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C3 is activated in hereditary angioedema, and C1/C1-inhibitor complexes rise during physical stress in untreated
E W Nielsen1, H T Johansen, O Gaudesen
1Department of Anaesthesiology, Nordland Central Hospital, Bodo, Norway.
Insights
Physical stress may enhance complement activation in hereditary angioedema (HAE) patients. This study found increased C1/C1-inhibitor complexes in untreated HAE patients after exercise, suggesting a link between physical activity and HAE attacks.
Area of Science:
- Immunology
- Complement System
- Hereditary Angioedema
Background:
- Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling attacks.
- The role of physical exercise in triggering HAE attacks requires further investigation.
- Complement system dysregulation is implicated in HAE pathogenesis.
Purpose of the Study:
- To investigate the impact of physical exercise on complement activation in HAE patients.
- To identify specific complement components and pathways affected by physical stress in HAE.
- To compare complement profiles in HAE patients with and without danazol treatment.
Main Methods:
- Studied seven HAE patients and controls undergoing controlled bicycle exercise.
- Measured complement components (C3, C4) and their activation products (C3bc, C4bc, C4d).
- Assessed C1-inhibitor (C1-INH) function, antigen levels, and C1/C1-INH complexes.
- Monitored fibrinolysis and high molecular weight kininogen levels.
Main Results:
- Untreated HAE patients showed significantly higher C1/C1-INH complexes post-exercise compared to controls.
- HAE patients exhibited elevated levels of C3 and C4 activation products.
- Danazol treatment in two patients resulted in intermediate complement values and lower split product levels.
- Fibrinolysis increased in both HAE patients and controls following exercise.
Conclusions:
- Physical stress appears to enhance complement activation in untreated HAE patients.
- A mild but significant activation of C3 occurs in HAE, particularly following physical exertion.
- Danazol treatment may modulate complement activation and reduce the formation of split products.
- These findings suggest a potential link between physical activity, complement pathways, and HAE attack induction.
Abstract:
Seven patients with hereditary angioedema (HAE) were studied to understand further how physical exercise may induce attacks. The most pronounced differences between patients and controls, however, were independent of the controlled bicycle run (mean values in patients/ controls); C4(g/L): 0.12/0.28 (P = 0.0122); C4bc (AU/ml): 137.0/18.0 (P = 0.0002); C4d (mg/mL): 5.03/2.35 (P = 0.0004); C3bc (AU/ml): 8.4/6.3 (P = 0.0049); C3a (AU/ml): 11.1/5.6 (P = 0.0102). The ratio C4bc to C4 was 1141 versus 64. Consequently, a substantial part of the low amount of C4 left in HAE patients consists of activation products, and the authors show for the first time that a mild but significant activation of C3 occurs in HAE. The two HAE patients treated with danazol had values of C1-INH function and antigen, C4, and C2 in-between those of normal and untreated patients, and lower levels of split products from C4 and high molecular weight kininogen than untreated patients. As a result of the exercise, fibrinolysis increased significantly in both patients and controls, while C1/C1-INH complexes rose significantly only in the five HAE patients without treatment when compared to the seven controls (P = 0.0089). This study thus suggests that complement activation is enhanced in untreated HAE patients following physical stress.