A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects

Bogaert, Debby; Bonroy, Carolien; Calvo, Katherine R.; Dehoorne, Joke; Vanlander, Arnaud; Bruyne, Marieke De; Cytlak, Urszula; Baets, Frans De; Baere, Elfride De; Rosenzweig, Sergio D.; Haerynck, Filomeen; Dullaers, Mélissa

doi:10.1016/j.jaci.2017.08.019

Cited by 41 publications

(40 citation statements)

References 17 publications

(52 reference statements)

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“…The near universal finding of this antigen presenting cell phenotype, independent of age, lymphocyte phenotype or clinical status, provides a cellular signature of human IKZF1 mutation. The quantitative changes were remarkably similar in all individuals with missense proteins (families B and C), or truncated protein (family G 27 ), but less severe in members of family F who carry a heterozygous, 11-gene deletion of chromosome 7. In homodimeric proteins, it has been proposed that a heterozygous missense mutation may result in a more severe phenotype than a null allele due to the lower proportion of WT/WT dimers (25% versus 50%, respectively) 32 .…”

Section: Discussionmentioning

confidence: 89%

“…Families B, C and F were studied by Kuehn et al 25 . Members of family G have been recently described 27 . Replicate B-cell counts performed on blood taken for this study were congruent with the analyses previously reported.…”

Section: Resultsmentioning

confidence: 99%

“…Normal IKZF1 protein levels are also necessary for the development of IFN-α-producing pDC in mice 22 , 23 . Recent descriptions of human IKZF1 haploinsufficiency have confirmed its role in human lymphocyte biology but human DC development has not been studied 25 – 27 . In this study we analysed blood monocytes and DCs from patients ex vivo carrying heterozygous IKZF1 mutations, or treated with lenalidomide, an IKZF1-depleting immunomodulatory drug.…”

Section: Discussionmentioning

confidence: 99%

“…Human germline heterozygous IKZF1 mutations, resulting in haploinsufficiency, cause a variably penetrant combined immunodeficiency associated with progressive attrition of B cells, hypogammaglobulinaemia and skewing of T-cell subsets 25 – 27 . Clinical manifestations include recurrent or severe respiratory tract infections, autoimmune phenomena and a predisposition to childhood B-cell acute lymphoblastic leukaemia.…”

Section: Introductionmentioning

confidence: 99%

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Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

et al. 2018

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Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

et al. 2018

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“…At present, GATA2 deficiency is increasingly thought of as a bone marrow failure state akin to aplastic anaemia based on a progressive depletion of the HSC pool (McReynolds et al, 2018 (Spinner et al, 2014). Comparable to other primary immunodeficiencies caused by haploinsufficient genes, there is no consistent phenotype-genotype correlation (Bogaert et al, 2018). The onset of clinical symptoms spans from infancy to late adulthood, with most patients presenting in adolescent and early adult years.…”

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confidence: 99%

GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner

et al. 2019

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Summary GATA2 deficiency, first described in 2011, is a bone marrow failure disorder resulting in a complex haematological and immunodeficiency syndrome characterised by cytopenias, severe infections, myelodysplasia and leukaemia. The only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). Although knowledge on this syndrome has greatly expanded, in clinical practice many challenges remain. In particular, guidelines on optimal donor and stem cell source and conditioning regimens regarding HSCT are lacking. Additionally, genetic analysis of GATA2 is technically cumbersome and could easily result in false‐negative results. With this report, we wish to raise awareness of these pitfalls amongst physicians dealing with haematological malignancies and primary immunodeficiencies.

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Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

2021

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Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B-or T-cells at different stages.

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A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects

Cited by 41 publications

References 17 publications

Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner

Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

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