Pathophysiology and underlying mechanisms in hereditary angioedema

Area of Science:

• Genetics
• Immunology
• Pathophysiology

Background:

• Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder.
• It stems from dysregulation of the plasma contact system/kallikrein-kinin system, causing excessive bradykinin generation.
• Bradykinin binding to endothelial cells triggers recurrent, potentially life-threatening swelling episodes.

Purpose of the Study:

• To review the primary pathophysiological mechanisms underlying hereditary angioedema development.
• To consolidate current knowledge on the genetic basis and molecular pathways of HAE.
• To highlight recent advances in understanding HAE pathophysiology.

Main Methods:

• Literature review of pathophysiological events in hereditary angioedema.
• Analysis of genetic variants associated with different HAE subtypes.
• Synthesis of information on bradykinin generation and signaling in HAE.

Main Results:

• HAE subtypes include C1-inhibitor deficiency (hypocomplementemia) and normocomplementemic forms.
• Normocomplementemic HAE is linked to gain-of-function variants in FXII, PLG, and KNG1 genes.
• Novel variants in ANGPT1 and MYOF genes further broaden the known genetic landscape of HAE.

Conclusions:

• Hereditary angioedema pathophysiology involves complex interactions within the kallikrein-kinin system.
• Genetic variations in C1-inhibitor, coagulation factors, and newly identified genes contribute to HAE.
• Continued research is crucial for a comprehensive understanding of HAE pathogenesis.