Glucosylsphingosine but not Saposin C, is the target antigen in Gaucher disease-associated gammopathy

Publication date: Available online 5 February 2020Source: Molecular Genetics and MetabolismAuthor(s): Shiny Nair, Noffar Bar, Mina L. Xu, Madhav Dhodapkar, Pramod K. MistryAbstractIn Gaucher disease type 1 (GD1), genetic deficiency of lysosomal glucocerebrosidase results in the accumulation of glucosylceramide and glucosylsphingosine (GlcSph), that underlie chronic lipid-mediated metabolic inflammation. An important age-related phenotype is high risk of monoclonal gammopathy (MG), including multiple myeloma. We identified GlcSph, a pathological lyso-sphingolipid exclusively elevated in GD, as a mediator of B cell activation and as an antigenic target for GD1-associated MG. Saposin C (SapC), is a lipid-binding protein and activator of lysosomal glucocerebrosidase, which when mutated, cause a rare variant of GD. Sera of GD1 patients with MG of diverse immunoglobulin types were compared to GD patients without gammopathy for reactivity against GlcSph and SapC. We show reactivity of clonal immunoglobulin in GD1 to GlcSph but not to SapC. In two patients with GD1 and gammopathy, GlcSph-reduction therapy with eliglustat resulted in reduction in clonal Ig. Together, our data show that GlcSph but not SapC is the antigenic target in GD1-associated MG and that therapy aimed at reducing the levels of immunogenic lipid resulted in reduction of clonal immunoglobulin in vivo.
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research

Related Links:

Publication date: February 2020Source: Molecular Genetics and Metabolism, Volume 129, Issue 2Author(s): Chanan Stauffer, Margo S. Breilyn, Manisha Balwani
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Publication date: October 2019Source: Clinical Lymphoma Myeloma and Leukemia, Volume 19, Issue 10, SupplementAuthor(s): Ioannis Ntanasis-Stathopoulos, Maria Gavriatopoulou, Despina Fotiou, Nikolaos Kanellias, Magdalini Migkou, Evangelos Eleutherakis-Papaiakovou, Efstathios Kastritis, Meletios A. Dimopoulos, Evangelos Terpos
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Publication date: Available online 9 October 2019Source: Hematology/Oncology and Stem Cell TherapyAuthor(s): Jorge Monge, Amy Chadburn, Usama GergisAbstractPseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders upon bone marrow aspirate and biopsy; however, Gaucher disease (GD) should be ruled out, particularly when the cytoplasmic inclusions cannot be adequately characterized. It is well known that GD may be associated with monoclonal gammopathies; however, although enzyme replacement therapy (ERT) may result in an improvement in polyclonal ga...
Source: Hematology Oncology and Stem Cell Therapy - Category: Cancer & Oncology Source Type: research
Gaucher disease (GD) constitutes the most frequent lysosomal storage disease and is attributed to an inherited deficiency of glucocerebrosidase with an autosomal recessive pattern. Although controversial, published data have demonstrated an increased incidence of monoclonal gammopathies, especially multiple myeloma (MM) in these patients. Under this prism, we decided to perform a screening test for GD in a large number of patients with plasma cell dyscrasias (PCDs).
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
Gaucher disease is a clinically heterogeneous disorder of glucocerebroside metabolism and may present incidentally late in life with unexplained thrombocytopenia, splenomegaly, or bony lesions. Clinicians should be aware that patients with Gaucher disease appear to have an increased risk for developing hematolymphoid malignancies, particularly monoclonal gammopathies and plasma cell myeloma. AbstractGaucher disease is a clinically heterogeneous disorder of glucocerebroside metabolism and may present incidentally late in life with unexplained thrombocytopenia, splenomegaly, or bony lesions. Clinicians should be aware that p...
Source: Clinical Case Reports - Category: General Medicine Authors: Tags: CASE REPORT Source Type: research
Authors: Nguyen Y, Stirnemann J, Belmatoug N Abstract Gaucher disease is a rare autosomal recessive genetic disease, caused by a deficiency of the lysosomal enzyme, glucocerebrosidase that leads to the accumulation of its substrate (glucosylceramide) in lysosomal macrophages. In the general population, its incidence varies between 0.4 and 5.8/100,000 inhabitants. Type 1 Gaucher disease is the most frequent and is characterized by its extreme heterogeneity including asymptomatic or more severe presentations. The most frequent symptoms are anemia, thrombocytopenia, splenomegaly, and/or hepatomegaly, and a potentially...
Source: Revue de Medecine Interne - Category: Internal Medicine Tags: Rev Med Interne Source Type: research
Source: Blood - Category: Hematology Authors: Tags: Multiple Myeloma, Free Research Articles, BloodWork, Red Cells, Iron, and Erythropoiesis, Lymphoid Neoplasia BLOOD WORK Source Type: research
In this study, we hypothesized that the changes in lipid profiles in MM patients contribute to disease progression.PPAR is the key transcription factor that potentiates adipocyte differentiation and its key functions including lipid synthesis and transportation. We found that the BM adipose tissue (BMAT) fraction from MGUS, and SMM patients showed significantly increased PPAR expression compared to the healthy donors. In vitro, MGUS and SMM BM stromal cells (BMSCs) showed increased adipogenic differentiation potential compared to the healthy donors. In-vitro, the proliferation of MM.1S human MM cells was significantly incr...
Source: Blood - Category: Hematology Authors: Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research
Multiple myeloma (MM) is an incurable cancer of plasma cells (PC), with a median survival of 5-7 years. Osteolytic bone disease and skeletal complications occur in more than 80% of MM patients and significantly contribute to the morbidity and mortality of these patients. Glycosphingolipid (GSL), an essential constituent of the outer leaflet of the cellular membrane, is altered in MM and other hematological cancers. We previously reported that GM3, a subtype of GSL promotes osteoclastogenesis. On the other hand, the GSL synthase inhibitor N-butyl-deoxynojirimycin (NB-DNJ) reduces myeloma bone disease in the 5TGM1 mouse mode...
Source: Blood - Category: Hematology Authors: Tags: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Poster I Source Type: research
SummaryPatients with Gaucher disease (GD) have an increased risk of monoclonal gammopathies for which antigenic targets might play a role in their pathogenesis. Here we report the identification of saposin C (sapC) as high ‐titre (1:1 000 000) target structure of 7/16 GD‐associated paraproteins. Anti‐sapC immunoglobulin (Ig) showed identity with the paraprotein Ig type and subclass in each patient that showed anti‐sapC immunoreactivity. Absorption and depletion studies completely removed the paraprotein from the sera of GD patients. No immunoreactivity against sapC was detected in healthy donors and in ot...
Source: British Journal of Haematology - Category: Hematology Authors: Tags: Research Paper Source Type: research
More News: Gaucher's Disease | Genetics | Myeloma