Angioedema is a medical condition characterized by recurrent, deep-tissue swelling, typically affecting the face, throat, limbs, and gastrointestinal tract. Unlike common allergic reactions involving hives and itching, this swelling occurs beneath the skin’s surface and is not mediated by histamine. A rare subtype is associated with immune dysfunction, leading to a breakdown in a protective protein that controls vascular permeability. This immune-related dysfunction is known as Acquired Angioedema (AAE), where the body’s defense system mistakenly triggers swelling episodes.
Understanding Angioedema Type 2 and the Acquired Form
The term “Type 2” historically refers to a hereditary form of angioedema (HAE). Hereditary Angioedema Type 2 is a genetic disorder where the C1-Inhibitor (C1-INH) protein is present in normal quantities but is structurally dysfunctional. This congenital form usually presents in childhood and is caused by a mutation in the SERPING1 gene.
The condition most relevant to autoimmune causes is Acquired Angioedema (AAE), which is not inherited and typically starts later in life, often after age 40. AAE is defined by an acquired deficiency of the C1-Inhibitor protein resulting from another underlying medical condition.
AAE is subdivided into two types based on the mechanism of C1-INH deficiency. Acquired Angioedema Type I involves the consumption of C1-Inhibitor, often due to an underlying lymphoproliferative disorder that excessively activates the complement system. Acquired Angioedema Type II is the form most strongly connected to classic autoimmunity, characterized by autoantibodies specifically targeting the C1-Inhibitor itself.
The Autoimmune Connection to C1-Inhibitor Deficiency
The autoimmune connection in Acquired Angioedema Type II centers on the misdirected production of autoantibodies. The immune system generates self-attacking antibodies, typically immunoglobulin G (IgG), that bind directly to the functional sites of the C1-Inhibitor protein. This binding effectively inactivates the C1-INH molecule, rendering it incapable of regulating the cascades it controls.
This autoantibody-driven mechanism is a hallmark of systemic autoimmune disorders, such as Systemic Lupus Erythematosus (SLE), which have been linked to AAE development. These systemic diseases trigger immune B-cells to produce anti-C1-Inhibitor autoantibodies, resulting in the acquired deficiency.
In many cases of AAE, particularly Type I, the underlying issue is a lymphoproliferative disorder, such as non-Hodgkin lymphoma or Monoclonal Gammopathy of Undetermined Significance (MGUS). These conditions involve the abnormal growth of B-cells, the immune cells responsible for producing antibodies. The abnormal B-cells may produce neutralizing autoantibodies or abnormal proteins that form immune complexes, which excessively consume the C1-Inhibitor protein.
How the C1-Inhibitor Pathway Triggers Swelling
The C1-Inhibitor protein regulates several biochemical pathways in the blood, primarily the complement system and the kinin-kallikrein cascade. Its function is to inhibit enzymes like activated Factor XII (Factor XIIa) and plasma kallikrein, which are components of the contact activation system.
In Acquired Angioedema, when C1-Inhibitor is neutralized or consumed, this regulatory brake is lost, allowing the contact pathway to run unchecked. The uncontrolled activity of Factor XIIa converts the inactive precursor pre-kallikrein into active plasma kallikrein.
Plasma kallikrein then cleaves High Molecular Weight Kininogen (HMWK) to generate the peptide Bradykinin. Bradykinin is the molecule responsible for the swelling, acting as a potent vasoactive mediator.
Bradykinin binds to the Bradykinin B2 receptor (BR2) on the surface of endothelial cells lining blood vessel walls. This binding triggers a cascade that causes endothelial cells to contract and retract from one another. This cellular retraction creates microscopic gaps, leading to increased vascular permeability and allowing fluid to leak rapidly into the surrounding deep tissues, resulting in characteristic, non-pitting edema.
Diagnosis and Treatment Strategies for Acquired Angioedema
Diagnosing Acquired Angioedema requires specific laboratory tests that assess the functional consequences of C1-Inhibitor deficiency. Physicians measure the level and function of C1-Inhibitor protein, looking for low levels of both the protein and its inhibitory activity. A key diagnostic finding is a persistently low level of the complement protein C4, which is consumed in the unregulated cascade.
The most distinguishing laboratory feature of AAE, setting it apart from hereditary forms, is the measurement of C1q. This complement component is low in AAE but normal in Hereditary Angioedema. Testing for autoantibodies specifically directed against the C1-Inhibitor confirms the autoimmune (Type II) mechanism.
Treatment for AAE involves two concurrent approaches: managing acute swelling attacks and treating the underlying disease responsible for the deficiency. Acute attacks, particularly those involving the airway, are treated with therapies that either replace the missing protein or block the effect of Bradykinin.
Plasma-derived C1-Inhibitor concentrates can be administered intravenously to temporarily restore regulatory function. Medications like Icatibant, a Bradykinin B2 receptor antagonist, can block the receptor and prevent swelling. For long-term management, treating the underlying autoimmune or lymphoproliferative disorder is the most effective strategy. Monoclonal antibody therapies like rituximab, which targets B-cells, have shown success by eliminating the source of autoantibodies or abnormal immune consumption.