Excerpt from Angioedema, Acquired

Synonyms, Key Words, and Related Terms: AAE, Caldwell syndrome, acquired angioedema

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Background: Acquired angioedema (AAE) is characterized by painless, nonpruritic, nonpitting swelling of the skin that is classified into 2 forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II). AAE-I is associated with other diseases, most commonly B-cell lymphoproliferative disorders. AAE-II is an autoimmune process defined by the presence of an autoantibody directed against the C1 inhibitor molecule (C1-INH).

Pathophysiology: The gene for C1-INH has been mapped to chromosome 11 (11q12-q13.1). C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated Hageman factor, the first protease in the contact system. Additionally, C1-INH is one of the major inhibitors of plasma kallikrein, the contact system protease that cleaves kininogen and releases bradykinin.

Presumably, uncontrolled activation of the contact system allows for release of kininlike mediators, resulting in vascular permeability with edema of subcutaneous and mucosal tissues. Although the issue of which vasoactive peptide is ultimately responsible for these changes remain controversial, direct evidence supports the importance of bradykinin in the clinical manifestations of angioedema. Other kinins may also be pathogenic. The specific trigger responsible for inducing the release of these vasoactive peptides is unclear. Factor XII activation (Hageman factor) may be secondary to phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin. The precise pathophysiology of AAE-I remains to be defined. Diminished levels of C1-INH are due to its increased catabolism.

In AAE-I, the associated disorders (usually lymphoproliferative malignancies) produce complement-activating factors, idiotype/anti-idiotype antibodies, or other immune complexes that destroy C1-INH function. Neoplastic lymphatic tissue has been found to play an active role in the consumption of C1-INH and the complement components of the classic pathway. The most commonly associated malignancy, B-cell lymphoma, has shown that anti-idiotypic antibody attached to immunoglobulin on the surface of B-cells causes C1-INH deficiency. Increased consumption of C1q followed by C2 and C4 results in subsequent release of vasoactive peptides that act on postcapillary venules.

In AAE-II, a normal 105-kd C1-INH molecule is synthesized in adequate amounts, but, because of an unknown event, a subpopulation of B cells secretes autoantibodies to the C1-INH molecule. This autoantibody, which may be any of the major immunoglobulin classes, binds to the reactive center of C1-INH. After binding to C1-INH and altering its structure, its regulatory capacity is diminished or abrogated.

In all reported cases of C1-INH deficiency caused by an autoantibody, C1-INH circulates in the blood in a form that has been cleaved by target proteases from its native molecule to a 95-kd fragment. Because of the higher affinity of the autoantibody for native C1-INH, the 95-kd antibody/C1-INH complex dissociates, and the freed antibody can bind to another native C1-INH molecule, allowing for the further depletion of C1-INH.

The distinction between AAE-I and AAE-II may be difficult to make at times and it is imperative to stress that overlap does occur. For instance, cases of monoclonal gammopathy have shown the monoclonal immunoglobulin itself to be the C1-INH antibody. Regarding malignancies and/or other diseases associated with AAE-I, it has been demonstrated that these patients may initially present with autoantibodies to C1-INH, or they may develop as the di .....