Leukocyte perturbation associated with Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disorder of glycosphingolipid catabolism due to the deficient activity of the enzyme alpha-galactosidase A. The non-degraded substrate, mainly globotriaosylceramide (Galα1-4Galβ1-4Glcβ1-1Cer; Gb(3)) accumulates progressively in the lysosome of various cells. The aim of this work was to analyse changes in leukocyte subpopulations and surface markers and to determine whether Gb(3) is increased in leukocytes of patients with untreated and treated Fabry disease. Blood samples obtained from 22 male Fabry patients (11 untreated and 11 on enzyme replacement therapy) and 22 normal controls were subjected to flow cytometric analysis of Gb(3) intracellular content, leukocyte subpopulations and cell markers. Based on the fluorescence intensity of bound monoclonal antibody, and relative to normal control leukocytes, Gb(3) appeared significantly increased in lymphocytes (but not in monocytes or granulocytes) from patients with Fabry disease. A significantly higher percentage of lymphocytes and CD19(+) cells and a reduced proportion of monocytes, CD8(+) cells and myeloid dendritic cells were detected in samples from Fabry patients compared with normal controls. CD1d expression was significantly lower and MHC class II surface expression was significantly higher in monocytes from Fabry patients than in normal controls. As previously observed for other adhesion molecules, the expression of CD31 (PECAM) was higher in leukocytes from Fabry patients. In conclusion, the differences recorded in this study reveal a leukocyte perturbation associated with the disease state in Fabry patients, whereas some abnormalities are less marked in treated patients.

Innate and Adaptive Immune Response in Fabry Disease

“…Of note, only 4 patients were treated among the 15 included, limiting the impact of ERT. Interestingly, Rozenfeld and Balreira showed a low level of CD1d that could correspond to an increase of internalization and an increase in the expression of MHC class II in monocytes from Fabry patients (Balreira et al 2008;Rozenfeld et al 2009). Therefore it seems that the GSL accumulation in FD induces disturbances in iNKT distribution and plays a proinflammatory role via CD1d pathway.…”

“…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).…”

Fabry Disease: Treatment and diagnosis

“…There are reports showing the coexistence of Fabry disease and autoimmune disorders (60,61). Abnormalities in the number of immune cell subsets in Fabry patients have been recently described (62). The gene NAIP (Neuronal apoptosis inhibitory protein) associated with inflammation was found to be upregulated in Fabry children (63).…”

From Lysosomal Storage Diseases to NKT Cell Activation and Back

“…In Table 3, studies on NKT in LSDs patients are listed. Earlier studies in Gaucher and Fabry disease patient, analyzed “iNKT-like” cells by the use of an antibody against Vα24 TCR α-chain, and no differences were observed between patients and controls [67,68,69]. Subsequent studies determined the frequency of iNKT cells in the peripheral blood of Fabry, Gaucher, and NPC disease patients, and no alterations in iNKT cell frequency were detected when compared with control subjects [13,70,71].…”

“…However, it was not capable of correcting the defect already existent at the beginning of the ERT [64]. When the number of iNKT cells was compared between patients receiving ERT and not receiving ERT, no significant alterations were found [69]. Similarly, a longitudinal analysis starting four months after the beginning of the ERT and along a total of 24 months (with a four month periodicity) revealed no significant alterations in the frequency of iNKT cells or iNKT CD4/CD8 subsets [71].…”