Innate and Adaptive Immune Response in Fabry Disease

Abstract

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.

The mutation p.D313Y is associated with organ manifestation in Fabry disease

“…This in turn results in the activation of inflammatory signalling pathways. A similar mechanism has been proposed in FD . It has been suggested that antigen‐presenting cells take up circulating Gb3 via the toll‐like receptor 4.…”

“…A similar mechanism has been proposed in FD. 12 It has been suggested that antigenpresenting cells take up circulating Gb3 via the toll-like receptor 4. This is presented to invariant natural killer T-cells leading to an activation of mononuclear cells and the release of proinflammatory cytokines.…”

The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders

“…This is complicated further by the cytokine microenvironment for example TGF-β alone induces ITregs production (Fantin et al 2004) but if Il6 is co-expressed then a pro inflammatory TH17 response occurs (Tran et al 2007). While it is beyond the scope of this review, given the proinflammatory nature of many LSDs (Eliyahu et al 2011;Schuchman et al 2013;Pandeyetal2012;de Francesco et al 2013), the inherent activation of Toll like receptors seen in some MPSs (Eliyahu et al 2011) and Fabry (Mauhin et al 2015) and the proinflammatory cytokine response generated by ERTs (Banati et al 2011) it seems likely that the Bsecond signal^needed for antibody production may often be inherently already present (Archer et al 2013).…”

Neurological Manifestations of Fabry Disease in Children and Adolescents

“…Нарушение функций эндотелия и стенок сосудов вызывает обструктивные процессы, аналогичные атеросклеротическому [67]. Запускается процесс поражения иммунной системы с воспалительными явлениями, вызывающими повре-ждение органов [52].…”