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Peripheral blood immunophenotyping in a large cohort of patients with Shwachman-Diamond syndrome.

ABSTRACT: Shwachman-Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes, characterized by neutropenia, occasional thrombocytopenia, and anemia. Bone marrow evaluation reveals an increased number of monocytes and mature B cells along with decreased granulocytes. However, little is known about the subpopulations of peripheral blood cells, and few previous publications have been based on a small number of patients. Here, we report a comprehensive immunophenotypic analysis from a cohort of 37 SDS patients who display impairment mostly in the myeloid compartment with a deficiency also in the number of B cells and CD4/CD8 double-negative T cells.

SUBMITTER: Bezzerri V

PROVIDER: S-EPMC8354004 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Peripheral blood immunophenotyping in a large cohort of patients with Shwachman-Diamond syndrome.

Bezzerri Valentino V Vella Antonio A Gennaro Gianfranco Di GD Ortolani Riccardo R Nicolis Elena E Cesaro Simone S Fabrizzi Benedetta B Bronte Vincenzo V Corey Seth J SJ Cipolli Marco M

Pediatric blood & cancer 20190102 5

Shwachman-Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes, characterized by neutropenia, occasional thrombocytopenia, and anemia. Bone marrow evaluation reveals an increased number of monocytes and mature B cells along with decreased granulocytes. However, little is known about the subpopulations of peripheral blood cells, and few previous publications have been based on a small number of patients. Here, we report a comprehensive immunophenotypic analysis ...[more]

PMID: 30604473

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Project description:Background and purposeShwachman-Diamond Syndrome (SDS) is an autosomal recessive disease belonging to the inherited bone marrow failure syndromes and characterized by hypocellular bone marrow, exocrine pancreatic insufficiency, and skeletal abnormalities. SDS is associated with increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). Although SDS is not primarily considered an inflammatory disorder, some of the associated conditions (e.g., neutropenia, pancreatitis and bone marrow dysfunction) may involve inflammation or immune system dysfunctions. We have already demonstrated that signal transducer and activator of transcription (STAT)-3 and mammalian target of rapamycin (mTOR) were hyperactivated and associated with elevated IL-6 levels in SDS leukocytes. In this study, we analyzed the level of phosphoproteins involved in STAT3 and mTOR pathways in SDS lymphoblastoid cells (LCLs) and the secretomic profile of soluble pro-inflammatory mediators in SDS plasma and LCLs in order to investigate the systemic inflammation in these patients and relative pathways.MethodsTwenty-six SDS patients and seven healthy donors of comparable age were recruited during the programmed follow-up visits for clinical evaluation at the Verona Cystic Fibrosis Center Human. The obtained samples (plasma and/or LCLs) were analyzed for: phosphoproteins, cytokines, chemokines and growth factors levels by Bio-plex technology; microRNAs profiling by next generation sequencing (NGS) and microRNAs expression validation by Real Time-PCR (RT-PCR) and droplet digital PCR (ddPCR) .ResultsWe demonstrated dysregulation of ERK1/2 and AKT phosphoproteins in SDS, as their involvement in the hyperactivation of the STAT3 and mTOR pathways confirmed the interplay of these pathways in SDS pathophysiology. However, both these signaling pathways are strongly influenced by the inflammatory environment. Here, we reported that SDS is characterized by elevated plasma levels of several soluble proinflammatory mediators. In vitro experiments show that these pro-inflammatory genes are closely correlated with STAT3/mTOR pathway activation. In addition, we found that miR-181a-3p is down-regulated in SDS. Since this miRNA acts as a regulator of several pro-inflammatory pathways such as STAT3 and ERK1/2, its down-regulation may be a driver of the constitutive inflammation observed in SDS patients.ConclusionsThe results obtained in this study shed light on the complex pathogenetic mechanism underlying bone marrow failure and leukemogenesis in SDS, suggesting the need for anti-inflammatory therapies for SDS patients.

Project description:Shwachman-Diamond syndrome is an autosomal recessive disorder in which severe bone marrow dysfunction causes neutropenia and an increased risk of leukemia. Recently, novel particulate cytoplasmic structures, rich in ubiquitinated and proteasomal proteins, have been detected in epithelial cells and neutrophils from patients with Helicobacter pylori gastritis and several epithelial neoplasms.Blood neutrophils from 13 cases of Shwachman-Diamond syndrome - ten with and three without SBDS gene mutation - and ten controls were investigated by confocal microscopy and ultrastructural immunocytochemistry using antibodies against ubiquitinated proteins, proteasomes, p62 protein, and Helicobacter pylori VacA, urease and outer membrane proteins.Many extensively disseminated particulate cytoplasmic structures, accounting for 22.78 ± 5.57% (mean ± standard deviation) of the total cytoplasm, were found in blood neutrophils from mutated Shwachman-Diamond syndrome patients. The particulate cytoplasmic structures showed immunoreactivity for polyubiquitinated proteins and proteasomes, but no reactivity for Helicobacter pylori products, which are present in particulate cytoplasmic structures of Helicobacter pylori-positive gastritis. Neutrophils from patients with Shwachman-Diamond syndrome frequently showed p62-positive autophagic vacuoles and apoptotic changes in 5% of cells. No particulate cytoplasmic structures were observed in most control neutrophils; however, in a few cells from two cases we noted focal development of minute particulate cytoplasmic structures, accounting for 0.74 ± 0.56% of the total cytoplasm (P<0.001 versus particulate cytoplasmic structures from mutated Shwachman-Diamond syndrome patients). Neutrophils from non-mutated Shwachman-Diamond-syndrome-like patients resembled controls in two cases, and a third case showed particulate cytoplasmic structure patterns intermediate between those in controls and those in mutated Shwachman-Diamond syndrome patients.Particulate cytoplasmic structures are a prominent feature of neutrophils from patients with Shwachman-Diamond syndrome. They may help us to understand the mechanism of granulocyte dysfunction and the neoplastic risk of the disease.

Project description:ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominant manifestations include exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive and susceptibility to short stature. Average birth weight is at the 25th percentile; by the first birthday, >50% of patients drop below the third percentile for height and weight.The study aims at estimating the growth charts for patients affected by SDS in order to give a reference tool helpful for medical care and growth surveillance through the first 8 years of patient's life.Setting and participantsThis retrospective observational study includes 106 patients (64 M) with available information from birth to 8 years, selected among the 122 patients included in the Italian National Registry of SDS and born between 1975 and 2016. Gender, birth date and auxological parameters at repeated assessment times were collected. The General Additive Model for Location Scale and Shape method was applied to build the growth charts. A set of different distributions was used, and the more appropriate were selected in accordance with the smallest Akaike information criterion.ResultsA total of 408 measurements was collected and analysed. The median number of observations per patient amounted to 3, range 1-11. In accordance with the methods described, specific SDS growth charts were built for weight, height and body mass index (BMI), separately for boys and girls.The 50th and 3rd percentiles of weight and height of the healthy population (WHO standard references) respectively correspond to the 97th and 50th percentiles of the SDS population (SDS specific growth charts), while the difference is less evident for the BMI.ConclusionsSpecific SDS growth charts obtained through our analysis enable a more appropriate classification of patients based on auxological parameters, representing a useful reference tool for evaluating their growth during childhood.

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Peripheral blood immunophenotyping in a large cohort of patients with Shwachman-Diamond syndrome.

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Peripheral blood immunophenotyping in a large cohort of patients with Shwachman-Diamond syndrome.

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