Contribution of inflammatory pathways to Fabry disease pathogenesis

Abstract

Lysosomal storage diseases are usually considered to be pathologies in which the passive deposition of unwanted materials leads to functional changes in lysosomes. Lysosomal deposition of unmetabolized glycolipid substrates stimulates the activation of pathogenic cascades, including immunological processes, and particularly the activation of inflammation. In lysosomal storage diseases, the inflammatory response is continuously being activated because the stimulus cannot be eliminated. Consequently, inflammation becomes a chronic process. Lysosomes play a role in many steps of the immune response. Leukocyte perturbation and over-expression of immune molecules have been reported in Fabry disease. Innate immunity is activated by signals originating from dendritic cells via interactions between toll-like receptors and globotriaosylceramide (Gb3) and/or globotriaosylsphingosine (lyso-Gb3). Evidence indicates that these glycolipids can activate toll-like receptors, thus triggering inflammation and fibrosis cascades. In the kidney, Gb3 deposition is associated with the increased release of transforming growth factor beta and with epithelial-to-mesenchymal cell transition, leading to the over-expression of pro-fibrotic molecules and to renal fibrosis. Interstitial fibrosis is also a typical feature of heart involvement in Fabry disease. Endomyocardial biopsies show infiltration of lymphocytes and macrophages, suggesting a role for inflammation in causing tissue damage. Inflammation is present in all tissues and may be associated with other potentially pathologic processes such as apoptosis, impaired autophagy, and increases in pro-oxidative molecules, which could all contribute synergistically to tissue damage. In Fabry disease, the activation of chronic inflammation over time leads to organ damage. Therefore, enzyme replacement therapy must be started early, before this process becomes irreversible.

Layer‐specific longitudinal strain in Anderson–Fabry disease at diagnosis: A speckle tracking echocardiography analysis

“…Further and probably more plausible cause of the more evident subepicardial longitudinal strain reduction could correspond to inflammatory processes that have been found to be associated with GLS reduction in early AFD stages . Endomyocardial biopsy has shown lymphocytes and macrophages infiltration, suggesting inflammation's role in myocardial damage .…”

“…[18][19][20][21] Further and probably more plausible cause of the more evident subepicardial longitudinal strain reduction could correspond to inflammatory processes that have been found to be associated with GLS reduction in early AFD stages. 32,33 Endomyocardial biopsy has shown lymphocytes and macrophages infiltration, suggesting inflammation's role in myocardial damage. 34 Glycosphingolipids myocardial accumulation could be considered a trigger of these phenomena, but we did not find any association between lysoGB3 levels, raw indicator of tissue substrate accumulation, 22 and layer-specific strain alteration in the present study.…”

“…In a case-control design, 33 Patients had the classic AFD as confirmed by α-Gal A activity testing and α-Gal A gene mutation analysis (sequencing of all exons and exon-intron boundaries of the α-Gal A gene, or specific α-Gal A gene mutation analysis in presence of a known family mutation) in accordance with the standardized criteria of our AFD Clinic. 13…”

Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease

“…For HF to develop, the concomitant action of a variety of pathogenic factors are needed, including the activation of the sympathetic nervous system, increased oxidative stress, inflammatory cytokines, and so on, all reported in patients with FD [28][29][30]. In particular, glomerular HF in Fabry patients may be mediated by angiotensin II, which increases to a different extent the vascular tone of both afferent and efferent glo- Data are expressed as mean ± SD or median (IQR) or n (%).…”

Elevated Ambulatory Blood Pressure Measurements Are Associated With a Progressive Form of Fabry Disease

“…Growing evidence indicates that the deposition of Gb3 in the endothelium activates oxidative enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases leading to the production of reactive oxygen species (ROS) 32 . Moreover, storage of glycosphingolipids in smooth muscle cells may promote cell proliferation with brotic remodelling of the arterial wall leading to arterial wall stiffness resulting in shear stress that may increase the expression of angiotensin 1 and 2 receptors in endothelial cells, increasing ROS, NF-kB, beta-integrin and cyclooxygenase 1 and 2 activity and decreasing nitric oxide synthesis 33 . These mechanisms may lead to oxidative stress and in ammatory damage which promotes endothelial and vascular dysfunction leading to the development of hypertension 34 .…”