Complement in relation to unexplained angioedema and to hemolytic anemia – a general introduction
The complement system, when not properly regulated may be the cause to several different symptoms and diseases such as angioedema and anemia.
Angioedema is a swelling of the skin that is similar to hives (urticaria), but the swelling is not on the surface but under the skin. There are many different causes and it may be an allergic reaction or importantly caused by a specific complement deficiency, namely C1 inhibitor (C1-INH) deficiency.
During the reaction, certain mediator molecules are released that affect the blood vessels and cause leakage into the tissue. In an allergic reaction mast cells and basophil granulocytes release histamine when IgE antibodies detect a foreign substance which then is called an allergen. In angioedema due to C1-INH deficiency another mediator molecule, bradykinin is responsible. The lack of C1-INH gives insufficient control of several serine proteases leading to increased bradykinin formation due to increased cleavage of HMW-kininogen by kallikrein (ref 1).
Angioedema as part of an allergic reaction may be caused by for example animal dander, some foods, pollen and certain medicines such as antibiotics. Insect bites and sometimes exposure to water, sunlight, cold or heat may start the reaction. Angioedema may also occur after infections, in blood disorders and other illnesses including autoimmune disorders. However, in many cases, the cause of angioedema is never found.
The angioedema due to C1-INH deficiency often runs in families and this form is therefore called hereditary angioedema (HAE). It is characterized by recurrent, self-limiting episodes of swelling which often is started by physical trauma, certain food and stress. The swelling is often in the skin but may also be in mucous membranes and when affecting the gastrointestinal tract cause severe pain. However, the most severe location of the swelling is the pharynx since this may cause asphyxiation. Thus, to get the diagnosis is important since several treatment possibilities now are available. The deficiency of C1-INH may also be acquired and the disease is then called acquired angioedema (AAE). There is also a form of HAE with normal C1-INH, which was first described in 2000 (ref 2). Also in this form of HAE, sometimes referred to as HAE type III, bradykinin causes the symptoms.
Anemia is a condition when the number of healthy red blood cells is too low not providing enough oxygen to the bodys tissues. Normally, red blood cells are in the circulation for about 4 months before they are removed, but in hemolytic anemia their lifespan is shorter. When the anemia is mild it causes tiredness and headache and when worse it gives more severe symptoms like pale skin color and shortness of breath.
In immune hemolytic anemia antibodies are formed against the red blood cells. The antibodies cause complement activation and through interaction with receptors the red cells are destroyed and removed. Possible causes to immune hemolytic anemia are exposure to certain chemicals, drugs and toxins. It may also be related to infections and occur if transfusion is made with a blood type that not match.
A certain type of hemolytic anemia, paroxysmal nocturnal hemoglobulinuria (PNH) is caused by a mutation in a gene called PIG-A in a progenitor cell in the bone marrow (ref 3). This gene allows a substance called glycosyl-phosphatidylinositol (GPI) to anchor certain proteins to cells. Thus, PNH is a rare acquired clonal disorder of haematopoietic stem cells. Red blood cells derived from this progenitor cell will then on their surface miss the lipid-anchored complement regulators decay accelerating factor (DAF, CD55) and protectin (CD59) . This makes the cells more vulnerable and red blood cells break down too early and leak hemoglobin into the blood, which can pass into the urine. This is more likely to occur during the night or early morning. In PNH a portion of the red blood cells are affected and the size of this portion influence the severity. A complement inhibitor has been proven safe and effective for the treatment of PNH patients.
2. Zuraw BL, Christiansen SC. Pathogenesis and laboratory diagnosis of hereditary angioedema. Allergy Asthma Proc. 30:487-92, 2009.
3. Risitano AM. Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv Exp Med Biol. 734:155-72, 2013.