Complement activation and cellular inflammation in Fabry disease patients despite enzyme replacement therapy

Area of Science:

• Biochemistry
• Immunology
• Genetics

Background:

• Fabry disease (FD) arises from defective α-galactosidase A (AGAL/GLA), leading to glycosphingolipid accumulation (Gb3, lyso-Gb3) and chronic inflammation.
• Enzyme replacement therapy (ERT) with agalsidase-alfa/-beta aids Gb3 clearance, but its effect on complement activation in FD is unclear.

Purpose of the Study:

• To investigate complement system activation in classical male FD patients before and after ERT.
• To explore the relationship between mutation type, anti-drug antibodies (ADA), and complement activation/cytokine profiles during FD treatment.

Main Methods:

• Serum levels of C3a, C5a, IL-6, IL-10, and TGF-ß1 were measured in 17 classical male FD patients.
• Patients were analyzed based on mutation type (missense vs. nonsense) and ERT status, including ADA development.

Main Results:

• Strong complement activation (elevated C3a, C5a) was observed in FD patients, independent of ERT.
• FD patients with nonsense mutations and ADA showed increased C3a/C5a under ERT, unlike ADA-negative missense mutation patients.
• Elevated IL-6, IL-10, and TGF-ß1 were found, particularly in missense mutation patients under ERT, correlating with mild nephropathy.

Conclusions:

• Complement system activation is a significant feature of FD, especially in males with nonsense mutations and ADA.
• Kidney cell-associated cytokine production may drive renal damage in FD, suggesting inflammation is a therapeutic target despite ERT.