Diseases of complement dysregulation-an overview

Area of Science:

• Nephrology
• Hematology
• Immunology

Background:

• Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are key disorders of complement dysregulation.
• While complement overactivation is a common feature, the specific pathway affected (alternative or terminal) and the resulting clinical phenotype differ among these diseases.

Purpose of the Study:

• To review the distinct mechanisms of complement dysregulation in aHUS, C3G, and PNH.
• To discuss the therapeutic landscape, including the efficacy of eculizumab and the potential of next-generation complement therapeutics.

Main Methods:

• Review of existing literature on aHUS, C3G, and PNH.
• Analysis of the underlying genetic and autoimmune mechanisms driving complement dysregulation.
• Evaluation of current and emerging complement-targeted therapies.

Main Results:

• aHUS involves cell surface alternative pathway dysregulation often due to inherited mutations.
• C3G is characterized by fluid phase alternative pathway dysregulation, frequently linked to autoimmune factors.
• PNH results from terminal pathway dysregulation driven by somatic mutations, effectively treated by eculizumab, which has shown less success in C3G.

Conclusions:

• Understanding the specific complement dysregulation in aHUS, C3G, and PNH is crucial for targeted therapy.
• Next-generation complement therapeutics are anticipated to build upon the success seen with eculizumab, particularly for aHUS and PNH, and potentially offer new avenues for C3G treatment.