenges in Laboratorial Diagnosis

“…ELISA plates covered with purified C1-INH are used for measuring anti-C1-INH antibodies, where the unbound antibodies from the patient sample are detected with different anti-human immunoglobulins, to show the presence of IgM-, IgG-, or IgA-type antibodies separately ( 46 , 47 ). A few semiquantitative, ELISA-based methods have been introduced for analyzing the antibodies’ inhibitory effect on C1-INH ( 46 , 48 , 49 ), but these tests are not available commercially.…”

“…A few semiquantitative, ELISA-based methods have been introduced for analyzing the antibodies’ inhibitory effect on C1-INH ( 46 , 48 , 49 ), but these tests are not available commercially. Remarkably, the binding strength of the antibodies mostly determines the antibodies’ inactivating effect exerted on C1-INH, as well as the specific binding site on the C1-INH molecule ( 47 , 50 ).…”

C1-inhibitor/C1-inhibitor antibody complexes in acquired angioedema due to C1-inhibitor deficiency

“…C1-INH-AAE can be associated with several further diseases, mainly lymphoproliferative ones, like monoclonal gammopathy of undetermined significance (MGUS) and non-Hodgkin lymphomas [ 3 , 22 , 28 , 29 ].…”

“…The decrease of C1-INH antigenic concentration may be due to the neoplastic lymphatic tissue enhancing activation of the classical pathway or due to the presence of neutralizing C1-INH-Ab. C1q consumption is attributed to the uncontrolled activation of the complement classical pathway due to high titers of circulating C1-INH/C1-INH antibody complexes (CAC), eventually causing the exhaustion of C1-INH inhibitory activities [ 3 , 30 , 33 ]. C1-INH-Ab can interfere with the function of CI-INH, and C1-INH-Ab can recognize different epitopes within C1-INH [ 30 , 33 ].…”

“…In case of C1-INH-AAE patients, free C1-INH is circulating in a cleaved/inactivated form [ 3 , 26 ].…”