Publications by authors named "Francesca A Ververs"

4 Publications

  • Page 1 of 1

Immunometabolic Activation of Invariant Natural Killer T Cells.

Front Immunol 2018 28;9:1192. Epub 2018 May 28.

Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.

Invariant natural killer T (iNKT) cells are lipid-reactive T cells with profound immunomodulatory potential. They are unique in their restriction to lipid antigens presented in CD1d molecules, which underlies their role in lipid-driven disorders such as obesity and atherosclerosis. In this review, we discuss the contribution of iNKT cell activation to immunometabolic disease, metabolic programming of lipid antigen presentation, and immunometabolic activation of iNKT cells. First, we outline the role of iNKT cells in immunometabolic disease. Second, we discuss the effects of cellular metabolism on lipid antigen processing and presentation to iNKT cells. The synthesis and processing of glycolipids and other potential endogenous lipid antigens depends on metabolic demand and may steer iNKT cells toward adopting a Th1 or Th2 signature. Third, external signals such as toll-like receptor ligands, adipokines, and cytokines modulate antigen presentation and subsequent iNKT cell responses. Finally, we will discuss the relevance of metabolic programming of iNKT cells in human disease, focusing on their role in disorders such as obesity and atherosclerosis. The critical response to metabolic changes places iNKT cells at the helm of immunometabolic disease.
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http://dx.doi.org/10.3389/fimmu.2018.01192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985373PMC
August 2019

Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype.

J Allergy Clin Immunol 2019 02 18;143(2):726-735. Epub 2018 Jun 18.

Pediatric Department A and the Immunology Service, "Edmond and Lily Safra" Children's Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer, Ramat-Gan and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Background: Mutations in recombination-activating gene (RAG) 1 and RAG2 are associated with a broad range of clinical and immunologic phenotypes in human subjects.

Objective: Using a flow cytometry-based assay, we aimed to measure the recombinase activity of naturally occurring RAG2 mutant proteins and to correlate our results with the severity of the clinical and immunologic phenotype.

Methods: Abelson virus-transformed Rag2 pro-B cells engineered to contain an inverted green fluorescent protein (GFP) cassette flanked by recombination signal sequences were transduced with retroviruses encoding either wild-type or 41 naturally occurring RAG2 variants. Bicistronic vectors were used to introduce compound heterozygous RAG2 variants. The percentage of GFP-expressing cells was evaluated by using flow cytometry, and high-throughput sequencing was used to analyze rearrangements at the endogenous immunoglobulin heavy chain (Igh) locus.

Results: The RAG2 variants showed a wide range of recombination activity. Mutations associated with severe combined immunodeficiency and Omenn syndrome had significantly lower activity than those detected in patients with less severe clinical presentations. Four variants (P253R, F386L, N474S, and M502V) previously thought to be pathogenic were found to have wild-type levels of activity. Use of bicistronic vectors permitted us to assess more carefully the effect of compound heterozygous mutations, with good correlation between GFP expression and the number and diversity of Igh rearrangements.

Conclusions: Our data support genotype-phenotype correlation in the setting of RAG2 deficiency. The assay described can be used to define the possible disease-causing role of novel RAG2 variants and might help predict the severity of the clinical phenotype.
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http://dx.doi.org/10.1016/j.jaci.2018.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295349PMC
February 2019

Characterization of T and B cell repertoire diversity in patients with RAG deficiency.

Sci Immunol 2016 12 16;1(6). Epub 2016 Dec 16.

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Recombination-activating genes 1 and 2 ( and ) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the and genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with mutations presenting with Omenn syndrome ( = 5), leaky SCID ( = 3), or CID-G/AI ( = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.
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http://dx.doi.org/10.1126/sciimmunol.aah6109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586490PMC
December 2016

Dendritic cells, T-cells and epithelial cells: a crucial interplay in immunopathology of primary Sjögren's syndrome.

Expert Rev Clin Immunol 2014 Apr 22;10(4):521-31. Epub 2014 Jan 22.

UMC Utrecht, Rheumatology & Clinical Immunology, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that is characterized by mononuclear cell infiltration of exocrine glands. T-cells have been shown to play a central role in tissue destruction and regulation of B-cell activity and the production of autoantibodies typifying pSS. Despite the fact that dendritic cells (DCs) are candidate key players in the activation of T- and B-cells in pSS, their contribution has been under evaluated. This manuscript reviews current insights in DC biology and examines literature on the role of DCs in the immunopathology of primary Sjögren's syndrome, focusing on the interplay between dendritic cells, epithelial cells and T-cells.
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http://dx.doi.org/10.1586/1744666X.2014.878650DOI Listing
April 2014