Fabry disease peripheral blood immune cells release inflammatory cytokines: Role of globotriaosylceramide

Francesco, Pablo N. De; Mucci, Juan Marcos; Ceci, Romina; Fossati, Carlos A.; Rozenfeld, Paula

doi:10.1016/j.ymgme.2013.02.003

Cited by 115 publications

(128 citation statements)

References 27 publications

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“…Therefore it seems that the GSL accumulation in FD induces disturbances in iNKT distribution and plays a proinflammatory role via CD1d pathway. The proinflammatory pattern in FD is well described with an increase of inflammatory cytokines (De Francesco et al 2013). Urinary Gb3 levels were found to be highly correlated with increased IL-6 plasma levels (r ¼ 0.971, p < 0.01) in 14 FD patients (Biancini et al 2012).…”

Section: Introductionmentioning

confidence: 84%

“…One mechanism suspected in the incomplete long-term response to ERT is the development of immune responses against agalsidase. Actually, immune reactions are described in both treatment-naive and agalsidase-treated FD patients (Rozenfeld et al 2009;De Francesco et al 2013). Antibodies against agalsidase are notably well described, but their role remains unclear (Linthorst et al 2004;Bénichou et al 2009;Wilcox et al 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Accumulated gangliosides in GM1 and GM2 gangliosidosis were reported to act as an endogenous ligand for TLR4 (Jou et al 2006). Hence, Gb3 is questioned to act as an endogenous ligand to TLR4 (De Francesco et al 2013). In fact, the Gb3 accumulation appears to be the starting point of an innate immunity reaction, involving CD1d and TLR4 pathways which would induce a dysregulation of one of the iNKT subsets and DCs, source of a pathological proinflammatory state with secretion of specific proinflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

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Innate and Adaptive Immune Response in Fabry Disease

et al. 2015

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Fabry disease is an X-linked lysosomal storage disease in which mutations of the gene (GLA) cause a deficiency of the lysosomal hydrolase α-galactosidase A (α-Gal). This defect results in an accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3) which causes a multisystemic vasculopathy. Available since 2001 in Europe, enzyme replacement therapy consists in the administration of agalsidase, a recombinant form of α-galactosidase A. Enzyme replacement therapy was shown to improve the global prognosis but allowed partial success in preventing critical events such as strokes and cardiac arrests. As in most lysosomal storage diseases, frequent immune reactions have been described in naive Fabry disease patients. Humoral immune responses following enzyme replacement therapy have also been described, with unclear consequences on the progression of the disease. While cost-effectiveness of enzyme replacement therapy in Fabry disease begins to be questioned and new therapeutic strategies arise such as chaperone or gene therapy, it appears necessary to better understand the immune responses observed in the treatment of naive patients and during enzyme replacement therapy with agalsidase. We propose a comprehensive review of the available literature concerning both innate and adaptive responses observed in Fabry disease. We particularly highlight the probable role of the toll-like receptor 4 (TLR4) and CD1d pathways triggered by Gb3 accumulation in the development of local and systemic inflammation that could lead to irreversible organ damages. We propose an immunological point of view of Fabry disease pathogenesis involving immune cells notably the invariant natural killer T cells. We finally review anti-agalsidase antibodies, their development and impact on outcomes.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Innate and Adaptive Immune Response in Fabry Disease

et al. 2015

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“…Finally, inflammation is believed to affect other organs with FD, including kidney,26 vessels,27 and brain 28. Control of systemic inflammation in FD may result in the improvement of patient prognosis and quality of life.…”

Section: Discussionmentioning

confidence: 99%

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Frustaci

Verardo

Grande

et al. 2018

JAHA

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BackgroundGlycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy (FDCM).Methods and ResultsMyocarditis, defined as CD3+ T lymphocytes >7/mm2 associated with necrosis of glycolipid‐laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with FDCM: 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with FDCM (38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes. CD3+ cells/mm2 correlated with myocyte necrosis, antimyosin autoantibody titer, and MWT (P<0.001,r=0.79; P<0.001, r=0.84; P<0.001, r=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4.ConclusionsMyocarditis is detectable at histology in up to 56% of patients with FDCM. It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of FDCM and resistance to enzyme replacement therapy.

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“…Indeed, there is some evidence to suggest that increased levels of urinary and plasma Gb 3 are not correlated with clinical Fabry symptoms (Vedder et al 2007). Perhaps there are other contributing pathogenic factors, such as degree of the inflammatory reaction (Biancini et al 2012;De Francesco et al 2013), the vulnerability of cardiomyocytes (modified by some cardiomyopathic genes or other unknown genes) (Desnick and Doheny 2014), or cell non-autonomous phenomena.…”

Section: Discussionmentioning

confidence: 99%

Age at First Cardiac Symptoms in Fabry Disease: Association with a Chinese Hotspot Fabry Mutation (IVS4+919G>A), Classical Fabry Mutations, and Sex in a Taiwanese Population from the Fabry Outcome Survey (FOS)

Liu

Perrin²,

Hsu

et al. 2015

JIMD Reports

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This is a descriptive analysis of a cohort of 59 Taiwanese patients with Fabry disease and either classical Fabry or cardiac variant IVS4+919G>A (IVS4) mutations from a disease registry, the Fabry Outcome Survey (FOS; sponsored by Shire). Most of our classical Fabry patients were symptomatic and were identified upon seeking medical advice at our clinics, whereas most of our IVS4 patients attended our clinics after newborn screening identified this mutation in their grandsons. The objective was to determine differences in cardiac manifestations between patients with classical Fabry or IVS4 mutations by comparing age at onset of selected cardiac symptoms.

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Fabry disease peripheral blood immune cells release inflammatory cytokines: Role of globotriaosylceramide

Cited by 115 publications

References 27 publications

Innate and Adaptive Immune Response in Fabry Disease

Innate and Adaptive Immune Response in Fabry Disease

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

Age at First Cardiac Symptoms in Fabry Disease: Association with a Chinese Hotspot Fabry Mutation (IVS4+919G>A), Classical Fabry Mutations, and Sex in a Taiwanese Population from the Fabry Outcome Survey (FOS)

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