Publications by authors named "Taco W Kuijpers"

353 Publications

CD47-SIRPα Checkpoint Inhibition Enhances Neutrophil-Mediated Killing of Dinutuximab-Opsonized Neuroblastoma Cells.

Cancers (Basel) 2021 Aug 24;13(17). Epub 2021 Aug 24.

Sanquin Research and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands.

High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting myeloid immune checkpoints, such as CD47-SIPRα, provide the opportunity to enhance antitumor effects of myeloid cells, including that of neutrophils, especially in the presence of cancer-opsonizing antibodies. Disialoganglioside (GD2)-expressing neuroblastoma cells targeted with anti-GD2 antibody dinutuximab are in part eradicated by neutrophils, as they recognize and bind the antibody targeted tumor cells through their Fc receptors. Therapeutic targeting of the innate immune checkpoint CD47-SIRPα has been shown to promote the potential of neutrophils as cytotoxic cells in different solid tumor indications using different cancer-targeting antibodies. Here, we demonstrate that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is also controlled by the CD47-SIRPα axis and can be further enhanced by antagonizing CD47-SIRPα interactions. In particular, CD47-SIRPa checkpoint inhibition enhanced neutrophil-mediated ADCC of dinutuximab-opsonized adrenergic neuroblastoma cells, whereas mesenchymal neuroblastoma cells may evade immune recognition by a reduction of GD2 expression. These findings provide a rational basis for targeting CD47-SIRPα interactions to potentiate dinutuximab responsiveness in neuroblastomas with adrenergic phenotype.
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http://dx.doi.org/10.3390/cancers13174261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428220PMC
August 2021

Hematopoietic stem cell transplantation in a patient with proteasome-associated autoinflammatory syndrome (PRAAS).

J Allergy Clin Immunol 2021 Aug 17. Epub 2021 Aug 17.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Experimental Immunology, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Background: Proteasome-associated autoinflammatory syndromes (PRAASs) form a family of recently described rare autosomal recessive disorders of disturbed proteasome assembly and proteolytic activity caused by mutations in genes coding for proteasome subunits. The treatment options for these proteasome disorders consist of lifelong immunosuppressive drugs or Janus kinase inhibitors, which may have partial efficacy and noticeable side effects. Because proteasomes are ubiquitously expressed, it is unknown whether hematopoietic stem cell transplantation (HSCT) may be a sufficient treatment option.

Objective: Our aim was to report the case of a young boy with a treatment-resistant cutaneous vasculitis that was initially suspected to be associated with a gene variant in SH2D1A.

Methods: Whole-exome sequencing was performed to identify the genetic defect. Molecular and functional analyses were performed to assess the impact of variants on proteasomal function. The immune characterization led to the decision to perform HSCT on our patient and conduct follow-up over the 7-year period after the transplant. Because loss of myeloid chimerism after the first HSCT was associated with relapse of autoinflammation, a second HSCT was performed.

Results: After the successful second HSCT, the patient developed mild symptoms of lipodystrophy, which raised the suspicion of a PRAAS. Genetic analysis revealed 2 novel heterozygous variants in PSMB4 (encoding proteasomal subunit β7). Retrospective analysis of patient cells stored before the first HSCT and patient cells obtained after the second HSCT demonstrated that HSCT successfully rescued proteasome function, restored protein homeostasis, and resolved the interferon-stimulated gene signature. Furthermore, successful HSCT alleviated the autoinflammatory manifestations in our patient.

Conclusion: Patients with treatment-resistant PRAAS can be cured by HSCT.
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http://dx.doi.org/10.1016/j.jaci.2021.07.039DOI Listing
August 2021

Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies.

Lancet Rheumatol 2021 Aug 6. Epub 2021 Aug 6.

Amsterdam Rheumatology and Immunology Center, location Reade, Department of Rheumatology, Amsterdam, Netherlands.

Background: Data are scarce on immunogenicity of COVID-19 vaccines in patients with autoimmune diseases, who are often treated with immunosuppressive drugs. We aimed to investigate the effect of different immunosuppressive drugs on antibody development after COVID-19 vaccination in patients with autoimmune diseases.

Methods: In this study, we used serum samples collected from patients with autoimmune diseases and healthy controls who were included in two ongoing prospective cohort studies in the Netherlands. Participants were eligible for inclusion in this substudy if they had been vaccinated with any COVID-19 vaccine via the Dutch national vaccine programme, which at the time was prioritising vaccination of older individuals. Samples were collected after the first or second COVID-19 vaccination. No serial samples were collected. Seroconversion rates and IgG antibody titres against the receptor-binding domain of the SARS-CoV-2 spike protein were measured. Logistic and linear regression analyses were used to investigate the association between medication use at the time of vaccination and at least until sampling, seroconversion rates, and IgG antibody titres. The studies from which data were collected are registered on the Netherlands Trial Register, Trial ID NL8513, and ClinicalTrials.org, NCT04498286.

Findings: Between April 26, 2020, and March 1, 2021, 3682 patients with rheumatic diseases, 546 patients with multiple sclerosis, and 1147 healthy controls were recruited to participate in the two prospective cohort studies. Samples were collected from patients with autoimmune diseases (n=632) and healthy controls (n=289) after their first (507 patients and 239 controls) or second (125 patients and 50 controls) COVID-19 vaccination. The mean age of both patients and controls was 63 years (SD 11), and 423 (67%) of 632 patients with autoimmune diseases and 195 (67%) of 289 controls were female. Among participants without previous SARS-CoV-2 infection, seroconversion after first vaccination were significantly lower in patients than in controls (210 [49%] of 432 patients 154 [73%] of 210 controls; adjusted odds ratio 0·33 [95% CI 0·23-0·48]; p<0·0001), mainly due to lower seroconversion in patients treated with methotrexate or anti-CD20 therapies. After the second vaccination, seroconversion exceeded 80% in all patient treatment subgroups, except among those treated with anti-CD20 therapies (three [43%] of seven patients). We observed no difference in seroconversion and IgG antibody titres between patients with a previous SARS-CoV-2 infection who had received a single vaccine dose (72 [96%] of 75 patients, median IgG titre 127 AU/mL [IQR 27-300]) and patients without a previous SARS-CoV-2 infection who had received two vaccine doses (97 [92%] of 106 patients, median IgG titre 49 AU/mL [17-134]).

Interpretation: Our data suggest that seroconversion after a first COVID-19 vaccination is delayed in older patients on specific immunosuppressive drugs, but that second or repeated exposure to SARS-CoV-2, either via infection or vaccination, improves humoral immunity in patients treated with immunosuppressive drugs. Therefore, delayed second dosing of COVID-19 vaccines should be avoided in patients receiving immunosuppressive drugs. Future studies that include younger patients need to be done to confirm the generalisability of our results.

Funding: ZonMw, Reade Foundation, and MS Center Amsterdam.
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http://dx.doi.org/10.1016/S2665-9913(21)00222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346242PMC
August 2021

A Novel Framework for Phenotyping Children With Suspected or Confirmed Infection for Future Biomarker Studies.

Front Pediatr 2021 28;9:688272. Epub 2021 Jul 28.

Department of General Pediatrics, Medical University of Graz, Graz, Austria.

The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0- <16 years: the Alder Hey emergency department ( = 1,120), Alder Hey pediatric intensive care unit ( = 355), Erasmus emergency department ( = 1,993), Maasstad emergency department ( = 714) and St. Mary's hospital ( = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination. Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis ("definite bacterial" category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis ("definite viral" category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of "definite bacterial" vs. "definite viral" following the PERFORM algorithm than using the "SBI" vs. "non-SBI" classification; summary AUC for PCT was 0.77 (95% CI 0.72-0.82) vs. 0.70 (95% CI 0.65-0.75); for NGAL this was 0.80 (95% CI 0.69-0.91) vs. 0.70 (95% CI 0.58-0.81); for resistin this was 0.68 (95% CI 0.61-0.75) vs. 0.64 (0.58-0.69) The three biomarkers combined had summary AUC of 0.83 (0.77-0.89) for "definite bacterial" vs. "definite viral" infections and 0.71 (0.67-0.74) for "SBI" vs. "non-SBI." Biomarkers of bacterial infection were strongly associated with the diagnostic categories using the PERFORM classification system in five independent cohorts. Our proposed algorithm provides a novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies.
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http://dx.doi.org/10.3389/fped.2021.688272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356564PMC
July 2021

Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration.

Am J Hum Genet 2021 08 13;108(8):1367-1384. Epub 2021 Jul 13.

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525GA, the Netherlands. Electronic address:

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10), FHR-2 (p = 1.47 × 10), FHR-3 (p = 1.05 × 10) and FHR-4A (p = 1.22 × 10) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10 and p = 2.81 × 10, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387287PMC
August 2021

Anti-rituximab antibodies affect pharmacokinetics and pharmacodynamics of rituximab in children with immune-mediated diseases.

Clin Exp Rheumatol 2021 Jun 26. Epub 2021 Jun 26.

Department of Paediatric Immunology, Rheumatology and Infectious diseases, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, The Netherlands.

Objectives: Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR).

Methods: All children <18 years who had received RTX treatment in our centre between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml.

Results: Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 μg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group.

Conclusions: In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.
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June 2021

Generation and characterization of a human iPSC line SANi006-A from a Gray Platelet Syndrome patient.

Stem Cell Res 2021 Aug 29;55:102443. Epub 2021 Jun 29.

Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands. Electronic address:

Induced pluripotent stem cells (iPSCs) were generated from erythroblasts (EBLs) obtained from a patient diagnosed with Gray Platelet Syndrome (GPS), caused by compound heterozygous NBEAL2 mutations (c.6568delT and c.7937T>C). GPS is an autosomal recessive bleeding disorder characterized by a lack of α-granules in platelets and progressive myelofibrosis. EBLs were reprogrammed with CytoTune-iPS 2.0 Sendai Reprogramming Kit, where the generated iPSCs showed normal karyotype, expression of pluripotency associated markers and in vitro spontaneous differentiation towards the three germ layers. The generated iPSCs can be used to study GPS pathophysiology and the basic functions of NBEAL2 protein in different cell types.
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http://dx.doi.org/10.1016/j.scr.2021.102443DOI Listing
August 2021

Generation and characterization of a human iPSC line SANi007-A from a patient with a heterozygous dominant mutation in ELANE.

Stem Cell Res 2021 Aug 27;55:102440. Epub 2021 Jun 27.

Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands. Electronic address:

Induced pluripotent stem cell (iPSC) line was generated from erythroblasts (EBLs) derived from a patient diagnosed with severe congenital neutropenia, caused by mutations in ELANE (c.614delG). Transgene-free iPSC line was generated using Sendai virus reprogramming. The iPSC line showed normal karyotype, expressed pluripotency associated genes and was capable of in vitro spontaneous differentiation towards the three germ layers. The generated iPSC line can be used to study severe congenital neutropenia and the role of neutrophil elastase protein.
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http://dx.doi.org/10.1016/j.scr.2021.102440DOI Listing
August 2021

Generation and characterization of a human iPSC line SANi008-A from a Chédiak-Higashi Syndrome patient.

Stem Cell Res 2021 Aug 24;55:102442. Epub 2021 Jun 24.

Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands. Electronic address:

Induced pluripotent stem cells (iPSCs) were generated from erythroblasts (EBLs) obtained from a patient diagnosed with Chédiak-Higashi Syndrome (CHS), caused by mutations in LYST (c.4322_4325delAGAG and c.10127A>G). EBLs were reprogrammed with CytoTune-iPS 2.0 Sendai Reprogramming Kit, where the generated iPSCs showed normal karyotype, expression of pluripotency associated markers and in vitro spontaneous differentiation towards the three germ layers. The generated iPSCs can be used to study CHS pathophysiology and the role of LYST in different cell types.
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http://dx.doi.org/10.1016/j.scr.2021.102442DOI Listing
August 2021

Generation and characterization of a control and patient-derived human iPSC line containing the Hermansky Pudlak type 2 (HPS2) associated heterozygous compound mutation in AP3B1.

Stem Cell Res 2021 07 23;54:102444. Epub 2021 Jun 23.

Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, The Netherlands; Department of Pediatric Immunology, Rheumatology & Infectious Diseases, Emma Children's Hospital, AUMC, University of Amsterdam, Amsterdam, The Netherlands.

Induced pluripotent stem cells (iPSCs) were generated from blood outgrowth endothelial cells (BOECs) obtained from a healthy donor and from a patient diagnosed with Hermansky Pudlak Syndrome type 2 (HPS2), caused by compound heterozygous AP3B1 mutations (c.177delA and c.1839-1842delTAGA). BOECs were reprogrammed with a hOKSM self-silencing polycistronic lentiviral vector, where the generated iPSCs showed normal karyotype, expression of pluripotency associated markers and in vitro spontaneous differentiation towards the three germ layers. The generated iPSCs can be used to study HPS2 pathophysiology and the basic functions of AP3B1 protein in different cell types.
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http://dx.doi.org/10.1016/j.scr.2021.102444DOI Listing
July 2021

Defective Neutrophil Transendothelial Migration and Lateral Motility in ARPC1B Deficiency Under Flow Conditions.

Front Immunol 2021 31;12:678030. Epub 2021 May 31.

Department of Blood Cell Research, Sanquin Research, AUMC, University of Amsterdam, Amsterdam, Netherlands.

The actin-related protein (ARP) 2/3 complex, essential for organizing and nucleating branched actin filaments, is required for several cellular immune processes, including cell migration and granule exocytosis. Recently, genetic defects in ARPC1B, a subunit of this complex, were reported. Mutations in result in defective ARP2/3-dependent actin filament branching, leading to a combined immunodeficiency with severe inflammation. , neutrophils of these patients showed defects in actin polymerization and chemotaxis, whereas adhesion was not altered under static conditions. Here we show that under physiological flow conditions human ARPC1B-deficient neutrophils were able to transmigrate through TNF-α-pre-activated endothelial cells with a decreased efficiency and, once transmigrated, showed definite impairment in subendothelial crawling. Furthermore, severe locomotion and migration defects were observed in a 3D collagen matrix and a perfusable vessel-on-a-chip model. These data illustrate that neutrophils employ ARP2/3-independent steps of adhesion strengthening for transmigration but rely on ARP2/3-dependent modes of migration in a more complex multidimensional environment.
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http://dx.doi.org/10.3389/fimmu.2021.678030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202084PMC
May 2021

Reliable detection of subtypes of nailfold capillary haemorrhages in childhood-onset systemic lupus erythematosus.

Clin Exp Rheumatol 2021 Sep-Oct;39(5):1126-1131. Epub 2021 Jun 8.

Department of Internal Medicine, Ghent University, and Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.

Objectives: In systemic lupus erythematosus (SLE), it is necessary to obtain biomarkers that predict cardiovascular complications due to premature atherosclerosis, which is related to endothelial dysfunction. Nailfold capillary abnormalities might be a biomarker for endothelial dysfunction. In adults and children with SLE, nailfold capillary haemorrhages have shown to be significantly correlated with disease activity. Recently, different subtypes of capillary haemorrhages have been described in childhood-onset SLE (cSLE). The aim of the current study was to assess the inter- and intra-rater reliability of observations of different subtypes of haemorrhages in cSLE patients.

Methods: Five raters blindly evaluated 140 capillaroscopy images from 35 cSLE-patients (diagnosed according to the 2012 SLICC criteria). The images were assessed qualitatively (present or absent) and quantitatively (total number) on four different subtypes of haemorrhages: 1) punctate extravasations, 2) perivascular haemorrhage, 3) large confluent haemorrhage and 4) non-definable. As subgroups 1) and 2) were interpreted as a continuous spectrum, a post-hoc analysis with "merged" (mean) kappa/ICC was additionally calculated as one sub-group.

Results: Qualitative assessment showed a kappa 0.65 (95% CI: 0.60-0.70) for "punctate extravasations and perivascular haemorrhages merged" and a kappa 0.78 (95% CI: 0.72-0.83) for large confluent haemorrhages. For the quantitative assessment, ICC was 0.82 (95% CI: 0.76-0.87) for the "merged groups" and ICC 0.93 (95% CI: 0.91-0.95) for large confluent haemorrhages.

Conclusions: Our study shows that different subtypes of capillary haemorrhages in cSLE-patients could be reliably reproduced by different raters. This confirms our recent observation of perivascular extravasations as a subgroup of capillary haemorrhage in cSLE that might reflect endothelial dysregulation.
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September 2021

Future Biomarkers for Infection and Inflammation in Febrile Children.

Front Immunol 2021 17;12:631308. Epub 2021 May 17.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, Netherlands.

Febrile patients, suffering from an infection, inflammatory disease or autoimmunity may present with similar or overlapping clinical symptoms, which makes early diagnosis difficult. Therefore, biomarkers are needed to help physicians form a correct diagnosis and initiate the right treatment to improve patient outcomes following first presentation or admittance to hospital. Here, we review the landscape of novel biomarkers and approaches of biomarker discovery. We first discuss the use of current plasma parameters and whole blood biomarkers, including results obtained by RNA profiling and mass spectrometry, to discriminate between bacterial and viral infections. Next we expand upon the use of biomarkers to distinguish between infectious and non-infectious disease. Finally, we discuss the strengths as well as the potential pitfalls of current developments. We conclude that the use of combination tests, using either protein markers or transcriptomic analysis, have advanced considerably and should be further explored to improve current diagnostics regarding febrile infections and inflammation. If proven effective when combined, these biomarker signatures will greatly accelerate early and tailored treatment decisions.
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http://dx.doi.org/10.3389/fimmu.2021.631308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165271PMC
September 2021

G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment.

J Immunother Cancer 2021 05;9(5)

Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands.

Background: Current immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma.

Methods: We compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions.

Results: We found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions.

Conclusions: Our preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting.
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http://dx.doi.org/10.1136/jitc-2020-002259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166600PMC
May 2021

Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer.

Cancer Immunol Res 2021 Jul 14;9(7):790-810. Epub 2021 May 14.

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287091PMC
July 2021

Biomarkers to predict infection and infection-related complications during chemotherapy-induced neutropenia in acute myeloid leukaemia: a pilot study.

Br J Haematol 2021 06 8;193(5):1008-1012. Epub 2021 Apr 8.

Department of Blood Cell Research, Division Research and Landsteiner Laboratory of Amsterdam UMC, Sanquin Blood Supply, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/bjh.17422DOI Listing
June 2021

C-Reactive Protein Enhances IgG-Mediated Cellular Destruction Through IgG-Fc Receptors .

Front Immunol 2021 15;12:594773. Epub 2021 Mar 15.

Sanquin Research and Landsteiner Laboratory, Department of Experimental Immunohematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Antibody-mediated blood disorders ensue after auto- or alloimmunization against blood cell antigens, resulting in cytopenia. Although the mechanisms of cell destruction are the same as in immunotherapies targeting tumor cells, many factors are still unknown. Antibody titers, for example, often do not strictly correlate with clinical outcome. Previously, we found C-reactive protein (CRP) levels to be elevated in thrombocytopenic patients, correlating with thrombocyte counts, and bleeding severity. Functionally, CRP amplified antibody-mediated phagocytosis of thrombocytes by phagocytes. To investigate whether CRP is a general enhancer of IgG-mediated target cell destruction, we extensively studied the effect of CRP on IgG-Fc receptor (FcγR)-mediated cell destruction: through respiratory burst, phagocytosis, and cellular cytotoxicity by a variety of effector cells. We now demonstrate that CRP also enhances IgG-mediated effector functions toward opsonized erythrocytes, in particular by activated neutrophils. We performed a first-of-a-kind profiling of CRP binding to all human FcγRs and IgA-Fc receptor I (FcαRI) using a surface plasmon resonance array. CRP bound these receptors with relative affinities of FcγRIa = FcγRIIa/b = FcγRIIIa > FcγRIIIb = FcαRI. Furthermore, FcγR blocking (in particular FcγRIa) abrogated CRP's ability to amplify IgG-mediated neutrophil effector functions toward opsonized erythrocytes. Finally, we observed that CRP also amplified killing of breast-cancer tumor cell line SKBR3 by neutrophils through anti-Her2 (trastuzumab). Altogether, we provide for the first time evidence for the involvement of specific CRP-FcγR interactions in the exacerbation of IgG-mediated cellular destruction; a trait that should be further evaluated as potential therapeutic target e.g., for tumor eradication.
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http://dx.doi.org/10.3389/fimmu.2021.594773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006934PMC
June 2021

[Lymphadenopathy in general practice].

Ned Tijdschr Geneeskd 2021 03 11;165. Epub 2021 Mar 11.

Lymphadenopathy (painfull or enlarged lymph nodes) is a common reason for consulting a physician working in primary or secondary health care. Lymphadenopathy can be the reason for consultation, but can also be observed in patients who present with other complaints. The differential diagnosis is very broad and varies from self-limiting benign disorders, where a wait-and-see policy is sufficient, to a more serious and life-threatening disease for which no further delay is warranted. In daily practice it can sometimes be challenging to determine which policy is indicated. In this article, we propose tools in order to assist the primary care physician to determine which policy is needed in patients presenting with lymphadenopathy.
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March 2021

Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting-Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases.

Front Immunol 2021 22;12:615477. Epub 2021 Feb 22.

Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological "actinopathies" primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely , , , and . Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.
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http://dx.doi.org/10.3389/fimmu.2021.615477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938309PMC
July 2021

2 Integrin Signaling Cascade in Neutrophils: More Than a Single Function.

Front Immunol 2020 18;11:619925. Epub 2021 Feb 18.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Neutrophils are the most prevalent leukocytes in the human body. They have a pivotal role in the innate immune response against invading bacterial and fungal pathogens, while recent emerging evidence also demonstrates their role in cancer progression and anti-tumor responses. The efficient execution of many neutrophil effector responses requires the presence of 2 integrins, in particular CD11a/CD18 or CD11b/CD18 heterodimers. Although extensively studied at the molecular level, the exact signaling cascades downstream of 2 integrins still remain to be fully elucidated. In this review, we focus mainly on inside-out and outside-in signaling of these two 2 integrin members expressed on neutrophils and describe differences between various neutrophil stimuli with respect to integrin activation, integrin ligand binding, and the pertinent differences between mouse and human studies. Last, we discuss how integrin signaling studies could be used to explore the therapeutic potential of targeting 2 integrins and the intracellular signaling cascade in neutrophils in several, among other, inflammatory conditions in which neutrophil activity should be dampened to mitigate disease.
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http://dx.doi.org/10.3389/fimmu.2020.619925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930317PMC
July 2021

Nailfold capillary abnormalities in childhood-onset systemic lupus erythematosus: a cross-sectional study compared with healthy controls.

Lupus 2021 Apr 3;30(5):818-827. Epub 2021 Mar 3.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centers (Amsterdam UMC), University of Amsterdam, Amsterdam, the Netherlands.

Objectives: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients.

Methods: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases.

Results: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001).

Conclusions: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.
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http://dx.doi.org/10.1177/0961203321998750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020305PMC
April 2021

SARS-CoV-2 and croup, a rare relationship or coincidence?

Am J Emerg Med 2021 Feb 18. Epub 2021 Feb 18.

Emma Children's Hospital, Amsterdam University Medical Centers, Department of Pediatric Pulmonology, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.ajem.2021.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891094PMC
February 2021

Neutrophil specific granule and NETosis defects in gray platelet syndrome.

Blood Adv 2021 01;5(2):549-564

Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, The Netherlands.

Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by a lack of α-granules in platelets and progressive myelofibrosis. Rare loss-of-function variants in neurobeachin-like 2 (NBEAL2), a member of the family of beige and Chédiak-Higashi (BEACH) genes, are causal of GPS. It is suggested that BEACH domain containing proteins are involved in fusion, fission, and trafficking of vesicles and granules. Studies in knockout mice suggest that NBEAL2 may control the formation and retention of granules in neutrophils. We found that neutrophils obtained from the peripheral blood from 13 patients with GPS have a normal distribution of azurophilic granules but show a deficiency of specific granules (SGs), as confirmed by immunoelectron microscopy and mass spectrometry proteomics analyses. CD34+ hematopoietic stem cells (HSCs) from patients with GPS differentiated into mature neutrophils also lacked NBEAL2 expression but showed similar SG protein expression as control cells. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as a potentially important regulator of granule release. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis, and killing of bacteria and fungi, were intact. NETosis was absent in circulating GPS neutrophils. Lack of NETosis is suggested to be independent of NBEAL2 expression but associated with SG defects instead, as indicated by comparison with HSC-derived neutrophils. Since patients with GPS do not excessively suffer from infections, the consequence of the reduced SG content and lack of NETosis for innate immunity remains to be explored.
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http://dx.doi.org/10.1182/bloodadvances.2020002442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839360PMC
January 2021

Genetic biomarkers for intravenous immunoglobulin response in chronic inflammatory demyelinating polyradiculoneuropathy.

Eur J Neurol 2021 05 6;28(5):1677-1683. Epub 2021 Feb 6.

Department of Immunology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.

Background And Purpose: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical and electrophysiological heterogeneous immune-mediated polyneuropathy. Intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange are proven effective treatments for CIDP. The clinical response to IVIg is variable between patients and currently unexplained. Finding biomarkers related to treatment response can help to understand the diversity of CIDP and personalise treatment choice.

Methods: We investigated whether genetic variation between patients may explain some of these differences in treatment response. Based on previous publications, we selected six candidate genes that might affect immune and axonal functions, IVIg metabolism, and treatment response in CIDP. Genetic variants were assessed in 172 CIDP patients treated with at least one course of IVIg (2 g/kg). A response to IVIg was defined by ≥1 grade improvement on the modified Rankin Scale. Blood samples were tested for variations in CNTN2, PRF1, FCGRT, FCGR2B, GJB1, and SH2D2A genes.

Results: In univariate analysis, patients with the FCGR2B promoter variant 2B.4/2B.1 responded more often to IVIg than patients with the 2B.1/2B.1 variant (odds ratio [OR] = 6.9, 95% confidence interval [CI] = 1.6-30; p = 0.003). Patients with the p.(Ala91Val) variant of PRF1 were less often IVIg responsive (OR = 0.34, 95% CI = 0.13-0.91; p = 0.038). In multivariate analysis, both PRF1 and FCGR2B showed discriminative ability to predict the chance of IVIg response (area under the curve = 0.67).

Conclusions: Variations in PRF1 and the promoter region of FCGR2B are associated with the response to IVIg in CIDP. These findings, which require validation, are a first step towards the understanding of the heterogeneity in the treatment response in CIDP.
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http://dx.doi.org/10.1111/ene.14742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247870PMC
May 2021

Kindlin3-Dependent CD11b/CD18-Integrin Activation Is Required for Potentiation of Neutrophil Cytotoxicity by CD47-SIRPα Checkpoint Disruption.

Cancer Immunol Res 2021 02 22;9(2):147-155. Epub 2020 Dec 22.

Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

The CD47-signal regulatory protein-alpha (SIRPα) immune checkpoint constitutes a therapeutic target in cancer, and initial clinical studies using inhibitors of CD47-SIRPα interactions in combination with tumor-targeting antibodies show promising results. Blockade of CD47-SIRPα interaction can promote neutrophil antibody-dependent cellular cytotoxicity (ADCC) toward antibody-opsonized targets. Neutrophils induce killing of antibody-opsonized tumor cells by a process identified as trogoptosis, a necrotic/lytic type of cancer cell death that involves trogocytosis, the antibody-mediated endocytic acquisition of cancer membrane fragments by neutrophils. Both trogocytosis and killing strictly depend on CD11b/CD18-(Mac-1)-mediated neutrophil-cancer cell conjugate formation, but the mechanism by which CD47-SIRPα checkpoint disruption promotes cytotoxicity has remained elusive. Here, by using neutrophils from patients with leukocyte adhesion deficiency type III carrying gene mutations, hence lacking the integrin-associated protein kindlin3, we demonstrated that CD47-SIRPα signaling controlled the inside-out activation of the neutrophil CD11b/CD18-integrin and cytotoxic synapse formation in a kindlin3-dependent fashion. Our findings also revealed a role for kindlin3 in trogocytosis and an absolute requirement in the killing process, which involved direct interactions between kindlin3 and CD18 integrin. Collectively, these results identified a dual role for kindlin3 in neutrophil ADCC and provide mechanistic insights into the way neutrophil cytotoxicity is governed by CD47-SIRPα interactions.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0491DOI Listing
February 2021

The Gardos effect drives erythrocyte senescence and leads to Lu/BCAM and CD44 adhesion molecule activation.

Blood Adv 2020 12;4(24):6218-6229

Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands.

Senescence of erythrocytes is characterized by a series of changes that precede their removal from the circulation, including loss of red cell hydration, membrane shedding, loss of deformability, phosphatidyl serine exposure, reduced membrane sialic acid content, and adhesion molecule activation. Little is known about the mechanisms that initiate these changes nor is it known whether they are interrelated. In this study, we show that Ca2+-dependent K+ efflux (the Gardos effect) drives erythrocyte senescence. We found that increased intracellular Ca2+ activates the Gardos channel, leading to shedding of glycophorin-C (GPC)-containing vesicles. This results in a loss of erythrocyte deformability but also in a marked loss of membrane sialic acid content. We found that GPC-derived sialic acid residues suppress activity of both Lutheran/basal cell adhesion molecule (Lu/BCAM) and CD44 by the formation of a complex on the erythrocyte membrane, and Gardos channel-mediated shedding of GPC results in Lu/BCAM and CD44 activation. This phenomenon was observed as erythrocytes aged and on erythrocytes that were otherwise prone to clearance from the circulation, such as sickle erythrocytes, erythrocytes stored for transfusion, or artificially dehydrated erythrocytes. These novel findings provide a unifying concept on erythrocyte senescence in health and disease through initiation of the Gardos effect.
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http://dx.doi.org/10.1182/bloodadvances.2020003077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757008PMC
December 2020

Comparison of the PU.1 transcriptional regulome and interactome in human and mouse inflammatory dendritic cells.

J Leukoc Biol 2020 Dec 2. Epub 2020 Dec 2.

Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.

Dendritic cells (DCs) are key immune modulators and are able to mount immune responses or tolerance. DC differentiation and activation imply a plethora of molecular and cellular responses, including transcriptional changes. PU.1 is a highly expressed transcription factor in DCs and coordinates relevant aspects of DC biology. Due to their role as immune regulators, DCs pose as a promising immunotherapy tool. However, some of their functional features, such as survival, activation, or migration, are compromised due to the limitations to simulate in vitro the physiologic DC differentiation process. A better knowledge of transcriptional programs would allow the identification of potential targets for manipulation with the aim of obtaining "qualified" DCs for immunotherapy purposes. Most of the current knowledge regarding DC biology derives from studies using mouse models, which not always find a parallel in human. In the present study, we dissect the PU.1 transcriptional regulome and interactome in mouse and human DCs, in the steady state or LPS activated. The PU.1 transcriptional regulome was identified by performing PU.1 chromatin immunoprecipitation followed by high-throughput sequencing and pairing these data with RNAsequencing data. The PU.1 interactome was identified by performing PU.1 immunoprecipitation followed by mass spectrometry analysis. Our results portray PU.1 as a pivotal factor that plays an important role in the regulation of genes required for proper DC activation and function, and assures the repression of nonlineage genes. The interspecies differences between human and mouse DCs are surprisingly substantial, highlighting the need to study the biology of human DCs.
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http://dx.doi.org/10.1002/JLB.6A1219-711RRRDOI Listing
December 2020

Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2.

J Allergy Clin Immunol 2021 Jun 3;147(6):2381-2385.e2. Epub 2020 Dec 3.

Immunity & Inflammation Theme, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Great North Children's Hospital (GNCH), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Electronic address:

Background: SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) has recently been shown to have a critical role in granulopoiesis in humans, mice, and zebrafish. Our patient presented with delayed cord separation, failure to thrive, and sepsis. Retrospective whole-exome sequencing confirmed a homozygous splice-site mutation in SMARCD2.

Objective: We sought to provide the second description of human SMARCD2 deficiency and the first functional analysis of human primary SMARCD2-deficient cells.

Methods: Heparinized venous blood and bone marrow were collected from the patient after obtaining informed consent. Patient leukocytes and CD34 cells were then isolated, phenotyped, and assessed functionally.

Results: Circulating neutrophils appeared phenotypically immature, lacking multilobed nuclei, and neutrophil granules lacked lactoferrin but showed normal levels of myeloperoxidase. Neutrophil oxidative burst was preserved in response to phorbol 12-myristate 13-acetate. Patient bone marrow-derived neutrophils and white blood cells showed a severely impaired chemotactic response. Furthermore, white blood cells showed defective in vitro killing of Staphylococcus aureus, consistent with a specific granule deficiency. Finally, patient bone marrow-derived CD34 cells showed markedly impaired in vitro expansion and differentiation toward the neutrophil lineage. Before her molecular diagnosis, our patient underwent hematopoietic stem cell transplantation and is well 8 years later.

Conclusions: This report highlights an important role for SMARCD2 in human myelopoiesis and the curative effect of hematopoietic stem cell transplantation for the hematopoietic features of SMARCD2 deficiency.
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http://dx.doi.org/10.1016/j.jaci.2020.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168953PMC
June 2021
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