Publications by authors named "Seiamak Bahram"

106 Publications

Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet.

Int J Mol Sci 2022 Jun 8;23(12). Epub 2022 Jun 8.

Center for Pediatric and Adolescent Medicine, Division of Pediatric Nephrology, University of Heidelberg, 69120 Heidelberg, Germany.

Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the osteoanabolic Gα/PKA and the Gα/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gα knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gα KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gα KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gα KO mice had similar bone morphology compared to WT, while CKD Gα-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gα-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gα-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gα/PKC KO further aggravates mineral bone disease.
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http://dx.doi.org/10.3390/ijms23126404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223847PMC
June 2022

A gain-of-function variant in the Wiskott-Aldrich syndrome gene is associated with a MYH9-related disease-like syndrome.

Blood Adv 2022 Apr 11. Epub 2022 Apr 11.

University of Strasbourg, Strasbourg, France.

While loss-of-function variants in the WAS gene are associated with Wiskott-Aldrich syndrome and lead to microthrombocytopenia, gain-of-function variants of WAS are associated with X-linked neutropenia (XLN) and absence of microthrombocytopenia. Only few XLN families have been reported so far and their platelet phenotype was not described in detail. To date, no renal involvement was described in XLN. In the present study we report exome sequencing of individuals from three generations of a family with a dominant disease combining neutropenia, macrothrombocytopenia and renal failure. We identified a heterozygous missense gain-of-function variant in the WAS gene (c.881T>C, p.I294T) that segregates with the disease and is already known to cause XLN. There was no pathogenic variant in MYH9, TUBB1, or ACTN1. This is the first report of a WAS gain-of-function variant associated with both the hematological phenotype of XLN (neutropenia, macrothrombocytopenia) and renal disease (proteinuria, renal failure) with glomerular tip lesion hyalinosis and actin condensations in effaced podocytes foot processes.
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http://dx.doi.org/10.1182/bloodadvances.2021006789DOI Listing
April 2022

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

Nat Med 2022 05 14;28(5):989-998. Epub 2022 Mar 14.

Laboratoire d'Excellence (LabEx) TRANSPLANTEX, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.
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http://dx.doi.org/10.1038/s41591-022-01725-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117142PMC
May 2022

Frequent, quantitative bone planar scintigraphy for determination of bone anabolism in growing mice.

PeerJ 2021 9;9:e12355. Epub 2021 Dec 9.

Imagerie Préclinique-UF6237, Pôle d'imagerie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Background: To provide insight into bone turnover, quantitative measurements of bone remodeling are required. Radionuclide studies are widely used in clinical care, but have been rarely used in the exploration of the bone in preclinical studies. We describe a bone planar scintigraphy method for frequent assessment of bone activity in mice across the growing period. Since repeated venous radiotracer injections are hardly feasible in mice, we investigated the subcutaneous route.

Methods: Repeated Tc-hydroxymethylene diphosphonate (HMDP) tracer bone planar scintigraphy studies of the knee region and µCT to measure femur growth rate were performed in eight mice between week 6 and week 27 of life, , during their growth period. Three independent investigators assessed the regions of interest (ROI). An index was calculated based on the counts in knees ROI (normalized by pixels and seconds), corrected for the activity administered, the decay between administration and imaging, and individual weights.

Results: A total of 93 scintigraphy studies and 85 µCT were performed. Repeated subcutaneous tracer injections were well tolerated and allowed for adequate radionuclide studies. Mean scintigraphic indexes in the knees ROI decreased from 87.4 ± 2.6 × 10 counts s pixel MBq g at week 6 to 15.0 ± 3.3 × 10 counts s pixel MBq g at week 27. The time constant of the fitted exponential decay was equal to 23.5 days. As control mean femur length assessed by µCT increased from 12.2 ± 0.8 mm at week 6 to 15.8 ± 0.2 mm at week 22. The time constant of the fitted Gompertz law was equal to 26.7 days. A correlation index of -0.97 was found between femur growth and decrease of bone tracer activity count between week 6 and 24.

Conclusion: This methodological study demonstrates the potential of repeated bone planar scintigraphy in growing mice, with subcutaneous route for tracer administration, for quantitative assessment of bone remodeling.
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http://dx.doi.org/10.7717/peerj.12355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667748PMC
December 2021

A Homozygous Missense Variant in PPP1R1B/DARPP-32 Is Associated With Generalized Complex Dystonia.

Mov Disord 2022 02 24;37(2):365-374. Epub 2021 Nov 24.

Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, ITI TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France.

Background: The dystonias are a heterogeneous group of hyperkinetic disorders characterized by sustained or intermittent muscle contractions that cause abnormal movements and/or postures. Although more than 200 causal genes are known, many cases of primary dystonia have no clear genetic cause.

Objectives: To identify the causal gene in a consanguineous family with three siblings affected by a complex persistent generalized dystonia, generalized epilepsy, and mild intellectual disability.

Methods: We performed exome sequencing in the parents and two affected siblings and characterized the expression of the identified gene by immunohistochemistry in control human and zebrafish brains.

Results: We identified a novel missense variant (c.142G>A (NM_032192); p.Glu48Lys) in the protein phosphatase 1 regulatory inhibitor subunit 1B gene (PPP1R1B) that was homozygous in all three siblings and heterozygous in the parents. This gene is also known as dopamine and cAMP-regulated neuronal phosphoprotein 32 (DARPP-32) and has been involved in the pathophysiology of abnormal movements. The uncovered variant is absent in public databases and modifies the conserved glutamate 48 localized close to the serine 45 phosphorylation site. The PPP1R1B protein was shown to be expressed in cells and regions involved in movement control, including projection neurons of the caudate-putamen, substantia nigra neuropil, and cerebellar Purkinje cells. The latter cells were also confirmed to be positive for PPP1R1B expression in the zebrafish brain.

Conclusions: We report the association of a PPP1R1B/DARPP-32 variant with generalized dystonia in man. It might be relevant to include the sequencing of this new gene in the diagnosis of patients with otherwise unexplained movement disorders. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28861DOI Listing
February 2022

Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort.

Sci Transl Med 2022 Jan 19;14(628):eabj7521. Epub 2022 Jan 19.

Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM (Institut de la Santé et de la Recherche Médicale) UMR_S 1109, Faculté de Médecine, Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Université de Strasbourg, 67085 Strasbourg, France.

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease . This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19 and was further confirmed at the transcriptional and protein level and by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified as a driver of disease severity and a candidate therapeutic target.
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http://dx.doi.org/10.1126/scitranslmed.abj7521DOI Listing
January 2022

Distinct antibody profiles in HLA-B∗57+, HLA-B∗57- HIV controllers and chronic progressors.

AIDS 2022 03;36(4):487-499

INSERM UMR_S 1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx Transplantex, Université de Strasbourg, Strasbourg.

Objective: Spontaneous control of HIV replication without treatment in HIV-1 controllers (HICs) was associated with the development of an efficient T-cell response. In addition, increasing data suggest that the humoral response participates in viral clearance.

Design: In-depth characterization of Ab response in HICs may help to define new parameters associated with this control.

Methods: We assessed the levels of total and HIV-specific IgA and IgG subtypes induction and their functional potencies - that is, neutralization, phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), according to the individual's major histocompatibility complex class I (HLA)-B∗57 status, and compared it with nontreated chronic progressors.

Results: We found that despite an undetectable viral load, HICs displayed HIV-specific IgG levels similar to those of chronic progressors. Interestingly, our compelling multifunctional analysis demonstrates that the functional Ab profile, by itself, allowed to discriminate HLA-B∗57+ HICs from HLA-B∗57- HICs and chronic progressors.

Conclusion: These results show that HICs display a particular HIV-specific antibody (Ab) profile that may participate in HIV control and emphasize the relevance of multifunctional Ab response analysis in future Ab-driven vaccine studies.
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http://dx.doi.org/10.1097/QAD.0000000000003080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876439PMC
March 2022

Refining "Long-COVID" by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection.

Infect Dis Ther 2021 Sep 10;10(3):1747-1763. Epub 2021 Jul 10.

Rheumatology Department, Centre Hospitalier Universitaire de Strasbourg, 1 Avenue Molière, 67098, Strasbourg, France.

Introduction: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied.

Methods: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group.

Results: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively.

Conclusions: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress.
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http://dx.doi.org/10.1007/s40121-021-00484-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270770PMC
September 2021

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells.

Sci Rep 2021 06 23;11(1):13144. Epub 2021 Jun 23.

Tumor Biomechanics, INSERM UMR_S1109, CRBS, 67000, Strasbourg, France.

Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.
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http://dx.doi.org/10.1038/s41598-021-92515-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222393PMC
June 2021

Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia.

Leukemia 2021 05 8;35(5):1463-1474. Epub 2021 Apr 8.

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand-receptor interactions.
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http://dx.doi.org/10.1038/s41375-021-01221-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102193PMC
May 2021

A Translational Investigation of IFN-α and STAT1 Signaling in Endothelial Cells during Septic Shock Provides Therapeutic Perspectives.

Am J Respir Cell Mol Biol 2021 08;65(2):167-175

ImmunoRhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale, UMR_S1109, Centre de Recherche d'Immunologie et d'Hematologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS).

Septic shock and disseminated intravascular coagulation (DIC) are known to be characterized by an endothelial cell dysfunction. The molecular mechanisms underlying this relationship are, however, poorly understood. In this work, we aimed to investigate human circulating IFN-α in patients with septic shock-induced DIC and tested the potential role of endothelial Stat1 (signal transducer and activator of transcription 1) as a therapeutic target in a mouse model of sepsis. For this, circulating type I, type II, and type III IFNs and procoagulant microvesicles were quantified in a prospective cohort of patients with septic shock. Next, we used a septic shock model induced by cecal ligation and puncture in wild-type mice, in Ifnar1 (type I IFN receptor subunit 1)-knockout mice, and in Stat1 conditional knockout mice. In human samples, we observed higher concentrations of circulating IFN-α and IFN-α1 in patients with DIC compared with patients without DIC, whereas concentrations of IFN-β, IFN-γ, IFN-λ1, IFN-λ2, and IFN-λ3 were not different. IFN-α concentration was positively correlated with CD105 microvesicle concentrations, reflecting endothelial injury. In Ifnar1 mice, cecal ligation and puncture did not induce septic shock and was characterized by lesser endothelial cell injury, with lower aortic inflammatory cytokine expression, endothelial inflammatory-related gene expression, and fibrinolysis. In mice in which Stat1 was specifically ablated in endothelial cells, a marked protection against sepsis was also observed, suggesting the relevance of an endothelium-targeted strategy. Our work highlights the key roles of type I IFNs as pathogenic players in septic shock-induced DIC and the potential pertinence of endothelial STAT1 as a therapeutic target.
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http://dx.doi.org/10.1165/rcmb.2020-0401OCDOI Listing
August 2021

Atypical focal segmental glomerulosclerosis associated with a new PODXL nonsense variant.

Mol Genet Genomic Med 2021 05 29;9(5):e1658. Epub 2021 Mar 29.

Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Université de Strasbourg, Strasbourg, France.

Background: Podocalyxin (PODXL) is a highly sialylated adhesion glycoprotein that plays an important role in podocyte's physiology. Recently, missense and nonsense dominant variants in the PODXL gene have been associated with focal segmental glomerulosclerosis (FSGS), a leading cause of nephrotic syndrome and kidney failure. Their histologic description, however, was superficial or absent.

Methods: We performed exome sequencing on a three-generation family affected by an atypical glomerular nephropathy and characterized the disease by light and electron microscopy.

Results: The disease was characterized by FSGS features and glomerular basement membrane duplication. Six family members displayed chronic proteinuria, ranging from mild manifestations without renal failure, to severe forms with end-stage renal disease. Exome sequencing of affected twin sisters, their affected mother, healthy father, and healthy maternal uncle revealed a new nonsense variant cosegregating with the disease (c.1453C>T, NM_001018111) in the PODXL gene, which is known to be expressed in the kidney and to cause nephropathy when mutated. The variant is predicted to lead to a premature stop codon (p.Q485*) that results in the loss of the intracytoplasmic tail of the protein.

Conclusion: This is the first description of a peculiar association combining a PODXL stop-gain variant and both FSGS and membranoproliferative glomerulonephritis features, described by light and electron microscopy.
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http://dx.doi.org/10.1002/mgg3.1658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172202PMC
May 2021

Aryl hydrocarbon receptor (Ahr)-dependent Il-22 expression by type 3 innate lymphoid cells control of acute joint inflammation.

J Cell Mol Med 2021 05 18;25(10):4721-4731. Epub 2021 Mar 18.

Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

The aryl hydrocarbon receptor (AHR) controls several inflammatory and metabolic pathways involved in various diseases, including the development of arthritis. Here, we investigated the role of AHR activation in IL-22-dependent acute arthritis using the K/BxN serum transfer model. We observed an overall reduction of cytokine expression in Ahr-deficient mice, along with decreased signs of joint inflammation. Conversely, we report worsened arthritis symptoms in Il-22 deficient mice. Pharmacological stimulation of AHR with the agonist VAG539, as well as injection of recombinant IL-22, given prior arthritogenic triggering, attenuated inflammation and reduced joint destruction. The protective effect of VAG539 was abrogated in Il-22 deficient mice. Finally, conditional Ahr depletion of Rorc-expressing cells was sufficient to attenuate arthritis, thereby uncovering a previously unsuspected role of AHR in type 3 innate lymphoid cells during acute arthritis.
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http://dx.doi.org/10.1111/jcmm.16433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107095PMC
May 2021

NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models.

Clin Exp Rheumatol 2021 Sep-Oct;39(5):982-987. Epub 2021 Jan 8.

Université de Strasbourg, INSERM, ImmunoRhumatologie Moléculaire UMR_S 1109, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Strasbourg, and Fédération Hospitalo-Universitaire, OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.

Objectives: NKG2D ligands (NKG2DLs) are stress-inducible molecules involved in multiple inflammatory settings. In this work, we quantified MICA, an NKG2DL, in the synovial fluid of patients suffering various arthritides and measured Nkg2dLs gene expression in murine models of acute joint inflammation.

Methods: Soluble MICA (sMICA) was quantified by ELISA is synovial fluids harvested from patients suffering osteoarthritis, rheumatoid arthritis, psoriatic arthritis, calcium pyrophosphate crystal arthritis, urate crystal arthritis and reactive arthritis. Transcripts encoding murine NKG2DLs were quantified by RT-qPCR in the joints of mouse models of rheumatoid arthritis, urate crystal arthritis and osteoarthritis.

Results: Marked overproduction of sMICA was observed in the synovial fluid of RA patients. Mouse studies highlighted the complex transcriptional regulation of Nkg2d ligands encoding genes depending on the inflammatory setting and microenvironment CONCLUSIONS: sMICA quantification could be an interesting biomarker to identify acute inflammation in RA patients in whom classical markers (i.e. anti-citrullinated protein antibodies, ACPA) are undetectable.
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http://dx.doi.org/10.55563/clinexprheumatol/klc3h6DOI Listing
September 2021

SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing.

Blood 2021 03;137(10):1340-1352

Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.

Heterozygous de novo missense variants of SRP54 were recently identified in patients with congenital neutropenia (CN) who display symptoms that overlap with Shwachman-Diamond syndrome (SDS). Here, we investigate srp54 knockout zebrafish as the first in vivo model of SRP54 deficiency. srp54-/- zebrafish experience embryonic lethality and display multisystemic developmental defects along with severe neutropenia. In contrast, srp54+/- zebrafish are viable, fertile, and show only mild neutropenia. Interestingly, injection of human SRP54 messenger RNAs (mRNAs) that carry mutations observed in patients (T115A, T117Δ, and G226E) aggravated neutropenia and induced pancreatic defects in srp54+/- fish, mimicking the corresponding human clinical phenotypes. These data suggest that the various phenotypes observed in patients may be a result of mutation-specific dominant-negative effects on the functionality of the residual wild-type SRP54 protein. Overexpression of mutated SRP54 also consistently induced neutropenia in wild-type fish and impaired the granulocytic maturation of human promyelocytic HL-60 cells and healthy cord blood-derived CD34+ hematopoietic stem and progenitor cells. Mechanistically, srp54-mutant fish and human cells show impaired unconventional splicing of the transcription factor X-box binding protein 1 (Xbp1). Moreover, xbp1 morphants recapitulate phenotypes observed in srp54 deficiency and, importantly, injection of spliced, but not unspliced, xbp1 mRNA rescues neutropenia in srp54+/- zebrafish. Together, these data indicate that SRP54 is critical for the development of various tissues, with neutrophils reacting most sensitively to the loss of SRP54. The heterogenic phenotypes observed in patients that range from mild CN to SDS-like disease may be the result of different dominant-negative effects of mutated SRP54 proteins on downstream XBP1 splicing, which represents a potential therapeutic target.
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http://dx.doi.org/10.1182/blood.2020008115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994924PMC
March 2021

Structural and Functional Impact of SRP54 Mutations Causing Severe Congenital Neutropenia.

Structure 2021 01 13;29(1):15-28.e7. Epub 2020 Oct 13.

Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Electronic address:

The SRP54 GTPase is a key component of co-translational protein targeting by the signal recognition particle (SRP). Point mutations in SRP54 have been recently shown to lead to a form of severe congenital neutropenia displaying symptoms overlapping with those of Shwachman-Diamond syndrome. The phenotype includes severe neutropenia, exocrine pancreatic deficiency, and neurodevelopmental as well as skeletal disorders. Using a combination of X-ray crystallography, hydrogen-deuterium exchange coupled to mass spectrometry and complementary biochemical and biophysical methods, we reveal extensive structural defects in three disease-causing SRP54 variants resulting in critical protein destabilization. GTP binding is mostly abolished as a consequence of an altered GTPase core. The mutations located in conserved sequence fingerprints of SRP54 eliminate targeting complex formation with the SRP receptor as demonstrated in yeast and human cells. These specific defects critically influence the entire SRP pathway, thereby causing this life-threatening disease.
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http://dx.doi.org/10.1016/j.str.2020.09.008DOI Listing
January 2021

selectBoost: a general algorithm to enhance the performance of variable selection methods.

Bioinformatics 2021 05;37(5):659-668

Institut de Recherche Mathématique Avancée, CNRS UMR 7501, Labex IRMIA, Université de Strasbourg, Strasbourg, France.

Motivation: With the growth of big data, variable selection has become one of the critical challenges in statistics. Although many methods have been proposed in the literature, their performance in terms of recall (sensitivity) and precision (predictive positive value) is limited in a context where the number of variables by far exceeds the number of observations or in a highly correlated setting.

Results: In this article, we propose a general algorithm, which improves the precision of any existing variable selection method. This algorithm is based on highly intensive simulations and takes into account the correlation structure of the data. Our algorithm can either produce a confidence index for variable selection or be used in an experimental design planning perspective. We demonstrate the performance of our algorithm on both simulated and real data. We then apply it in two different ways to improve biological network reverse-engineering.

Availability And Implementation: Code is available as the SelectBoost package on the CRAN, https://cran.r-project.org/package=SelectBoost. Some network reverse-engineering functionalities are available in the Patterns CRAN package, https://cran.r-project.org/package=Patterns.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097688PMC
May 2021

A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report.

BMC Med Genet 2020 09 17;21(1):182. Epub 2020 Sep 17.

Stem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.

Background: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene.

Case Presentation: Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon.

Conclusions: We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.
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http://dx.doi.org/10.1186/s12881-020-01121-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499997PMC
September 2020

Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.

Commun Biol 2020 08 21;3(1):465. Epub 2020 Aug 21.

Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.
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http://dx.doi.org/10.1038/s42003-020-01185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442816PMC
August 2020

NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation.

J Exp Med 2020 12;217(12)

Department of Pediatrics, King Abdulaziz Medical City, King Abdullah Specialized Children's Hospital, Riyadh, Saudi Arabia.

The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.
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http://dx.doi.org/10.1084/jem.20192275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526481PMC
December 2020

A FcɣRIIa polymorphism has a HLA-B57 and HLA-B27 independent effect on HIV disease outcome.

Genes Immun 2020 08 5;21(4):263-268. Epub 2020 Aug 5.

Université de Strasbourg, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Faculté de Médecine, plateforme GENOMAX, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.

Fcɣ receptors (FcɣRs) are key immune regulatory receptors that connect antibody-mediated immune responses to cellular effector functions. They are involved in the control of various immune functions including responses to infections. Genetic polymorphisms of FcɣRs coding genes (FCGR) have been associated with the regulation of HIV infection and progression. In this study, we analyzed the potential impact of five candidate FcɣR SNPs on viral control by genotyping 251 HIV controllers and 250 progressors. The rs10800309 AA genotype of the FcɣRIIa coding gene FCGR2A was found to be significantly associated with HIV control and this association was independent of HLA-B57 and HLA-B27 (OR, 2.84; 95% CI, 1.20-6.89; P = 0.033). We further confirmed the functional role of this polymorphism by showing an association of this same AA genotype with an increased in vitro FcɣRII expression on myeloid cells including dendritic cells (P = 0.0032). Together, these results suggest that the AA genotype of rs10800309 confers an improved immune response through FcɣRII upregulation and that this polymorphism may serve as an additional predictive marker of HIV control.
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http://dx.doi.org/10.1038/s41435-020-0106-8DOI Listing
August 2020

JAK-STAT Targeting Offers Novel Therapeutic Opportunities in Sepsis.

Trends Mol Med 2020 11 3;26(11):987-1002. Epub 2020 Jul 3.

Université de Strasbourg, Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive et Réanimation, Nouvel Hôpital Civil, Strasbourg, France; ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. Electronic address:

Sepsis is a life-threatening condition caused by exaggerated host responses to infections taking place in two phases: (i) a systemic (hyper)inflammatory response syndrome (SIRS), participating in multiple organ failure (MOF), a major complication of septic shock, followed by (ii) a compensatory anti-inflammatory response syndrome (CARS), leading to sepsis-induced immunosuppression and resulting in late infections and long-term mortality. The Janus kinase-signal transducer and activator of transcription (JAK-STAT)-dependent signaling pathway is involved in both manifestations, hence playing a key role during sepsis. It is also involved in emergency myelopoiesis, which participates in host defense. The aim of this review is to highlight and refine the recent implications of this signaling pathway in sepsis and illustrate why its central position makes it a potential biomarker and therapeutic target.
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http://dx.doi.org/10.1016/j.molmed.2020.06.007DOI Listing
November 2020

Capturing Differential Allele-Level Expression and Genotypes of All Classical HLA Loci and Haplotypes by a New Capture RNA-Seq Method.

Front Immunol 2020 29;11:941. Epub 2020 May 29.

Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan.

The highly polymorphic human major histocompatibility complex (MHC) also known as the human leukocyte antigen (HLA) encodes class I and II genes that are the cornerstone of the adaptive immune system. Their unique diversity (>25,000 alleles) might affect the outcome of any transplant, infection, and susceptibility to autoimmune diseases. The recent rapid development of new next-generation sequencing (NGS) methods provides the opportunity to study the influence/correlation of this high level of HLA diversity on allele expression levels in health and disease. Here, we describe the NGS capture RNA-Seq method that we developed for genotyping all 12 classical HLA loci (, and ) and assessing their allelic imbalance by quantifying their allele RNA levels. This is a target enrichment method where total RNA is converted to a sequencing-ready complementary DNA (cDNA) library and hybridized to a complex pool of RNA-specific HLA biotinylated oligonucleotide capture probes, prior to NGS. This method was applied to 161 peripheral blood mononuclear cells and 48 umbilical cord blood cells of healthy donors. The differential allelic expression of 10 HLA loci (except for and ) showed strong significant differences ( < 2.1 × 10). The results were corroborated by independent methods. This newly developed NGS method could be applied to a wide range of biological and medical questions including graft rejections and HLA-related diseases.
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http://dx.doi.org/10.3389/fimmu.2020.00941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272581PMC
April 2021

Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status.

Bone Marrow Transplant 2020 07 14;55(7):1367-1378. Epub 2020 Apr 14.

Department of Hematology and ErasmusMC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.

Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
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http://dx.doi.org/10.1038/s41409-020-0886-5DOI Listing
July 2020

Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients.

Trials 2020 Mar 18;21(1):274. Epub 2020 Mar 18.

Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Service d'Anesthésie-Réanimation Chirurgicale, 1 Avenue Molière, 67098, Strasbourg, France.

Background: Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients.

Methods: TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals.

Discussion: If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients.

Trial Registration: ClinicalTrials.gov, NCT03368092. Registered on 11 December 2017.
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http://dx.doi.org/10.1186/s13063-020-4141-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079402PMC
March 2020

High-Throughput Genotyping of Over Two Million Samples: Workflow and Allele Frequencies.

Front Immunol 2020 21;11:314. Epub 2020 Feb 21.

DKMS Life Science Lab, Dresden, Germany.

MICA and MICB are ligands of the NKG2D receptor and thereby influence NK and T cell activity. gene polymorphisms, expression levels and the amount of soluble MICA/B in the serum have been linked to autoimmune diseases, infections, and cancer. In hematopoietic stem cell transplantation, matching between donor and patient has been correlated with reduced acute and chronic graft-vs.-host disease and improved survival. Hence, we developed an extremely cost-efficient high-throughput workflow for genotyping for newly registered potential stem cell donors. Since mid-2017, we have genotyped over two million samples using NGS amplicon sequencing for exons 2-5. In donors of German origin, * is the most common allele with a frequency of 42.3%. It is followed by * (11.7%) and * (8.8%). The three most common alleles are * (43.9%), * (21.7%), and * (18.9%). In general, is less diverse than and only 6 alleles, instead of 15, account for a cumulative allele frequency of 99.5%. In 0.5% of the samples we observed at least one allele of or which has so far not been reported to the IPD/IMGT-HLA database. By providing typed voluntary donors, clinicians become empowered to include into their donor selection process to further improve unrelated hematopoietic stem cell transplantation.
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http://dx.doi.org/10.3389/fimmu.2020.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047279PMC
March 2021

A mouse model of MSU-induced acute inflammation suggests imiquimod-dependent targeting of as relevant therapy for gout patients.

Theranostics 2020 12;10(5):2158-2171. Epub 2020 Jan 12.

Université de Strasbourg, INSERM, ImmunoRhumatologie Moléculaire UMR_S 1109, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, F-67000 Strasbourg, France.

: The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1β in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1β secretion , the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. : Acute urate crystal inflammation was obtained by subcutaneous injections of MSU crystals in mice. Symptoms were followed by scoring, cytokine quantification by ELISA and western blot, gene expression by RT-qPCR and RNAseq; Magnetic Resonance Imaging was also used to assess inflammation. : We provide an extensive clinical, biological and molecular characterization of an acute uratic inflammation mouse model which accurately mimics human gout. We report the efficacy of topical imiquimod treatment and its impact on Interferon-dependent down modulation of gene expression in this experimental model. : Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities for gout patients.
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http://dx.doi.org/10.7150/thno.40650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019178PMC
April 2021

Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization.

Front Immunol 2019 18;10:2968. Epub 2019 Dec 18.

INSERM U1109, LabEx TRANSPLANTEX, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Antibodies (Abs) are the major component of the humoral immune response and a key player in vaccination. The precise Ab-mediated inhibitory mechanisms leading to protection against HIV have not been elucidated. In addition to the desired viral capture and neutralizing Ab functions, complex Ab-dependent mechanisms that involve engaging immune effector cells to clear infected host cells, immune complexes, and opsonized virus have been proposed as being relevant. These inhibitory mechanisms involve Fc-mediated effector functions leading to Ab-dependent cellular cytotoxicity, phagocytosis, cell-mediated virus inhibition, aggregation, and complement inhibition. Indeed, the decreased risk of infection observed in the RV144 HIV-1 vaccine trial was correlated with the production of non-neutralizing inhibitory Abs, highlighting the role of Ab inhibitory functions besides neutralization. Moreover, Ab isotypes and subclasses recognizing specific HIV envelope epitopes as well as pecular Fc-receptor polymorphisms have been associated with disease progression. These findings further support the need to define which Fc-mediated Ab inhibitory functions leading to protection are critical for HIV vaccine design. Herein, based on our previous review Su & Moog Front Immunol 2014, we update the different inhibitory properties of HIV-specific Abs that may potentially contribute to HIV protection.
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http://dx.doi.org/10.3389/fimmu.2019.02968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930241PMC
November 2020
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