An unexpected player in Gaucher disease: The multiple roles of complement in disease development. (June 2018)

• Record Type: Journal Article
• Authors: Pandey, Manoj K.; Grabowski, Gregory A.; Köhl, Jörg
• Is Part Of: Seminars in immunology. Volume 37(2018)
• Page Start: 30
• Page End: 42
• Publication Date: 2018-06
• Subjects: ADA anti-drug antibodies -- AMPK 5′ adenosine monophosphate-activated protein kinase -- aHUS atypical hemolytic uremic syndrome -- AMD age-related macular degeneration -- APC antigen presenting cells -- AT anaphylatoxin -- BTK Bruton's tyrosine kinase -- C1q complement 1q -- C3a complement 3a fragement of C3 -- C3aR C3a receptors -- C5a complement 5a fragment of C5 -- C5aR1 C5a receptor 1 -- C5aR2 C5a receptor 2 -- CBE conduritol B epoxide -- CCL2 CC-chemokine ligand 2 -- CLEAR Coordinated Lysosomal Expression and Regulation -- CMIA Complement-Metabolism-Inflammasome Axis -- CNS central nervous system -- CR complement receptor -- CRIg complement receptor of the immoglubin superfamily -- CXCR5 C-X-C chemokine receptor Type 5 -- CSF-1 colony stimulating factor 1 -- CSF-2 colony-stimulating factor 2 -- DAG diacylglycerol -- DAMP danger or damage-associatted molecular pattern -- DC dendritic cell -- ERT enzyme replacement therapy -- FcγR IgG Fc receptor -- GAGs glycosaminoglycans -- GC/GL1 glucosylceramide -- GD Gaucher disease -- GL1-IC immune complexes comprising GL1 and GL1-specific autoantibodies -- GLS Greater Lysosomal System -- GPCRs G protein-coupled receptors -- ICOS induced costimulatory molecule -- IFN-γ interferon gamma -- IL interleukin -- ITAM immunoreceptor tyrosine-based activating motif -- ITIM immunoreceptor tyrosine-based inhibiting motif -- LAL lysosomal acid lipase -- LAT linker for activation of T cells -- LGL1 lysoGL1 or glucosylsphingosine -- LSD lysosomal storage disease -- MACs multimolecular adaptor complexes -- MAPK mitogen-activated protein kinase -- MBL mannan-binding lectin -- MiT micropthalmia transcription -- MMR Mϕ mannose receptor -- Mϕ macrophage -- MOs monocytes -- mTORC1 mammalian target of rapamycin complex 1 -- NF-κB nuclear factor kappa B -- NKT natural killer T cells -- NLRP3 nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 -- PAMP pathogen-associated molecular pattern -- PD-1 programmed cell death-1 -- PI phosphoinositide base -- PI3K phosphoinositide 3-kinase -- PGP pGlycoprotein -- PLC-γ phospholipase C gamme -- PNH paroxysmal nocturnal hemoglbinuria -- PMN polymorphonuclear cells -- PRR pattern-recognition receptor -- ROS reactive oxygen species -- SREBP sterol regulatory element binding protein -- SRTs substrate reduction therapies TCC, terminal complement complex -- TFEB and TFE3 transcription factor EB or E3 -- TFH T follicular helper cells -- Th T helper -- TLR Toll-like receptor -- Treg regulatory T cells; C5a -- C5a receptor -- Gaucher disease -- Antibodies -- Immune complex -- Autoimmunity; Immunology -- Periodicals; Allergy and Immunology -- Periodicals; Immunity -- Periodicals; Immunologie -- Périodiques; Electronic journals; 616.079
• DOI: 10.1016/j.smim.2018.02.006
• Languages: English
• ISSNs: 1044-5323

Abstract

Highlights: 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. Abstract: 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.