Hereditary Angioedema (HAE) is a rare disorder characterized by recurrent, unpredictable episodes of severe swelling in the skin, gastrointestinal tract, and upper airway. These attacks are not mediated by histamine, the cause of common allergic swelling, making HAE a distinct medical condition. HAE involves a protein deficiency that impacts the immune system, leading to frequent questions about whether it is an autoimmune disease. This article clarifies the fundamental genetic mechanism of HAE and explains why it is classified differently from autoimmune disorders.
HAE is a Genetic Disorder, Not Autoimmune
Hereditary Angioedema is correctly categorized as a genetic disorder, specifically a primary immunodeficiency, and not an autoimmune condition. Autoimmune diseases involve the immune system mistakenly attacking the body’s own healthy tissues. In contrast, HAE results from a deficiency or dysfunction of a single regulatory protein, which is a structural or functional defect rather than a failure of immune recognition.
The primary forms of the condition are classified based on the status of the regulatory protein, C1 inhibitor (C1-INH). Type I HAE, accounting for approximately 85% of cases, involves a low production level of C1-INH. Type II HAE, representing about 15% of cases, is characterized by a normal quantity of C1-INH that is structurally defective and non-functional.
A third category, HAE with normal C1-INH (HAE-nl-C1INH), presents with the same swelling attacks but has normal C1-INH levels and function. These distinctions emphasize that the underlying problem is a protein-level defect or a genetic miscommunication. This mechanism is fundamentally different from a systemic autoimmune attack and initiates the specific biochemical cascade that causes the swelling.
The Role of C1 Inhibitor and Bradykinin
The defining feature of HAE is the uncontrolled production and accumulation of the small peptide called bradykinin. The C1 inhibitor protein (C1-INH) normally acts as a regulator across several biological systems, including the complement, coagulation, and contact (kallikrein-kinin) systems. Its function is to inhibit specific serine proteases within these pathways, maintaining balance within the blood plasma.
When C1-INH is deficient or dysfunctional, as in Type I and Type II HAE, its regulatory function is lost. This lack of control leads to the uncontrolled activation of the contact system, particularly the enzyme plasma kallikrein. Plasma kallikrein then cleaves high-molecular-weight kininogen to generate excessive amounts of bradykinin.
Bradykinin is directly responsible for the swelling attacks because it acts on blood vessel walls. It binds to the bradykinin B2 receptor on endothelial cells, triggering an increase in vascular permeability. This allows fluid from the bloodstream to leak rapidly into the surrounding tissues, causing non-itchy and non-pitting edema. This mechanism is a biochemical cascade resulting from a genetic defect, not a misdirected immune response.
Patterns of Inheritance
The term “hereditary” reflects the typical pattern of genetic transmission. HAE is predominantly inherited in an autosomal dominant manner, meaning a child needs only one copy of the affected gene from either parent to develop the disorder. This pattern results in a 50% chance for an affected parent to pass the condition on to their offspring.
Types I and II HAE are caused by mutations in the SERPING1 gene, which provides the instructions for making the C1-INH protein. Hundreds of different mutations in this gene lead to either quantitative deficiency (Type I) or qualitative dysfunction (Type II). For HAE with normal C1-INH, the genetic causes are more varied, with mutations identified in genes such as Factor XII (F12) and plasminogen (PLG).
Approximately 20 to 25% of all HAE cases arise from a spontaneous de novo mutation in the SERPING1 gene during conception. In these instances, the patient develops the condition without a family history of the disorder. This underscores the molecular basis of the disease, as the genetic defect can manifest even without an affected parent.
Targeted Treatment Approaches
Understanding HAE as a bradykinin-mediated disorder, rather than an inflammatory or autoimmune disease, has led to the development of highly specific treatments. Unlike autoimmune diseases, which are often managed with broad immunosuppressive agents, HAE therapies target the precise mechanism of swelling. Antihistamines and corticosteroids, the standard treatments for allergic angioedema, are ineffective for HAE attacks.
Current treatment strategies focus on either replacing the missing protein or blocking the overactive bradykinin pathway. These targeted interventions confirm that the core pathology of HAE is a failure to regulate the bradykinin cascade.
Types of Targeted HAE Treatments
Targeted treatments for HAE fall into three main categories:
- C1-INH replacement therapy, which supplies the deficient or dysfunctional protein to restore regulatory balance.
- Plasma kallikrein inhibitors, such as lanadelumab or berotralstat, which block the enzyme responsible for generating bradykinin.
- Bradykinin B2 receptor antagonists, such as icatibant, which directly block the receptor on endothelial cells, stopping the signal that causes blood vessels to leak fluid.