Publications by authors named "Yenan T Bryceson"

129 Publications

LIR-1 educates expanded human NK cells and defines a unique antitumor NK cell subset with potent antibody-dependent cellular cytotoxicity.

Clin Transl Immunology 2021 5;10(10):e1346. Epub 2021 Oct 5.

Department of Medicine Center for Hematology and Regenerative Medicine Karolinska Institutet Stockholm Sweden.

Objective: KIR and NKG2A receptors educate human NK cells to stay responsive to cells with diminished HLA class I. Here, we addressed whether the HLA class I-binding receptor LIR-1 (LILRB1/ILT2/CD85j), which is widely expressed on human NK cells, can mediate education and contribute to antitumor functions of NK cells.

Methods: Healthy donor NK cells either unstimulated, overnight cytokine-activated or -expanded were used to target human cell lines. Phenotype and function were analysed using flow cytometry and Cr-release assays.

Results: We found that the inhibitory receptor LIR-1 can mediate NK cell education under specific conditions. This novel finding was exclusive to expanded NK cells and further characterisation of the cells revealed high expression of granzyme B and DNAM-1, which both previously have been linked to NK cell education. Corroborating the rheostat education model, LIR-1 co-expression with an educating KIR further increased the responsiveness of expanded NK cells. Inversely, antibody masking of LIR-1 decreased the responsiveness. LIR-1 expanded NK cells displayed high intrinsic ADCC that, in contrast to KIR and NKG2A, was not inhibited by HLA class I.

Conclusion: These findings identify a unique NK cell subset attractive for adoptive cell therapy to treat cancer. Given that LIR-1 binds most HLA class I molecules, this subset may be explored in both autologous and allogeneic settings to innately reject HLA class I tumor cells as well as HLA class I target cells when combined with antitumor antibodies. Further studies are warranted to address the potential of this subset .
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http://dx.doi.org/10.1002/cti2.1346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491220PMC
October 2021

Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy.

Cell Stem Cell 2021 Sep 9. Epub 2021 Sep 9.

University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA. Electronic address:

Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.
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http://dx.doi.org/10.1016/j.stem.2021.08.013DOI Listing
September 2021

Hobit identifies tissue-resident memory T cell precursors that are regulated by Eomes.

Sci Immunol 2021 Aug;6(62)

Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Tissue-resident memory CD8 T cells (T) constitute a noncirculating memory T cell subset that provides early protection against reinfection. However, how T arise from antigen-triggered T cells has remained unclear. Exploiting the T-restricted expression of Hobit, we used T reporter/deleter mice to study T differentiation. We found that Hobit was up-regulated in a subset of LCMV-specific CD8 T cells located within peripheral tissues during the effector phase of the immune response. These Hobit effector T cells were identified as T precursors, given that their depletion substantially decreased T development but not the formation of circulating memory T cells. Adoptive transfer experiments of Hobit effector T cells corroborated their biased contribution to the T lineage. Transcriptional profiling of Hobit effector T cells underlined the early establishment of T properties including down-regulation of tissue exit receptors and up-regulation of T-associated molecules. We identified Eomes as a key factor instructing the early bifurcation of circulating and resident lineages. These findings establish that commitment of T occurs early in antigen-driven T cell differentiation and reveal the molecular mechanisms underlying this differentiation pathway.
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http://dx.doi.org/10.1126/sciimmunol.abg3533DOI Listing
August 2021

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Sci Immunol 2021 08;6(62)

Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious variants in the male general population is < 6.5x10 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
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http://dx.doi.org/10.1126/sciimmunol.abl4348DOI Listing
August 2021

Genetics and pathophysiology of haemophagocytic lymphohistiocytosis.

Acta Paediatr 2021 Jun 30. Epub 2021 Jun 30.

Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

Haemophagocytic lymphohistiocytosis (HLH) represents a life-threatening hyperinflammatory syndrome. Familial studies have established autosomal and X-linked recessive causes of HLH, highlighting a pivotal role for lymphocyte cytotoxicity in the control of certain virus infections and immunoregulation. Recently, a more complex etiological framework has emerged, linking HLH predisposition to variants in genes required for metabolism or immunity to intracellular pathogens. We review genetic predisposition to HLH and discuss how molecular insights have provided fundamental knowledge of the immune system as well as detailed pathophysiological understanding of hyperinflammatory diseases, highlighting new treatment strategies.
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http://dx.doi.org/10.1111/apa.16013DOI Listing
June 2021

Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity.

J Allergy Clin Immunol 2021 May 24. Epub 2021 May 24.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.

Background: Rubella virus-induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive.

Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas.

Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays.

Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses.

Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.
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http://dx.doi.org/10.1016/j.jaci.2021.05.007DOI Listing
May 2021

The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation.

Sci Immunol 2021 Mar;6(57)

Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, N-5021 Bergen, Norway.

Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing and in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in -mutated patients and by ectopic Bcl11b expression. Moreover, was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.
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http://dx.doi.org/10.1126/sciimmunol.abc9801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274449PMC
March 2021

Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis.

J Rheumatol 2021 Oct 15;48(10):1596-1602. Epub 2021 Feb 15.

T. von Bahr Greenwood, MD, J.I. Henter, Professor, MD, PhD, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's Health, Karolinska University Hospital, Stockholm.

Objective: Macrophage activation syndrome (MAS) constitutes 1 subtype of the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH), and the term MAS-HLH was recently proposed for HLH with underlying autoimmune/autoinflammatory conditions. The mortality of MAS-HLH has been estimated at 5-10%. Here we report our experiences with moderately dosed etoposide in severe MAS-HLH; the objective was to effectively reduce severe hyperinflammatory activity with limited side effects.

Methods: In addition to conventional antiinflammatory treatment, moderately dosed etoposide was administered to 7 children affected by rapidly progressing MAS-HLH with central nervous system (n = 5) and/or pulmonary (n = 5) involvement. Three had underlying systemic juvenile idiopathic arthritis (sJIA), 2 had atypical sJIA (no arthritis at diagnosis), and 2 had systemic lupus erythematosus. We performed lymphocyte cytotoxicity analyses in all 7 and genetic analyses in 6.

Results: All children promptly responded to moderately dosed etoposide (50-100 mg/m once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m (range 300-1050 mg/m) as compared to 1500 mg/m recommended in the first 8 weeks of the HLH-94/HLH-2004 protocols. One child developed neutropenic fever and another neutropenic sepsis (neutrophils 0.3 × 10/L at therapy onset). Five of 7 children had low percentages (< 5%) of circulating natural killer (NK) cells prior to or in association with diagnosis; NK cell activity was pathologically low in 2 of 5 children studied. Disease-causing variants in HLH-associated genes were not found. All children were alive at latest follow-up (2-9 yrs after onset); neurological symptoms had normalized in 4 of 5 affected children.

Conclusion: Moderately dosed etoposide may be beneficial in severe and/or refractory MAS-HLH.
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http://dx.doi.org/10.3899/jrheum.200941DOI Listing
October 2021

RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis.

Blood 2021 04;137(15):2033-2045

St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.
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http://dx.doi.org/10.1182/blood.2020008738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057258PMC
April 2021

Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation: A retrospective observational study.

Eur J Anaesthesiol 2021 07;38(7):692-701

From the Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden (TvBG, YW, BT, J-IH), Section of Paediatric Oncology, Theme of Children's Health, Karolinska University Hospital, Stockholm, Sweden (TvBG, J-IH), Hedenstierna Laboratory, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden (BH), Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden (SCCC, YTB), Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China (YW), Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet (BT) and Karolinska University Laboratory, Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden (BT).

Background: Severe pandemic influenza has been associated with the hyperinflammatory condition secondary haemophagocytic lymphohistiocytosis (HLH).

Objectives: To determine the frequency, degree, character and possible cause of influenza-associated HLH in critically ill patients with severe acute respiratory distress syndrome due to influenza A (H1N1) infection requiring extracorporeal membrane oxygenation (ECMO) support at our hospital.

Design: A retrospective observational study.

Patients And Setting: Medical data were retrieved retrospectively from 11 consenting patients of thirteen adults infected with pandemic influenza A (H1N1) 2009 requiring ECMO between July 2009 and January 2010 at the ECMO Centre of Karolinska University Hospital, Stockholm, Sweden. All patients were evaluated for HLH using HLH-2004 criteria and HScore.

Results: Eleven patients (median age 31 years) were included in the study and all survived. All patients showed signs of multiple organ dysfunction and pronounced inflammation, more severe in the four patients with HLH who had significantly higher peak serum concentrations of ferritin (P = 0.024), alkaline phosphatase (P = 0.012) and gamma-glutamyl transferase (P = 0.024), lower concentration of albumin (P = 0.0086) and more frequently hepatomegaly (P = 0.048). Abnormal lymphocyte cytotoxicity (lytic units <10) and a low proportion of natural killer (NK) cells were observed in three of four patients with HLH. Notably, we found a significant inverse correlation between serum ferritin concentration and NK cell and cytotoxic T lymphocyte percentages (rs = -0.74, P = 0.0013 and rs = -0.79, P = 0.0025, respectively). One HLH patient received HLH-directed cytotoxic therapy, another intravenous immunoglobulin and the other two no specific HLH-directed therapy.

Conclusion: Critically ill patients, including healthy young adults, with pandemic influenza may develop HLH and should be monitored for signs of hyperinflammation and increasing organ dysfunction, and evaluated promptly for HLH because HLH-directed therapy may then be beneficial. The association of low NK percentages with hyperferritinaemia may suggest a role for reduced NK cell numbers, possibly also cytotoxic T lymphocytes, and subsequently reduced lymphocyte cytotoxicity, in the pathogenesis of hyperinflammation and secondary HLH.
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http://dx.doi.org/10.1097/EJA.0000000000001386DOI Listing
July 2021

Patients with both Langerhans cell histiocytosis and Crohn's disease highlight a common role of interleukin-23.

Acta Paediatr 2021 04 8;110(4):1315-1321. Epub 2020 Oct 8.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Aim: To present the first case series of patients with Langerhans cell histiocytosis (LCH) also affected by Crohn's disease (CD), both of which are granulomatous diseases, and in LCH investigate the role of interleukin (IL)-23, which is a well-described disease mediator in CD.

Methods: A case series of three patients with LCH and CD were described; a cohort of LCH patients (n = 55) as well as controls (n = 55) were analysed for circulating IL-23 levels; and the relation between the percentage of LCH cells in lesions and circulating IL-23 levels was analysed in seven LCH patients.

Results: Differential diagnostic challenges for these two granulomatous diseases were highlighted in the case series, and it took up to 3 years to diagnose CD. Elevated IL-23 levels were found in LCH patients. The amount of lesional LCH cells correlated with the levels of circulating IL-23.

Conclusion: Both CD and LCH should be considered in patients with inflammatory gastrointestinal involvement. The IL-23 pathway is a common immunological trait between these two granulomatous diseases.
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http://dx.doi.org/10.1111/apa.15590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984331PMC
April 2021

Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity.

PLoS Biol 2020 03 17;18(3):e3000648. Epub 2020 Mar 17.

Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia.

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.
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http://dx.doi.org/10.1371/journal.pbio.3000648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077837PMC
March 2020

Dynamic Changes in Natural Killer Cell Subset Frequencies in the Absence of Cytomegalovirus Infection.

Front Immunol 2019 22;10:2728. Epub 2019 Nov 22.

Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.

Individuals lacking functional natural killer (NK) cells suffer severe, recurrent infections with cytomegalovirus (CMV), highlighting the critical role of NK cells in antiviral defense. Therefore, ongoing attempts to develop an efficacious vaccine to prevent CMV infection should potentially aim to elicit NK-cell antiviral responses as an accessory to conventional T- and B-cell based approaches. In this regard, CMV infection provokes marked phenotypic and functional differentiation of the NK-cell compartment, including development of adaptive NK cells that exhibit enhanced antiviral activity. We examined longitudinal blood samples collected from 40 CMV-seronegative adolescents to ascertain whether a CMV glycoprotein B (gB) vaccine in the absence of CMV infection can stimulate differentiation or expansion of CMV-associated subsets of NK cells. Study participants uniformly lacked the CMV-dependent NKG2C subset of NK cells, suggesting that an adjuvanted CMV gB vaccine alone is an inadequate stimulus for sustained expansion of these cells. In contrast, we observed unexpected dynamic fluctuations in the frequency of NK cells lacking FcRγ, EAT-2, and SYK, which were independent of vaccination or CMV infection. Whereas, FcRγ NK cells in CMV infection are reported to express increased levels of the maturation marker CD57, the FcRγ NK cells observed in our CMV-negative vaccine cohort express less CD57 than their FcRγ counterparts. The FcRγ NK cells in CMV-negative individuals were also functionally distinct from this subset in CMV infection, exhibiting comparable IFN-γ production and degranulation as FcRγ NK cells in response to cytokine or antibody-dependent stimuli. These results suggest that frequencies of some NK cell subsets may increase in response to unknown environmental or inflammatory cues distinct from that which occurs after CMV infection. Greater understanding of the nature of the signals driving CMV-independent accumulation of these subsets should permit development of mechanisms to facilitate vaccine-driven expansion of CMV-reactive NK cells.
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http://dx.doi.org/10.3389/fimmu.2019.02728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882915PMC
November 2020

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.

J Exp Med 2019 12 10;216(12):2778-2799. Epub 2019 Oct 10.

Baylor-Hopkins Center for Mendelian Genomics, Houston, TX.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.
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http://dx.doi.org/10.1084/jem.20190147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888978PMC
December 2019

Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper) inflammation and lymphocyte cytotoxicity.

Minerva Anestesiol 2019 12 3;85(12):1289-1298. Epub 2019 Sep 3.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Background: Critically ill patients may develop a potentially fatal hyperinflammatory condition known as secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill patients, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25.

Methods: In a prospective observational study, 32 patients with ferritin ≥500 µg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible.

Results: Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, P=0.008); both associated with other risk factors of poor outcome in critically ill, such as thrombocytopenia (rs=-0.534, P=0.002 and rs=-0.421, P=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, P<0.001) and life support treatments (rs=0.479, P=0.006). Interestingly, ferritin levels were inversely associated with natural killer (NK)-cell cytotoxicity (rs=-0.462, P=0.047) and degranulation (rs=-0.504, P=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells.

Conclusions: Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity.
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http://dx.doi.org/10.23736/S0375-9393.19.13534-1DOI Listing
December 2019

Cytotoxic Granule Exocytosis From Human Cytotoxic T Lymphocytes Is Mediated by VAMP7.

Front Immunol 2019 7;10:1855. Epub 2019 Aug 7.

Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany.

Cytotoxic T lymphocytes kill infected or malignant cells through the directed release of cytotoxic substances at the site of target cell contact, the immunological synapse. While genetic association studies of genes predisposing to early-onset life-threatening hemophagocytic lymphohistiocytosis has identified components of the plasma membrane fusion machinery, the identity of the vesicular components remain enigmatic. Here, we identify VAMP7 as an essential component of the vesicular fusion machinery of primary, human T cells. VAMP7 co-localizes with granule markers throughout all stages of T cell maturation and simultaneously fuses with granule markers at the IS. Knock-down of VAMP7 expression significantly decreased the killing efficiency of T cells, without diminishing early T cell receptor signaling. VAMP7 exerts its function in a SNARE complex with Syntaxin11 and SNAP-23 on the plasma membrane. The identification of the minimal fusion machinery in T cells provides a starting point for the development of potential drugs in immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2019.01855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692471PMC
October 2020

Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.

Nat Commun 2019 07 15;10(1):3106. Epub 2019 Jul 15.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11CTLA-4 vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
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http://dx.doi.org/10.1038/s41467-019-10812-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629652PMC
July 2019

Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease.

NPJ Genom Med 2019 27;4:14. Epub 2019 Jun 27.

1Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, , associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.
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http://dx.doi.org/10.1038/s41525-019-0088-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597545PMC
June 2019

maintains immune harmony.

J Exp Med 2019 06 8;216(6):1231-1233. Epub 2019 May 8.

Center for Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

How the IL-2 receptor β-chain specifically shapes immunity has remained enigmatic. In this issue of , Zhang et al. (https://doi.org/10.1084/jem.20182304) and Fernandez et al. (https://doi.org/10.1084/jem.20182015) independently report the first observations of autosomal recessive mutations in , revealing a requirement for in immunity and peripheral immune tolerance.
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http://dx.doi.org/10.1084/jem.20190546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547856PMC
June 2019

Adaptive NK cells in people exposed to correlate with protection from malaria.

J Exp Med 2019 06 12;216(6):1280-1290. Epub 2019 Apr 12.

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD

How antibodies naturally acquired during infection provide clinical immunity to blood-stage malaria is unclear. We studied the function of natural killer (NK) cells in people living in a malaria-endemic region of Mali. Multi-parameter flow cytometry revealed a high proportion of adaptive NK cells, which are defined by the loss of transcription factor PLZF and Fc receptor γ-chain. Adaptive NK cells dominated antibody-dependent cellular cytotoxicity responses, and their frequency within total NK cells correlated with lower parasitemia and resistance to malaria. -infected RBCs induced NK cell degranulation after addition of plasma from malaria-resistant individuals. Malaria-susceptible subjects with the largest increase in PLZF-negative NK cells during the transmission season had improved odds of resistance during the subsequent season. Thus, antibody-dependent lysis of -infected RBCs by NK cells may be a mechanism of acquired immunity to malaria. Consideration of antibody-dependent NK cell responses to antigens is therefore warranted in the design of malaria vaccines.
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http://dx.doi.org/10.1084/jem.20181681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547858PMC
June 2019

Haploinsufficiency of UNC13D increases the risk of lymphoma.

Cancer 2019 06 13;125(11):1848-1854. Epub 2019 Feb 13.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

Background: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors' knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity.

Methods: The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13-4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status.

Results: Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004).

Conclusions: Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte-mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma.
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http://dx.doi.org/10.1002/cncr.32011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593970PMC
June 2019

Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population.

Front Immunol 2018 15;9:3146. Epub 2019 Jan 15.

Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017. The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected. A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered. Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders.
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http://dx.doi.org/10.3389/fimmu.2018.03146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340972PMC
October 2019

Clonal expansion and compartmentalized maintenance of rhesus macaque NK cell subsets.

Sci Immunol 2018 11;3(29)

Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.

Natural killer (NK) cells recognize and eliminate infected and malignant cells. Their life histories are poorly understood, particularly in humans, due to lack of informative models and endogenous clonal markers. Here, we apply transplantation of barcoded rhesus macaque hematopoietic cells to interrogate the landscape of NK cell production, expansion, and life histories at a clonal level long term and after proliferative challenge. We identify oligoclonal populations of rhesus CD56CD16 NK cells that are characterized by marked expansions and contractions over time yet remained long-term clonally uncoupled from other hematopoietic lineages, including CD56CD16 NK cells. Individual or groups of CD56CD16 expanded clones segregated with surface expression of specific killer immunoglobulin-like receptors. These clonally distinct NK cell subpopulation patterns persisted for more than 4 years, including after transient in vivo anti-CD16-mediated depletion and subsequent regeneration. Profound and sustained interleukin-15-mediated depletion was required to generate new oligoclonal CD56CD16 NK cells. Together, our results indicate that linear NK cell production from multipotent hematopoietic progenitors or less mature CD56CD16 cells is negligible during homeostasis and moderate proliferative stress. In such settings, peripheral compartmentalized self-renewal can maintain the composition of distinct, differentiated NK cell subpopulations.
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http://dx.doi.org/10.1126/sciimmunol.aat9781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393805PMC
November 2018

Serum cytokine measurements and biological therapy of psoriasis - Prospects for personalized treatment?

Scand J Immunol 2018 Dec 4;88(6):e12725. Epub 2018 Nov 4.

Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.

Psoriasis is an immune-mediated disease where the IL-23/Th17 axis as well as TNF comprise main targets of biological therapy. Immune profiling has so far not been embraced as a clinical tool. We aimed to investigate relationships between individual serum cytokine levels in 40 psoriasis patients before and after receiving biological therapy and Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI). Serum concentration of 25 cytokines was determined by Luminex technology. Mean PASI and DLQI decreased by 71% and 65%, respectively. Increase of IL-2 positively correlated with improvement of PASI and DLQI. Moreover, increase of IL-5, IL-10, IL-12, IL-22 and GM-CSF correlated with treatment effect. Notably, logistic regression revealed four times higher risk of having severe psoriasis when IL-17A increased by 1 pg/mL (OR: 4.06, P < 0.05). Selected serum cytokines might constitute useful biomarkers for monitoring disease activity and optimizing therapeutic strategies in psoriasis patients.
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http://dx.doi.org/10.1111/sji.12725DOI Listing
December 2018

NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development.

Nat Immunol 2018 10 17;19(10):1083-1092. Epub 2018 Sep 17.

Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.

The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1 mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats.
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http://dx.doi.org/10.1038/s41590-018-0209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166863PMC
October 2018

Fatal Central Nervous System Lymphocytic Vasculitis after Treatment for Burkitt Lymphoma in a Patient with a SH2D1A Mutation.

Pediatr Infect Dis J 2019 02;38(2):e29-e31

Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge.

Very rarely, patients with X-linked lymphoproliferative syndrome type 1 present central nervous system vasculitis. We report a patient carrying a SH2D1A mutation that, after treatment for lymphoma developed fatal central nervous system vasculitis. He lacked signs of ongoing Epstein-Barr virus infection. We propose that impaired T cell homeostasis caused by SAP deficiency facilitates aberrant CD8 T cell activation against vascular antigens promoting clinical manifestations.
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http://dx.doi.org/10.1097/INF.0000000000002154DOI Listing
February 2019

Natural killer cells in inflammation and autoimmunity.

Cytokine Growth Factor Rev 2018 08 10;42:37-46. Epub 2018 Aug 10.

Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway. Electronic address:

First described 40 years ago, natural killer (NK) cells represent the founding members of the innate lymphoid cell (ILC) family. They were initially defined by their ability to kill cancer cells of hematopoietic origin. More recently, NK cells are recognized not only for their ability to kill infected or malignant cells, but also for mediating cytotoxicity against a range of normal immune cells. They thereby play an important physiological role in controlling immune responses and maintaining homeostasis. Besides cytotoxic activity, NK cells activation is accompanied by secretion of pro-inflammatory cytokines. Hence, NK cells have the potential to act both in driving inflammation and in restricting adaptive immune responses that may otherwise lead to excessive inflammation or even autoimmunity. Here, we highlight how NK cell activity is linked to inflammasome activation and review new molecular insights to the roles of NK cells in inflammation and autoimmunity. Furthermore, in light of new insights to NK cell differentiation and memory, we deliberate on how distinct NK cell subsets may impact immunoregulatory functions. Hypothetically, memory-like or adaptive NK cells could drive NK cell-mediated autoreactive diseases. Together, new findings underscore the complex yet important physiological roles of NK cells in both promoting inflammation and exerting immunoregulation and maintenance of immune homeostasis. Insights raise intriguing questions as to how NK cells themselves maintain self-tolerance.
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http://dx.doi.org/10.1016/j.cytogfr.2018.08.001DOI Listing
August 2018

ARID5B regulates metabolic programming in human adaptive NK cells.

J Exp Med 2018 09 30;215(9):2379-2395. Epub 2018 Jul 30.

Department of Medicine, University of Minnesota, Minneapolis, MN

Natural killer (NK) cells with adaptive immunological properties expand and persist in response to human cytomegalovirus. Here, we explored the metabolic processes unique to these cells. Adaptive CD3CD56CD57NKG2C NK cells exhibited metabolic hallmarks of lymphocyte memory, including increased oxidative mitochondrial respiration, mitochondrial membrane potential, and spare respiratory capacity. Mechanistically, we found that a short isoform of the chromatin-modifying transcriptional regulator, AT-rich interaction domain 5B (ARID5B), was selectively induced through DNA hypomethylation in adaptive NK cells. Knockdown and overexpression studies demonstrated that ARID5B played a direct role in promoting mitochondrial membrane potential, expression of genes encoding electron transport chain components, oxidative metabolism, survival, and IFN-γ production. Collectively, our data demonstrate that ARID5B is a key regulator of metabolism in human adaptive NK cells, which, if targeted, may be of therapeutic value.
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http://dx.doi.org/10.1084/jem.20172168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122973PMC
September 2018
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