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Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype.

May 1, 2019 By Manish Butte

Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype.

Proc Natl Acad Sci U S A. 2019 Apr 29;:

Authors: Blommaert E, Péanne R, Cherepanova NA, Rymen D, Staels F, Jaeken J, Race V, Keldermans L, Souche E, Corveleyn A, Sparkes R, Bhattacharya K, Devalck C, Schrijvers R, Foulquier F, Gilmore R, Matthijs G

Abstract
Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. We identified two patients with defective serum transferrin glycosylation and mutations in the MAGT1 gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability. MAGT1 has been described to be a subunit of the oligosaccharyltransferase (OST) complex and more specifically of the STT3B complex. However, it was also claimed that MAGT1 is a magnesium (Mg2+) transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg2+ homeostasis defect (XMEN). We compared the clinical and cellular phenotype of our two patients to that of an XMEN patient that we recently identified. All three patients have an N-glycosylation defect, as was shown by the study of different substrates, such as GLUT1 and SHBG, demonstrating that the posttranslational glycosylation carried out by the STT3B complex is dysfunctional in all three patients. Moreover, MAGT1 deficiency is associated with an enhanced expression of TUSC3, the homolog protein of MAGT1, pointing toward a compensatory mechanism. Hence, we delineate MAGT1-CDG as a disorder associated with two different clinical phenotypes caused by defects in glycosylation.

PMID: 31036665 [PubMed – as supplied by publisher]

A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells.

May 1, 2019 By Manish Butte

A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells.

Mol Immunol. 2019 01;105:173-180

Authors: Lai N, Min Q, Xiong E, Liu J, Zhang L, Yasuda S, Wang JY

Abstract
CD40 ligand (CD40 L) expressed by activated T cells interacts with CD40 on B cells and triggers B cell survival, proliferation and differentiation. Deficiency in CD40 L or CD40 in humans causes hyper IgM syndrome due to a defect in T-B interaction that is essential for Ig gene class switch recombination (CSR). CD40 L belongs to the tumor necrosis factor family and normally forms a homotrimer on the cell surface, which is important for its biological activity. To generate a multimeric CD40 L that can be used to stimulate both mouse and human B cells, we fused the extracellular domain of mouse CD40 L, which is known to also bind human CD40, with streptavidin (SA) that forms a stable tetramer under physiological conditions. As expected, 293 T cells transiently transfected with an SA-CD40 L expression vector secreted tetrameric SA-CD40 L in the culture supernatant. The secreted SA-CD40 L exhibited > 25-fold stronger activities in inducing the survival, activation and proliferation of both mouse and human primary B cells than did an agonistic anti-mouse or anti-human CD40 antibody. In the presence of IL-4, SA-CD40 L also induced efficient CSR and plasma cell differentiation in both mouse and human B cells. Moreover, administration of SA-CD40 L in mice induced activation and proliferation of spleen B cells in vivo. These results demonstrate that the SA-CD40 L fusion protein generated in the present study recapitulates the function of membrane-bound trimeric CD40 L and has potent biological activities in both mouse and human primary B cells.

PMID: 30529036 [PubMed – indexed for MEDLINE]

A Rare Case of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Presenting With Hemophagocytosis Complicated With Hodgkin Lymphoma.

April 30, 2019 By Manish Butte

A Rare Case of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Presenting With Hemophagocytosis Complicated With Hodgkin Lymphoma.

J Pediatr Hematol Oncol. 2019 Apr 24;:

Authors: Cansever M, Zietara N, Chiang SCC, Ozcan A, Yilmaz E, Karakukcu M, Rohlfs M, Somekh I, Canoz O, Abdulrezzak U, Bryceson Y, Klein C, Unal E, Patiroglu T

Abstract
Gain of function mutations in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) classified as activated phosphoinositide 3-kinase delta syndrome (APDS) are the cause of a primary immunodeficiency characterized by recurrent sinopulmonary infections, and lymphoproliferation. Previously, autoimmunity and Epstein-Barr virus-related B-cell lymphoma have been documented for patients with APDS; here, we present a case that extends the picture, as the patient shows the full diagnostic criteria of hemophagocytic lymphohistiocytosis at 6 months of age. He experienced Hodgkin lymphoma as a 2.5-year-old baby. Next-generation sequencing returned a de novo heterozygous missense variant in PIK3CD (LRG_191t1: c.3061G>A; p.Glu1021Lys), confirming the primary immunodeficiency. After 2 courses of ifosfamide, cisplatin, and etoposide combined with brentuximab, the patient successfully underwent allogeneic hematopoietic stem cell transplantation from his HLA full matched sister, and he has been well for 18 months after that. The hematologist treating Hodgkin lymphoma and/or hemophagocytic lymphohistiocytosis should be vigilant about the possible underlying immune deficiency, and they should consider APDS in their differential diagnosis.

PMID: 31033788 [PubMed – as supplied by publisher]

Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome.

April 30, 2019 By Manish Butte

Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome.

Front Immunol. 2019;10:753

Authors: Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ

Abstract
Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4+ T cells to a T follicular helper (TFH) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote TFH differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that TFH should be monitored in APDS patients.

PMID: 31031754 [PubMed – in process]

ZBTB24 regulates the apoptosis of human T cells via CDCA7/TRAIL-receptor axis.

April 30, 2019 By Manish Butte

ZBTB24 regulates the apoptosis of human T cells via CDCA7/TRAIL-receptor axis.

Biochem Biophys Res Commun. 2019 Apr 25;:

Authors: Qin XY, Feng J, Chen G, Dou XW, Dai XQ, Dong HL, Gong FY, Xiao F, Zhao Y, Gao XM, Wang J

Abstract
Mutations in ZBTB24 and CDCA7 cause the Immunodeficiency, Centromeric Instability and Facial Anomalies syndrome type 2 and 3 (ICF2/3), respectively. Most ICF2 patients carry ZBTB24 nonsense mutations and are thus ZBTB24-deficient. Although the immune deficiency in ICF2 patients is primarily regarded as a B-cell defect due to the greatly reduced serum antibodies and circulating memory B cells, the reduced expansions of PBMCs stimulated by mitogens or recall antigens suggest a T-cell defect in these patients as well. However, the molecular mechanisms behind this T-cell dysfunction remain unknown. In the present study, we demonstrated that ZBTB24-deficiency significantly represses the proliferation of human T cells by promoting TRAIL-induced cell death. Downregulation of ZBTB24 in both Jurkat and human primary T cells upregulates the expression of TRAIL and/or its death receptors (TRAIL-R1/2), and induces significant amount of cells to undergo apoptosis. The profound survival defects of ZBTB24-deficient cells are largely reversed by blocking TRAIL/TRAIL-R interactions with exogenous recombinant TRAIL-R2. Moreover, ZBTB24-downregulation reduces the expression of CDCA7, and knockdown of the latter in human T cells results in a phenotype resembling that caused by ZBTB24-depletion. Functionally, overexpression of CDCA7 abrogates the increased apoptosis in ZBTB24-depleted Jurkat T cells. Together, these data indicated that ZBTB24 regulates human T-cell apoptosis via CDCA7/TRAIL-R axis. Our study thus not only provides a molecular explanation for the T-cell defects in ZBTB24-deficient ICF2 patients, but also highlights a convergence between ZBTB24 and CDCA7, the two ICF genes, in modulating the functions of T cells.

PMID: 31030944 [PubMed – as supplied by publisher]

Surgical treatment of monogenic inflammatory bowel disease: A single clinical center experience.

April 28, 2019 By Manish Butte

Surgical treatment of monogenic inflammatory bowel disease: A single clinical center experience.

J Pediatr Surg. 2019 Apr 13;:

Authors: Sun S, Ye Z, Zheng S, Chen G, Qian X, Dong K, Huang Y

Abstract
PURPOSE: With the wide application of immunologic reconstitution treatment, such as hematopoietic stem-cell transplantation (HSCT), most patients of inflammatory bowel disease (IBD) with immunodeficiency owing to monogenic abnormalities need surgical intervention during the course of treatment, which is quite different from traditional IBD surgery. The aim of this study was to generalize the surgical strategies as a part of comprehensive therapy for these rare diseases.
METHODS: A retrospective study was conducted based on the clinical data of children with immunodeficiency-derived IBD who underwent surgical treatment in Children’s Hospital of Fudan University between January 2015 and December 2017.
RESULTS: A total of 18 patients with monogenic abnormalities were enrolled. The major surgical indications included 11 cases of acute or chronic intestinal obstructions, 4 refractory intestinal infections, and 3 pneumoperitoneum, while 12 cases had perforations noted during intraoperative exploration. All of the patients underwent varieties of enterostomies to divert the affected or obstructed intestine during the primary surgery. Wound infections or dehiscence occurred in 7 patients, and 2 patients underwent reoperations for adhesive intestinal obstruction and prolapse. Postoperatively, 15 patients survived, 13 of which achieved immune reconstitution through subsequent HSCT or immunoglobulin supplementation. In the second-stage surgery, a posterior sagittal approach rectal resection was performed in 5 patients with complex anorectal complications. Twelve patients had undergone stoma closure procedures.
CONCLUSION: Surgical intervention should be performed earlier because the perforations are usually insidious in monogenic IBD. Preventative enterostomies are suggested in preparation for HSCT among patients with severe anorectal complications. Wound infections are the most common complication after the primary operation. Posterior sagittal rectal resection is a good option for patients with complex anorectal complications.
TYPE OF STUDY: Clinical research paper.
LEVEL OF EVIDENCE: Level IV.

PMID: 31027905 [PubMed – as supplied by publisher]

Immunodeficiencies that predispose to pathologies by human oncogenic γ-herpesviruses.

April 27, 2019 By Manish Butte

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Immunodeficiencies that predispose to pathologies by human oncogenic γ-herpesviruses.

FEMS Microbiol Rev. 2019 03 01;43(2):181-192

Authors: Damania B, Münz C

Abstract
Human γ-herpesviruses include the closely related tumor viruses Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). EBV is the most growth-transforming pathogen known and is linked to at least seven human malignancies. KSHV is also associated with three human cancers. Most EBV- and KSHV-infected individuals fortunately remain disease-free despite persistent infection and this is likely due to the robustness of the immune control that they mount against these tumor viruses. However, upon immune suppression EBV- and KSHV-associated malignancies emerge at increased frequencies. Moreover, primary immunodeficiencies with individual mutations that predispose to EBV or KSHV disease allow us to gain insights into a catalog of molecules that are required for the immune control of these tumor viruses. Curiously, there is little overlap between the mutation targets that predispose individuals to EBV versus KSHV disease, even so both viruses can infect the same host cell, human B cells. These differences will be discussed in this review. A better understanding of the crucial components in the near-perfect life-long immune control of EBV and KSHV should allow us to target malignancies that are associated with these viruses, but also induce similar immune responses against other tumors.

PMID: 30649299 [PubMed – indexed for MEDLINE]

Viral infection in primary antibody deficiency syndromes.

April 25, 2019 By Manish Butte

Viral infection in primary antibody deficiency syndromes.

Rev Med Virol. 2019 Apr 24;:e2049

Authors: Jones TPW, Buckland M, Breuer J, Lowe DM

Abstract
Patients with primary antibody deficiency syndromes such as X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID) are at increased risk of severe and invasive infection. Viral infection in these populations has been of increasing interest as evidence mounts that viruses contribute significant morbidity and mortality: this is mediated both directly and via aberrant immune responses. We explain the importance of the humoral immune system in defence against viral pathogens before highlighting several significant viral syndromes in patients with antibody deficiency. We explore historical cases of hepatitis C via contaminated immunoglobulin products, the predisposition to invasive enteroviral infections, prolonged excretion of vaccine-derived poliovirus, the morbidity of chronic norovirus infection, and recent literature revealing the importance of respiratory viral infections. We discuss evidence that herpesviruses may play a role in driving the inflammatory disease seen in a subset of patients. We explore the phenomenon of within-host evolution during chronic viral infection and the potential emergence of new pathogenic strains. We highlight novel and emerging viruses identified via deep sequencing techniques. We describe the treatment strategies that have been attempted in all these scenarios and the urgent outstanding questions for research.

PMID: 31016825 [PubMed – as supplied by publisher]

Clinical and immunological features in a cohort of patients with partial DiGeorge syndrome followed at a single centre.

April 25, 2019 By Manish Butte

Clinical and immunological features in a cohort of patients with partial DiGeorge syndrome followed at a single centre.

Blood. 2019 Apr 23;:

Authors: Giardino G, Radwan N, Koletsi P, Morrogh DM, Adams S, Ip W, Worth A, Jones A, Meyer-Parsonson I, Gaspar HB, Gilmour K, Davies EG, Ladomenou F

Abstract
DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity and allergy. The aim of this study was to assess the impact of different factors in the development of infections, autoimmunity and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low IgM levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+ and naïve CD4+CD45RA+CD27+ T-lymphocytes as compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients as compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T-cells, as suggested by an accelerated decline of the naïve T-lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.

PMID: 31015189 [PubMed – as supplied by publisher]

CCL5 and related genes might be the potential diagnostic biomarkers for the therapeutic strategies of rheumatoid arthritis.

April 24, 2019 By Manish Butte

CCL5 and related genes might be the potential diagnostic biomarkers for the therapeutic strategies of rheumatoid arthritis.

Clin Rheumatol. 2019 Apr 22;:

Authors: Huang Y, Zheng S, Wang R, Tang C, Zhu J, Li J

Abstract
OBJECTIVE: Rheumatoid arthritis (RA) is a common disease of rheumatic diseases. The aim of this study was to identify gene signatures in RA and uncover their potential mechanisms.
METHOD: Gene expression profiles of GSE1919, GSE55235, GSE55457, and GSE77928 were downloaded from GEO database. The above four series contained 76 samples, including 44 RA patients and 32 normal controls. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed by Cytoscape software.
RESULTS: Up-regulated DEGs were significantly enriched in biological processes, including immune response, positive regulation of immune system process and regulation of immune system process, while down-regulated DEGs were significantly enriched in biological processes, including response to oxygen-containing compound, cellular lipid metabolic process, and lipid metabolic process. KEGG pathway analysis showed the up-regulated DEGs were enriched in cytokine-cytokine receptor interaction, chemokine signaling pathway, and primary immunodeficiency. The 104 hub genes, which were significantly differently expressed between patients and normal controls in at least two datasets, were identified from the PPI network, and subnetworks revealed that these genes were involved in significant pathways, including cytokine-cytokine receptor interaction, chemokine signaling pathway, and primary immunodeficiency.
CONCLUSION: The present study indicated that the identified DEGs and hub genes promote our understanding of molecular mechanisms underlying the development of RA, such as C-C motif chemokine 5 (CCL5), might have a negative impact in the development of RA. CCL5 and its related genes might be the potential diagnostic biomarkers for the therapeutic strategies of RA.

PMID: 31011897 [PubMed – as supplied by publisher]