An unexpected player in Gaucher disease: The multiple roles of complement in disease development

• Published in: Seminars in immunology 2018-06, Vol.37, p.30-42
• Main Authors: Pandey, Manoj K., Grabowski, Gregory A., Köhl, Jörg
• Format: Article
• Language: English
• Subjects: Antibodies; Autoimmunity; C5a; C5a receptor; Gaucher disease; Immune complex
• ISSN: 1044-5323; 1096-3618
• DOI: 10.1016/j.smim.2018.02.006

•Glucosylceramide-specific auto-antibodies induce systemic and local complement production.•The C5a/C5aR1 axis in dendritic cells drives the activation of Natural killer T cells eventually sparking chronic inflammation and tissue destruction•The C5a/C5aR1 axis tips the balance of glucosylceramide and lyso-glucsoylceramide formation through stimulation of glucosylceramide synthase production.•C5aR1 may serve as a novel therapeutic target in Gaucher disease. The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell-derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism. Genetic mutations of such lysosomal enzymes or their receptors can result in the compartmental accumulation of specific classes of substrates in this organelle summarized as lysosomal storage diseases (LSD). A frequent LSD is Gaucher disease (GD), caused by autosomal recessively inherited mutations in GBA1, resulting in functional defects of the encoded enzyme, acid β-glucosidase (glucocerebrosidase, GCase). Such mutations promote excessive accumulation of β-glucosylceramide (GC or GL1) in innate and adaptive immune cells frequently associated with chronic inflammation. Recently, we uncovered an unexpected link between the C5a and C5a receptor 1 (C5aR1) axis and the accumulation of GL1 in experimental and clinical GD. Here, we will review the pathways of complement activation in GD, its role as a mediator of the inflammatory response, and its impact on glucosphingolipid metabolism. Further, we will discuss the potential role of the C5a/C5aR1 axis in GL1-specific autoantibody formation and as a novel therapeutic target in GD.