Yenan T Bryceson

University of Bergen, Bergen, Hordaland, Norway

Are you Yenan T Bryceson?

Claim your profile

Publications (89)616.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Perforin, encoded by PRF1, is a pore-forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early-onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later-onset disease and more variable manifestations. We retrospectively searched our database for patients from families with siblings carrying biallelic PRF1 missense mutations where at least one sibling did not develop HLH, and for patients with biallelic PRF1 missense mutations and an atypical presentation of disease. We reviewed their clinical, genetic, and immunological characteristics. In all, we identified 10 such patients, including three sibling pairs with discordant manifestations. Interestingly, in two families, siblings of late-onset HLH patients developed Hodgkin lymphoma but no HLH. In a third family, one sibling presented with recurrent HLH episodes, whereas the other remains healthy. Of note, the affected sibling also suffered from systemic lupus erythematosus. Additional unrelated patients with biallelic PRF1 missense mutations were affected by neurological disease without classical signs of HLH, gastrointestinal inflammation as initial presentation of disease, as well as a hematological malignancy. Compared to early-onset FHL2 patients, the patients with an atypical presentation displayed a partial recovery of NK cell cytotoxicity upon IL-2 stimulation in vitro. Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking PRF1 missense mutations to lymphoma susceptibility and highlighting clinical variability within families. PRF1 mutations should, therefore, be considered as a cause of several diseases disparate to HLH. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 07/2015; DOI:10.1002/pbc.25646 · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytomegalovirus (CMV) reactivates in >30% of CMV seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of NK cells expressing NKG2C, CD57 and inhibitory killer-cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation post-HCT. These NK cells persist after the resolution of infection and display 'adaptive' or memory properties. Despite these findings, the differential impact of persistent/inactive vs. reactivated CMV on NK vs. T cell maturation following HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pre-transplant CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an 'adaptive' phenotype (NKG2C(+)CD57(+)). Compared to CMV seronegative recipients, those who reactivated CMV (React(+)) had the highest adaptive cell frequencies, while intermediate frequencies were observed in CMV seropositive recipients harboring persistent/non-replicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV seropositive recipients of sibling, but not UCB grafts, and correlated with lower rates of CMV reactivation (sibling 33% vs. UCB 51%; p<0.01). These data suggest that persistent/non-replicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling, but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 06/2015; DOI:10.1016/j.bbmt.2015.05.025 · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hematopoietic cell transplantation (HCT) has been used as a part of cancer therapy for over half a decade. Beyond the necessity for donor-derived cells to reconstitute hematopoiesis after radiation and chemotherapy, immunologic reconstitution from allogeneic cells is important for the elimination of residual tumor cells. Natural killer (NK) cells are first among lymphocytes to reconstitute post-transplant and protect against cancer relapse. In this review, we provide a historical perspective on the role of NK cells in cancer control in the transplant setting and focus on current research aimed at improving NK cell responses for therapeutic benefit.
    Current topics in microbiology and immunology 06/2015; DOI:10.1007/82_2015_445 · 3.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. This includes patients with primary immunodeficiencies, in whom pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/ml T-cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower soluble CD25 and higher ferritin. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus, (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies. (ii) this syndrome can develop despite severe deficiency of T- and NK-cells, implicating that pathophysiology is distinct and not appropriately described as Lympho-Histiocytosis in these patients (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogenesis. This is important because of implications for therapy, in particular for protocols targeting T-cells. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 05/2015; DOI:10.3324/haematol.2014.121608 · 5.87 Impact Factor
  • Clinical Immunology 05/2015; 159(1). DOI:10.1016/j.clim.2015.04.015 · 3.99 Impact Factor
  • Source
    Konrad Krzewski, Yenan T Bryceson
  • [Show abstract] [Hide abstract]
    ABSTRACT: The functional capacity of NK cells is dynamically tuned by integrated signals from inhibitory and activating cell surface receptors in a process termed NK cell education. However, the understanding of the cellular and molecular mechanisms behind this functional tuning is limited. In this study, we show that the expression of the adhesion molecule and activation receptor DNAX accessory molecule 1 (DNAM-1) correlates with the quantity and quality of the inhibitory input by HLA class I-specific killer cell Ig-like receptors and CD94/NKG2A as well as with the magnitude of functional responses. Upon target cell recognition, the conformational state of LFA-1 changed in educated NK cells, associated with rapid colocalization of both active LFA-1 and DNAM-1 at the immune synapse. Thus, the coordinated expression of LFA-1 and DNAM-1 is a central component of NK cell education and provides a potential mechanism for controlling cytotoxicity by functionally mature NK cells. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 03/2015; DOI:10.4049/jimmunol.1401972 · 5.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 03/2015; 42(3):443-56. DOI:10.1016/j.immuni.2015.02.008 · 19.75 Impact Factor
  • Source
    Journal of Allergy and Clinical Immunology 01/2015; 135(6). DOI:10.1016/j.jaci.2014.11.030 · 11.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Recently we serendipitously identified a patient with systemic lupus erythematosus (SLE) who was positive for autoantibodies to CD94/natural killer receptor group 2A (NKG2A). The present study was undertaken to investigate the occurrence and function of autoantibodies targeting lectin-like NK cell receptors in SLE.Methods Sera from 203 SLE patients and 90 healthy individuals were analyzed, by flow cytometry, for Ig binding to Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C, or NKG2D. Autoantibodies identified were characterized with regard to interference with HLA-E binding, effect on NK cell activation in response to HLA-E-transfected K562 cells, and capacity to facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). Levels of autoantibodies were determined in longitudinally sampled sera, and correlations with disease activity (SLE Disease Activity Index 2000) and severity (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were investigated.ResultsAnti-CD94/NKG2A autoantibodies were identified in 7 SLE patients. The autoantibodies from 6 patients inhibited binding of HLA-E to CD94/NKG2A, whereas those from the seventh patient augmented this binding. Autoantibodies from 2 patients also reacted with the activating receptor CD94/NKG2C, with inhibition of the binding of HLA-E to CD94/NKG2C observed in 1 case and enhancement of this binding in the other. None of the sera contained anti-NKG2D autoantibodies. The levels of anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies correlated with disease activity and with a more severe SLE phenotype. Mechanistically, anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with HLA-E-mediated regulation of NK cell activation and facilitated the elimination of target cells expressing CD94/NKG2A or CD94/NKG2C through ADCC.Conclusion Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies occur in a subset of patients with clinically active SLE. Given their capacity to deplete certain NK cell subsets and interfere with particular NK cell function, such autoantibodies may promote the pathogenesis of SLE.
    12/2014; 67(4). DOI:10.1002/art.38999
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Individuals with biallelic truncating PRF1 mutations typically present with fulminant early-onset familial hemophagocytic lymphohistiocytosis (FHL). We report a 19-year-old male with a 5-year history of recurrent fever and headaches progressing to refractory seizures. Brain imaging revealed multiple ring enhancing lesions. Laboratory investigations demonstrated that the patient displayed defective lymphocyte cytotoxicity and carried a homozygous missense PRF1 mutation, c.394G > A (p.Gly132Arg). The patient was successfully treated with chemo-immunotherapy followed by matched related allogeneic hematopoietic stem cell transplantation (HSCT). Our findings demonstrate that prompt HSCT of late-onset FHL with primarily neurological manifestation can reverse central nervous system symptoms and improve long-term outcome. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2014; 61(12). DOI:10.1002/pbc.25166 · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971–1986 of 0.12 per 100,000 children. Here, we determined if the incidence had increased with concomitant awareness.ProcedureChildren <15 years old presenting with HLH 1987–2006 in Sweden were identified through the national mortality registry as well as by nation-wide inquiries to all pediatric centers. HLH was diagnosed according to the HLH-2004 diagnostic guidelines (in case of missing data of at least three of the eight diagnostic criteria, fulfillment of four was sufficient for inclusion). We defined primary HLH as patients presenting with HLH requiring transplantation or dying of disease.ResultsRemarkably, the minimal annual incidence rate of primary HLH remained 0.12 per 100,000 children, equating to 1.8 per 100,000 live births. Notably, an increased overall survival was observed in 1997–2006, relative to the period 1987–1996. During the subsequent 5-year period, 2007–2011, the incidence of genetically and/or functionally verified primary HLH was 0.15 per 100,000 children per year, suggesting that new assays may aid the identification of patients with primary HLH.Conclusion The annual incidence of primary HLH in Sweden is 0.12–0.15 per 100,000 children per year. Pediatr Blood Cancer 2014;9999: 1–7. © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2014; DOI:10.1002/pbc.25308 · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The prognosis of malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) is dismal, and knowledge on its etiology and treatment is limited. The aim of this study was to review treatment and outcome of patients with M-HLH. Methods: Between January 2008 and March 2012, 56 adult patients were referred to the Hematology Center Karolinska with suspicion of HLH. Medical records were retrospectively evaluated with respect to malignancy, clinical and laboratory features, therapy and outcome. Hemophagocytosis was re-evaluated cytohistologically. Results: Of the 56 evaluated patients, 31 fulfilled at least four HLH-2004 criteria and had a concomitant malignancy. Eleven patients (35%) suffered from myeloid malignancies, eleven from B-cell malignancies, eight from T/NK-cell malignancies, whereas one had an endocrine carcinoma. Eight patients debuted with HLH, of which six were later diagnosed with T/NK-cell malignancy. The majority of patients developed HLH subsequently to immunosuppressive therapy. At initial evaluation, hemophagocytosis was found in 17 patients (55%). However, re-evaluation performed by an experienced hematopathologist confirmed hemophagocytosis in 28 patients (90%). All patients displayed hyperferritinemia (max-value range: 1,442–645,291 µg/L). Twenty-one patients received HLH-targeted therapy with IVIG and corticosteroids. Etoposide and cyclosporine were administered in 10 and 8 patients, respectively. Overall survival was 16% (mean follow-up 219 days) and 40-day survival was 58%. The worst prognosis was noted for patients with T-cell malignancies (overall follow-up 0%, mean survival 58 days). There was no difference in survival between patients that fulfilled four versus five or more HLH criteria. Conclusions: Malignancy-associated HLH occurs in patients with hematological malignancies of all cell lineages and occasionally in patients with solid tumors. In patients with T/NK-cell malignancies HLH often preceded the diagnosis of malignancy, whereas in other malignancies HLH predominately followed immunosuppressive therapy. Survival rates were dismal, especially in patients with T/NK-cell malignancies, highlighting the need for improved treatment of adults with M-HLH.
    Pediatric Blood & Cancer 11/2014; 61(11):2132-2133. · 2.56 Impact Factor
  • Pediatric Blood & Cancer 11/2014; 61(11):2141-2141. · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.
    Blood 10/2014; 125(4). DOI:10.1182/blood-2014-04-570101 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Histiocytic disorders are rare entities that are becoming more recognized as our understanding of the molecular pathogenesis lead to novel diagnostic tests and targeted drug development. A symposium held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2013 Annual Meeting discussed new insights into histiocytic disorders. This review highlights the symposium presentations, divided into three sections encompassing Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) and Rosai Dorfman disease (RDD) including subsections on pathogenesis, clinical diagnostic criteria and novel insights into treatment. Details of other histiocytic disorders as well as the standard treatment guidelines have been published elsewhere and are beyond the scope of this discussion [Haupt et al. (2013). Pediatr Blood Cancer 60:175–184; Henter et al. (2007). Pediatr Blood Cancer 48:124–131]. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 07/2014; 61(7). DOI:10.1002/pbc.25017 · 2.56 Impact Factor
  • Source
    Konrad Krzewski, Yenan T Bryceson
    Frontiers in Immunology 06/2014; 5:279. DOI:10.3389/fimmu.2014.00279
  • Journal of Allergy and Clinical Immunology 05/2014; 134(1). DOI:10.1016/j.jaci.2014.04.026 · 11.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal recessive mutations in UNC13D, the gene that encodes Munc13-4, are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Munc13-4 expression is obligatory for exocytosis of lytic granules, facilitating cytotoxicity by T cells and natural killer (NK) cells. The mechanisms regulating Munc13-4 expression are unknown. Here, we report that Munc13-4 is highly expressed in differentiated human NK cells and effector CD8(+) T lymphocytes. A UNC13D c.118-308C>T mutation, causative of FHL3, disrupted binding of the ETS family member ELF1 to a conserved intronic sequence. This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus. The intronic sequence acted as an overall enhancer of Munc13-4 expression in cytotoxic lymphocytes in addition to representing an alternative promoter encoding a novel Munc13-4 isoform. Mechanistically, T cell receptor engagement facilitated STAT4-dependent Munc13-4 expression in naive CD8(+) T lymphocytes. Collectively, our data demonstrates how chromatin remodeling within an evolutionarily conserved regulatory element in intron 1 of UNC13D regulates the induction of Munc13-4 expression in cytotoxic lymphocytes and suggests that an alternative Munc13-4 isoform is required for lymphocyte cytotoxicity. Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.
    Journal of Experimental Medicine 05/2014; 211(6). DOI:10.1084/jem.20131131 · 13.91 Impact Factor
  • Frank Cichocki, Ewa Sitnicka, Yenan T. Bryceson
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone marrow-derived natural killer (NK) cells constitute the major subset of cytotoxic lymphocytes in peripheral blood. They provide innate defense against intracellular infection or malignancy and contribute to immune homeostasis. Large numbers of NK cells are also present in tissues, including the liver and uterus, where they can mediate immunosurveillance but also play important roles in tissue remodeling and vascularization. Here, we review the pathways involved in NK cell lineage commitment and differentiation, discussing relationships to other lymphocyte populations and highlighting genetic determinants. Characterizing NK cells from distinct tissues and during infections have revealed subset specializations, reflecting inherent cellular plasticity. In this context, we discuss how different environmental and inflammatory stimuli may shape NK cells. Particular emphasis is placed on genes identified as being critical for NK cell development, differentiation, and function from studies of model organisms or associations with disease. Such studies are also revealing important cellular redundancies. Here, we provide a view of the genetic framework constraining NK cell development and function, pinpointing molecules required for these processes but also underscoring plasticity and redundancy that may underlie robust immunological function. With this view, built in redundancy may highlight the importance of NK cells to immunity.
    Seminars in Immunology 04/2014; DOI:10.1016/j.smim.2014.02.003 · 6.12 Impact Factor

Publication Stats

3k Citations
616.80 Total Impact Points


  • 2013–2015
    • University of Bergen
      • Department of Clinical Science
      Bergen, Hordaland, Norway
  • 2008–2015
    • Karolinska Institutet
      • Center for Infectious Medicine
      Solna, Stockholm, Sweden
  • 2007–2015
    • Karolinska University Hospital
      • Center for Infectious Medicine (CIM)
      Tukholma, Stockholm, Sweden
  • 2011
    • Freie Universität Berlin
      • Division of Biochemistry
      Berlin, Land Berlin, Germany
  • 2002–2009
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2005
    • University of Oslo
      • Department of Anatomy
      Kristiania (historical), Oslo, Norway