Angioedema and the immune system: Exploring the autoimmune connection
Fact-checked by Some types of angioedema are driven by underlying autoimmune processes, where the immune system becomes mistakenly reactive to the body’s own tissues.
Angioedema is characterized by recurrent swelling episodes in the deep layers of the skin and mucous membranes. It has several possible causes, some of which are immune-related.
There are a few different ways that autoimmune reactions can ultimately lead to angioedema. During the diagnostic process, it is important to recognize when swelling may be related to autoimmunity and to distinguish it from an allergic reaction, as treatment approaches differ.
The link between angioedema and autoimmunity
Autoimmune diseases occur when the immune system fails to recognize tissues or proteins as healthy parts of the body and mistakenly targets them. In some cases, this immune dysregulation can interfere with molecules that normally prevent excessive inflammation and lead to the swelling attacks that characterize angioedema.
In acquired angioedema, a rare form of the condition, people have abnormally low activity of C1 esterase inhibitor (C1-INH). This leads to excessive production of a signaling molecule called bradykinin, which makes blood vessels become more leaky and allows fluid to seep into nearby tissues, ultimately causing swelling.
Acquired angioedema is classified into two forms based on the mechanisms leading to abnormally low C1-INH activity. Autoimmune conditions that dysregulate the immune system can drive both subtypes:
- Type 1: Overactivation of the immune system’s complement pathway, which C1-INH helps regulate, causes C1-INH to become depleted because it is consumed faster than the body can replace it.
- Type 2: The immune system produces self-reactive antibodies that bind to C1-INH, blocking its normal function and accelerating its inactivation.
Autoimmune diseases linked to acquired angioedema include lupus, rheumatoid arthritis, and Sjögren’s disease. Certain lymphoproliferative disorders, a group of conditions including some blood cancers that cause immune cells to grow uncontrolled, are also recognized angioedema comorbidities, or co-occurring conditions, because they can disrupt normal immune regulation and reduce C1-INH activity.
Lymphoproliferative disorders, a group of conditions including some blood cancers that cause immune cells to grow uncontrolled, can also drive it.
Another condition called chronic spontaneous urticaria (CSU), which has an autoimmune origin in most people, is also linked to angioedema. This has distinct mechanisms from acquired angioedema, but is still ultimately caused by autoimmune activity that promotes swelling.
Allergic vs. autoimmune swelling
Although both involve the immune system and swelling, autoimmune-related angioedema is distinct from allergic angioedema, the most common type of the disorder.
In allergic angioedema, swelling is caused by the immune system’s exaggerated response to a harmless external substance, such as a food or medication. It is driven by excess histamine, an inflammatory signaling molecule released during allergic reactions that causes blood vessels to become leaky and results in rapid swelling.
In contrast, swelling in autoimmune forms of angioedema develops because abnormal immune mechanisms disrupt C1-INH activity, leading to excessive bradykinin production instead.
While swelling itself may appear similar, several features can help distinguish the two:
- Appearance of hives: Allergic reactions are usually accompanied by hives, or urticaria, which are raised, itchy welts on top of the skin. Other signs of an allergic reaction include a runny nose or watery eyes.
- Triggers: Allergic angioedema occurs upon exposure to an offending substance, while autoimmune triggers may not be obvious
- Duration: Swelling in allergic angioedema usually comes on quickly and resolves relatively quickly as the reaction subsides and exposure to the trigger is removed. With angioedema linked to autoimmune conditions, attacks may last much longer.
Angioedema related to autoimmune disease may also be accompanied by other signs of such conditions, including fatigue or joint pain.
Shared pathways between CSU and autoimmunity
CSU and autoimmunity are increasingly recognized as being closely connected. CSU causes recurrent hives that persist for six weeks or longer without an obvious external trigger, and about 40% of people with CSU also experience angioedema.
Research suggests that many cases of CSU are driven by autoimmune reactions. In these individuals, the immune system mistakenly produces self-reactive antibodies that activate immune mast cells. These cells then release large amounts of histamine and other inflammatory molecules, increasing blood vessel permeability and causing both hives and swelling.
CSU-related angioedema can seem similar to an allergic reaction because it is histamine-mediated and causes hives in most people. However, it is distinct, with some cases driven by an underlying autoimmune process or a form of allergic reaction against a protein found naturally within the body, rather than a reaction to an external substance.
Working with an immunologist
People who experience recurrent, unexplained swelling or develop angioedema alongside an autoimmune disease should discuss their symptoms with an allergist/immunologist, who has special training in allergy and immunology.
These specialists can help determine whether symptoms are caused by an autoimmune condition or another immune system disorder. And if angioedema and autoimmune disease occur together, these clinicians can also develop a safe and effective management plan that addresses both conditions.
Identifying and appropriately managing the underlying immune disorder is often an important part of long-term care for people with angioedema, who may also require specific medications to prevent and manage swelling episodes.
Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
