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#32755457   2020/08/05 To Up

DNGR1-Cre-mediated Deletion of /A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice.

Chronic perivascular inflammation is a prominent feature in the lungs of idiopathic pulmonary arterial hypertension (IPAH). Although the proportions of conventional dendritic cells (cDCs) and plasmacytoid DCs are increased in IPAH lungs, it remains unknown whether activated cDCs play a pathogenic role. The Tnfaip3 gene encodes the ubiquitin-binding protein A20, which is a negative regulator of NF-κB, critically involved in DC activation. Targeting of Tnfaip3/A20 in cDCs was achieved by Clec9a (DNGR1)-Cre-mediated excision of the Tnfaip3 gene in Tnfaip3DNGR1-KO mice. Mice were evaluated for signs of pulmonary hypertension (PH) using right heart catheterization, echocardiography and measurement of the Fulton index. Inflammation was assessed by immunohistochemistry and flow cytometry. Pulmonary cDCs and mo-DCs from 31-week-old Tnfaip3DNGR1-KO mice showed modulated expression of cell surface activation markers compared to Tnfaip3DNGR1-WT mice. Tnfaip3DNGR1-KO mice developed elevated right ventricular (RV) systolic pressure and RV hypertrophy. The lungs of these mice displayed increased vascular remodeling and perivascular and peribronchial immune cell infiltration resembling tertiary lymphoid organs. Proportions of activated T cells and expression of IL-1β, IL-6 and IL-10 were enhanced in the lungs of Tnfaip3DNGR1-KO mice. Autoreactive IgA and IgG1 was detected in bronchoalveolar lavage and autoreactive IgA recognizing pulmonary endothelial antigens was present in the serum of Tnfaip3DNGR1-KO mice. All signs of PH were ameliorated in Tnfaip3DNGR1-KO mice by anti-IL-6 antibody treatment. These results indicate that activation of the NF-κB pathway in DCs, through deletion of A20/Tnfaip3, leads to experimental PH with accompanied pulmonary inflammation in an IL-6-dependent fashion.
Thomas Koudstaal, Jennifer A C van Hulst, Tridib Das, Stefan F H Neys, Daphne Merkus, Ingrid M Bergen, Michiel A de Raaf, Harm Jan Bogaard, Louis Boon, Geert van Loo, Joachim G J V Aerts, Karin A Boomars, Mirjam Kool, Rudi W Hendriks

2005 related Products with: DNGR1-Cre-mediated Deletion of /A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice.

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#32743991   2020/08/03 To Up

The First Case of an Infant with Familial A20 Haploinsufficiency in Korea.

Haploinsufficiency of A20 (HA20) is a newly described autoinflammatory disease caused by loss-of-function mutations in the gene. Clinical phenotypes are heterogenous and resemble Behçet's disease, juvenile idiopathic arthritis, inflammatory bowel disease, or periodic fever syndrome, with symptoms developing at an early age. Here, we report the first case of infantile familial HA20 in Korea, which mimics neonatal lupus erythematosus (NLE). A 2-month-old infant exhibited symptoms including recurrent fever, erythematous rashes, and oral ulcers, with elevated liver enzymes, and tested positive for several autoantibodies, similar to systemic lupus erythematosus (SLE); therefore, she was suspected to have NLE. However, six months after birth, symptoms and autoantibodies persisted. Then, we considered the possibility of other diseases that could cause early onset rashes and abnormal autoantibodies, including autoinflammatory syndrome, monogenic SLE, or complement deficiency, all of which are rare. The detailed family history revealed that her father had recurrent symptoms, including oral and genital ulcers, knee arthralgia, abdominal pain, and diarrhea. These Behcet-like symptoms last for many years since he was a teenager, and he takes medications irregularly only when those are severe, but doesn't want the full-scale treatment. Whole-exome sequencing was conducted to identify a possible genetic disorder, which manifested as pathogenic variant nonsense mutation in the gene, leading to HA20. In conclusion, HA20 should be considered in the differential diagnosis of an infant with an early-onset dominantly inherited inflammatory disease that presents with recurrent oral and genital ulcerations and fluctuating autoantibodies. Additionally, it also should be considered in an infant with suspected NLE, whose symptoms and abnormal autoantibodies persist.
Hye Young Kim, Ji Yeon Song, Woo Il Kim, Hyun Chang Ko, Su Eun Park, Ja Hyun Jang, Seong Heon Kim

1247 related Products with: The First Case of an Infant with Familial A20 Haploinsufficiency in Korea.



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#32738175   2020/08/01 To Up

Targeted Next Generation Sequencing Reveals Molecular Heterogeneity in non-CLL Clonal B-Cell Lymphocytosis.

Non-chronic lymphocytic leukemia (non-CLL) clonal B-cell lymphocytosis (CBL) encompasses a heterogeneous group of hematologic disorders that are still poorly understood. To shed light on their biological aspects, we retrospectively analyzed a highly selected series of 28 patients, who had a clonal B-cell population in the peripheral blood and in the bone marrow, without evidence of lymphoma. Extended targeted-next generation sequencing revealed wide molecular heterogeneity with MYD88 (14%), PDE4DIP (14%), BIRC3 (11%), CCND3 (11%), NOTCH1 (11%) and TNFAIP3 (11%) as the most mutated genes. Mutations of MYD88 were "non classic" in most cases. Although some genetic lesions were overlapping with indolent lymphomas, mainly splenic B-cell lymphomas of marginal zone origin and splenic diffuse red pulp small B-cell lymphoma, the genetic profile of our non-CLL CBL series seemed to suggest that various pathways could be involved in the pathogenesis of these disorders, not mirroring any specific lymphoma entity. These data better enlighten the molecular characteristics of non-CLL CBL; however, more efforts are needed in order to improve the diagnostic process, prognostication, and clinical management. This article is protected by copyright. All rights reserved.
Irene Defrancesco, Silvia Zibellini, Emanuela Boveri, Marco Frigeni, Virginia Valeria Ferretti, Ettore Rizzo, Arturo Bonometti, Francesca Capuano, Chiara Candido, Sara Rattotti, Annamaria Tenore, Cristina Picone, Elena Flospergher, Caterina Zerbi, Fabio Bergamini, Nicole Fabbri, Caterina Cristinelli, Marzia Varettoni, Marco Paulli, Luca Arcaini

2307 related Products with: Targeted Next Generation Sequencing Reveals Molecular Heterogeneity in non-CLL Clonal B-Cell Lymphocytosis.

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#32734503   2020/07/30 To Up

Correction to: A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus.

Figure 4a in Manuscript ID#JOCI-D-19-00318 has been revised due to the replacement of immunoblot lane of β-catenin by Zo-1 in NHA group.
Ruonan Duan, Qi Liu, Jiangxia Li, Xianli Bian, Qianqian Yuan, Yan Li, Feng Long, Shang Gao, Shijun Wei, Pengyu Li, Fei Gao, Wenjie Sun, Xi Li, Qiji Liu

1709 related Products with: Correction to: A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus.

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#32719680   2020/07/03 To Up

A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report.

Intestinal Behcet's disease (iBD) is an autoimmune disorder diagnosed by typical intestinal ulcers and systemic Behcet's disease (BD) manifestations. Haploinsufficiency of A20 (HA20) is a recently described autoinflammatory disease with a phenotype resembling BD, caused by heterozygous loss-of-function mutations in gene (encoding A20). We described a 29-year-old female with iBD-like symptoms including relapsing ulceration of intestinal anastomosis, recurrent oral ulcers and vasculitis in extremities. Due to the atypical intestinal ulcers with long segmental involvement and intestinal obstruction, whole exome sequencing (WES) was performed to screen for the underlying genetic defect and the identified gene was confirmed by Sanger sequencing. The expression levels of A20 was evaluated by Western blot. Sanger sequencing and Western blot were also performed in the patient's family members. A heterozygous mutation of (c.305A>G, p. Asn 102 Ser) was identified in the patient. The identical mutation was also found in her father and brother who had suffered from recurrent oral ulcers since childhood. Functional experiments revealed that the expression of A20 was decreased in the peripheral blood mononuclear cells of the patient and her family members who carried the TNFAIP3 mutation. We described a Chinese patient with a novel heterozygous mutation in who developed iBD-like symptoms. We proposed that the heterozygous mutation (c.305A>G, p. Asn 102 Ser) with an insufficient expression of A20 may be associated with the iBD phenotype in patients.
Yu Chen, Huanjun Huang, Yao He, Minhu Chen, Ursula Seidler, De'an Tian, Fang Xiao

1293 related Products with: A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report.



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#32714711   2020/07/21 To Up

A Saudi Child With Chronic Immune Thrombocytopenia and Vitiligo.

Chronic immune thrombocytopenia (ITP) is less commonly found in the children presenting with ITP. Patients usually present with petechiae, purpura, or active bleeding in the form of epistaxis or hematuria. The main aim of treatment in chronic ITP is to prevent major bleeding and to increase the platelet count. High doses of corticosteroids, intravenous immunoglobulin, rituximab, and eltrombopag, a thrombopoietin receptor agonist (TPO-RA), are medications that can be used. In this report, we present a case of chronic ITP in a 12-year-old child. In addition to features of chronic ITP, he also has vitiligo around his eyes and limbs. During treatment, he was resistant to steroids and did not respond to rituximab or eltrombopag. To understand the cause of his presenting features, we did multiple diagnostic evaluations. The whole-exome sequencing raises the possibility of auto-inflammatory syndrome Behcet-like (AISBL), which is a rare genetic disorder and not frequently reported in the available medical literature. AISBL is caused by mutations in the TNFAIP3 gene. According to our best knowledge, this is the first Saudi child diagnosed with chronic ITP and vitiligo with the possibility of AISBL that needs further genetic work-up to confirm the diagnosis.
Abdulqader Alhebshi, Hasanat Abbas, Hidayah M Alotaibi, Maryam Attaf, Arwa Al-Yamani

2795 related Products with: A Saudi Child With Chronic Immune Thrombocytopenia and Vitiligo.

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#32709905   2020/07/24 To Up

Identification of TNFAIP3 as relapse biomarker and potential therapeutic target for MOG antibody associated diseases.

MOG-antibody associated disease (MOG-AAD) is a recently recognized demyelinating disorder predominantly affecting children but also occurs in adults, with a relapsing course in approximately 50% of patients. We evaluated peripheral blood mononuclear cells from MOG-AAD patients by flow cytometry and found a strong antigen specific central memory cell (CMC) response with increased Th1 and Th17 cells at the time of a relapse. Transcriptomic analysis of CMCs by three independent sequencing platforms revealed TNFAIP3 as a relapse biomarker, whose expression was down regulated at a relapse compared to remission in MOG-AAD patients. Serum in an additional cohort of patients showed decreased TNFAIP3 levels at relapse compared to remission state in MOG-AAD patients. Our studies suggest that alterations in TNFAIP3 levels are associated with relapses in MOG-AAD patients, which may have clinical utility as a disease course biomarker and therapeutic target.
Shrishti Saxena, Hrishikesh Lokhande, Grace Gombolay, Radhika Raheja, Timothy Rooney, Tanuja Chitnis

2759 related Products with: Identification of TNFAIP3 as relapse biomarker and potential therapeutic target for MOG antibody associated diseases.

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#32707296   2020/07/21 To Up

Time-resolved RNA-seq provided a new understanding of intestinal immune response of European eel (Anguilla anguilla) following infection with Aeromonas hydrophila.

No studies systematically examined the intestinal immune response for yellow stage of European eel (Anguilla anguilla) with Aeromonas hydrophila infection by time-resolved RNA-seq. Here, we examined transcriptional profiles of the intestines at three-time points following infection with A. hydrophila. Intraperitoneal injections caused mortalities within 48 h post-injection (hpi), with the survival rate 87.5% at 24 hpi and 83.9% at 48 hpi. The result from KEGG pathway enrichment analysis showed that the immune related "cytosolic DNA-sensing pathway" was significantly enriched at the first and second time points (6 hpi and 18 hpi), with the up-regulated expression of irf3, il1b, tnfaip3, cxcl8a, ap1-2, c-fos, polr3d, polr3g and polr3k both at 6 hpi and 18 hpi, but not at the third time point (36 hpi). According to the KEGG annotation, 326 immune and inflammation-related DEGs were found. The co-expression network of those 326 DEGs revealed the existence of three modules, and tlr1 was found to be in the center of the biggest module which contained massive DEGs from "signal transduction" and "transport and catabolism". The c3 isoforms showed different expression pattern among the three time points, indicating a unique activation of complement systems at 18 hpi. Furthermore, two cathelicidins (aaCATH_1 and aaCATH_2) were highly up-regulated at the first two time points, and the bacterial growth inhibition assay revealed their antibacterial properties against A. hydrophila. Our data indicated the important roles of cytosolic DNA-sensing pathway, as well as transcripts including tlr1, c3, polr and cathelicidins in the intestine of A. anguilla in response to A. hydrophila infection. The present study will provide leads for functional studies of host-pathogen interactions.
Fan Xiong, Jing Xiong, Ya Fang Wu, Lu Cao, Wen Shu Huang, Ming Xian Chang

2463 related Products with: Time-resolved RNA-seq provided a new understanding of intestinal immune response of European eel (Anguilla anguilla) following infection with Aeromonas hydrophila.

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#32686499   2020/07/19 To Up

Identification of key potential targets for TNF-α/TNFR1-related intervertebral disc degeneration by bioinformatics analysis.

Bioinformatics analysis was performed on gene expression profile microarray data to identify the key genes activated through the TNF-α/TNFR1 signaling pathway in intervertebral disc degeneration (IDD). The common differentially expressed genes (co-DEGs) were calculated in nucleus pulposus (NP) cells and annulus fibrosus (AF) cells under TNF-α treatment or TNFR1 knockdown, which reveals the potential mechanism of TNF-α involvement in IDD and may provide new therapeutic targets for IDD.
Junmin Hong, Jiansen Yan, Jiancong Chen, Shuangxing Li, Yingjie Huang, Zhengqi Huang, Weijian Chen, Anjing Liang, Wei Ye

2968 related Products with: Identification of key potential targets for TNF-α/TNFR1-related intervertebral disc degeneration by bioinformatics analysis.

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#32674293   2020/07/14 To Up

Activation of NOTCH1 by Shear Force Elicits Immediate Cytokine Expression in Human Chondrocytes.

Osteoarthritis is caused by overloading of joints and is characterized by inflammation-induced disruption of cartilage structure. Current treatment strategy aims to relieve inflammation and prevent further deterioration of joint function. However, how mechanical force leads to inflammation and deterioration of chondrocyte function still remains incompletely understood. To explore the force-regulated molecular mechanism, an in vitro hydraulic shear force experiment to simulate the condition of force loading was required. The result demonstrated that multiple cytokines and immune regulators, including interleukin 8, interferon β, TRAF1 and TNFAIP3, were significantly increased by shear force within two hours of treatment. Moreover, JAG1 and HES1 were drastically upregulated as well, suggesting that NOTCH1 signaling is activated by shear force. Short-term expression of NOTCH1 intracellular domain activated a similar set of cytokines, indicating that NOTCH1 responds to shear force and activates downstream genes. When incubated under the medium conditioned by NOTCH1-activated chondrocyte, osteoblasts expressed higher levels of interferon β and interferon λ. Together, our results indicated that NOTCH1 functions as a force sensor and promotes expression of cytokines and immune regulators from shear-force bearing chondrocytes.
Hao-Jen Cheng, Wan-Ting Hsu, Cheng-Nan Chen, Chin Li

2393 related Products with: Activation of NOTCH1 by Shear Force Elicits Immediate Cytokine Expression in Human Chondrocytes.

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