Articles de revues : « Cd40lg- »

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Hubbard, Nicholas, David Hagin, Karen Sommer, Yumei Song, Iram Khan, Courtnee Clough, Hans D. Ochs, David J. Rawlings, Andrew M. Scharenberg et Troy R. Torgerson. « Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome ». Blood 127, n^o 21 (26 mai 2016) : 2513–22. http://dx.doi.org/10.1182/blood-2015-11-683235.

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Key PointsThe CD40LG locus can be specifically targeted and repaired in primary human T cells by insertion of a spliced CD40LG complementary DNA. Gene editing restores regulated CD40L expression in X-HIGM T cells, reconstituting B-cell immunoglobulin class switching.

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Hubbard, Nicholas Wesley, David Hagin, Karen Sommer, Yumei Song, Iram Khan, Courtnee Clough, Hans D. Ochs, David J. Rawlings, Andrew Scharenberg et Troy R. Torgerson. « Targeted Gene Editing Restores Regulated CD40L Expression and Function in X-HIGM T cells. » Journal of Immunology 196, n^o 1_Supplement (1 mai 2016) : 214.28. http://dx.doi.org/10.4049/jimmunol.196.supp.214.28.

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Abstract Loss of CD40L expression or function results in X-Linked Hyper-IgM Syndrome (X-HIGM), characterized by recurrent infections due to impaired immunoglobulin class-switching and somatic hypermutation. Previous attempts using retroviral gene transfer to correct murine CD40L expression restored immune function; however, treated mice developed lymphoproliferative disease, likely due to viral-promoter dependent constitutive CD40L expression. These observations highlight the importance of preserving endogenous gene regulation in order to safely correct this disorder. Here we report efficient, on-target, homology directed repair (HDR) editing of the CD40LG locus in primary human T cells using a combination of a TALEN-induced double-strand break and a donor template delivered by recombinant Adeno-Associated Virus (rAAV). HDR mediated insertion of a coding sequence (GFP or CD40L) upstream of the translation start site within Exon 1 allowed transgene expression to be regulated by endogenous CD40LG promoter/enhancer elements. Additionally, inclusion of the CD40LG 3′-untranslated region (3′-UTR) in the transgene preserved post-transcriptional regulation. Expression kinetics of the transgene paralleled that of endogenous CD40L in unedited T cells, both at rest and in response to T cell stimulation. The use of this method to edit X-HIGM patient T cells restored normal expression of CD40L and CD40-muIg binding, and rescued IgG class switching of naïve B-cells in vitro. These results demonstrate the feasibility of engineered nuclease-directed gene repair to restore endogenously regulated CD40L, and the potential for its use in T cell therapy for X-HIGM syndrome.

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Kutukculer, Necil, Neslihan Edeer Karaca, Guzide Aksu, Ayca Aykut, Erhan Pariltay et Ozgur Cogulu. « An X-Linked Hyper-IgM Patient Followed Successfully for 23 Years without Hematopoietic Stem Cell Transplantation ». Case Reports in Immunology 2018 (14 octobre 2018) : 1–4. http://dx.doi.org/10.1155/2018/6897935.

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When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P. jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (IVIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.Arg11Ter) mutation was found in CD40LG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serum IgM levels, CD40LG levels on activated T cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy.

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Kato, Kazunori, Yukari Masuta, Kei Tomihara, Katsunori Sasaki et Hirofumi Hamada. « A Novel Non-Cleavable Cell Surface Mutant of CD40-Ligand Induces Anti-Leukemic Immune Response and Prevent Systemic Inflammatory Reaction. » Blood 104, n^o 11 (16 novembre 2004) : 3174. http://dx.doi.org/10.1182/blood.v104.11.3174.3174.

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Abstract CD40-ligand (CD40L), a member of the TNF family, is expressed transiently on activated CD4-positive T cells and mediates cognate interaction between T cell and antigen-presenting cell (APC) such as dendritic cells. We and other investigators have reported previously that transduction of human leukemia cells with adenovirus encoding full-length CD40-ligand resulted in upregulation of immune costimulatory molecules, enhance APC activity and generation of CTL to leukemia B cells. However, CD40L is cleaved to a soluble form (sCD40L) by metalloproteases and high levels of sCD40L may contribute to the systemic inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, suggesting a potentially deleterious side effect of CD40L gene therapy. In this study we generated a non-cleavable mutant of CD40L to develop a potentially less toxic molecule for CD40L gene therapy. Four mutants of human CD40L (termed CD40Lm1, m2, m3 and m4) with point mutation of amino acids from E112 to P120 (suggested cleavage site) were created by RT-PCR and cloned into retrovirus and adenovirus vectors. These four mutants of CD40L were transduced into tumor cells and assessed sCD40L production by ELISA, demonstrating that all four mutants resulted in a fully non-cleavable mutant of CD40L. We also confirmed that CD40L mutants could stimulate CD40-positive B and dendritic cells and induce phenotypic alterations and IL-12 production. In order to examine systemic side effect of CD40L, we transplanted tumor cells expressing wild-type (CD40Lwt) or non-cleavable mutant of CD40L (CD40Lm3) in nude mice and have observed for one month period. Two weeks after transplantation, mice with tumors expressing CD40Lwt exhibited arthritis, systemic edema and slight diarrhea, but CD40Lm3 did not induce any systemic inflammatory effect. We also found increased plasma levels of sCD40L (>800 pg/ml) in mice transplanted with CD40Lwt transfectant but not in CD40Lm3 transplanted mice. Additionally, mice with CD40Lwt resulted in increased number of infiltrating mononuclear cells in the liver and kidney, whereas no inflammatory cells were observed in the liver of mice with CD40Lm3. Overall, non-cleavable mutant of CD40L is fully capable of inducing immune response with less toxic molecule and useful tool for CD40L gene therapy of leukemia and lymphoma.

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Yeh, Yu-Min, Peng-Chan Lin, Wu-Chou Su et Meng-Ru Shen. « CD40 Pathway and IL-2 Expression Mediate the Differential Outcome of Colorectal Cancer Patients with Different CSF1R c.1085 Genotypes ». International Journal of Molecular Sciences 22, n^o 22 (22 novembre 2021) : 12565. http://dx.doi.org/10.3390/ijms222212565.

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Colony-stimulating factor 1 receptor (CSF-1R) acts as the receptor for colony stimulating factor 1, a cytokine that controls the production, differentiation, and function of macrophages. Prior studies showed cancer patients harboring germline CSF1R c.1085A>G genetic variant had better survival. Here, primary tumor samples from a stage III colorectal cancer (CRC) cohort were analyzed by a targeted gene expression assay containing 395 immune-related genes to study the immune mechanism underlying the different outcomes. CRC patients with CSF1R c.1085 genotype A_G had a better disease-free and overall survival than those with CSF1R genotype A_A. Compared to the group of patients without CSF1R variant, higher CD40LG expression, a surface marker of T cells, was found in the tumor tissues of patients with CSF1R c.1085 variant. In parallel with the higher CD40LG gene expression, immunofluorescent staining also showed more CD3+CD40L+ T cell infiltrates in tumors with CSF1R c.1085 genotype A_G. Moreover, higher IL-2 expression, known to be regulated by CD40 pathway, was also observed in tumors with CSF1R c.1085 genotype A_G than genotype A_A. Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with CSF1R c.1085A>G variant is the potential mechanism explaining the different outcomes.

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Dong, Qiuting, Jinxia Zhao, Zhongqiang Yao, Xiangyuan Liu et Huiying He. « A Case Report of X-Linked Hyperimmunoglobulin M Syndrome with Lipoma Arborescens of Knees ». Case Reports in Medicine 2016 (2016) : 1–4. http://dx.doi.org/10.1155/2016/5797232.

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The X-linked hyperimmunoglobulin M syndrome (HIGM), caused by mutations in the CD40LG gene, is a kind of primary immunodeficiency disease (PID). Patients with X-linked HIGM are susceptible to infection as well as autoimmune diseases. Lipoma arborescens (LA) is a rare benign tumor, of which the pathogenesis mechanism has not been clearly understood. We report a case of HIGM combined with LA in a 22-year-old male patient. A new deletion mutation of CD40LG gene was detected in this case. The possible relationship between HIGM and LA was also discussed.

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Rigaud, Stéphanie, Eduardo Lopez-Granados, Sophie Sibéril, Geoffrey Gloire, Nathalie Lambert, Christelle Lenoir, Cindy Synaeve et al. « Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG ». Blood 118, n^o 2 (14 juillet 2011) : 252–61. http://dx.doi.org/10.1182/blood-2011-01-328849.

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Abstract The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus–driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAPG466X) that cosegregated with a rare polymorphism in CD40LG (CD40 ligandG219R). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAPG466X or CD40LG219R had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.

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Horrillo, Angélica, Tomás Fontela, Elena G. Arias-Salgado, Dolores Llobat, Gracia Porras, Matilde S. Ayuso et Consuelo González-Manchón. « Generation of mice with conditional ablation of the Cd40lg gene : new insights on the role of CD40L ». Transgenic Research 23, n^o 1 (13 septembre 2013) : 53–66. http://dx.doi.org/10.1007/s11248-013-9743-2.

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Brune, Zarina, Bharati Matta et Betsy Barnes. « IRF5 regulation of CD4+ T cell metabolism controls CD40L expression ». Journal of Immunology 208, n^o 1_Supplement (1 mai 2022) : 165.02. http://dx.doi.org/10.4049/jimmunol.208.supp.165.02.

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Abstract Systemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that results from failure of the immune system to distinguish “self” from “non-self”. Studies in our lab and others demonstrated that human SLE CD4+ T cells have elevated levels of IRF5 and increased metabolism, while Irf5 knockout murine CD4+ T cells show diminished utilization of oxidative phosphorylation and glycolysis, respectively. However, how IRF5 contributes to CD4+ T cell support of B cell function and dysfunction has not been fully elucidated. Here, using IRF5 KO C57BL/6J mice, we show that loss of IRF5 in CD4+ T cells directly contributes to defects in plasmablast generation. Examination of the CD40-CD40L interaction shows significant decreases in CD40L expression in Irf5 KO CD4+ T cells. Examination of Cd40lg transcript expression shows no difference in mRNA expression in Irf5 KO murine CD4+ T cells when compared to WT. This finding indicated a novel post-transcriptional regulatory role for IRF5. Examination of the canonical mTOR pathway, a key translational regulator, shows decreased phosphorylation of the S6 ribosomal protein upon loss of Irf5, indicating diminished activity of the mTOR pathway. mTOR inhibition with rapamycin in turn results in decreased CD40L expression, supporting a role for mTOR in CD40L regulation. As mTOR signaling is known to be regulated by cellular metabolism, we examined if loss of IRF5 results in altered T cell metabolism. We found that Irf5 KO T cells have decreased glucose metabolism and increased glutamine metabolism. This data has increased our understanding of how metabolism influences CD4+ T cell function and provided insight into novel post-translational regulatory roles for IRF5 via T cell metabolic regulation.

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López-Herrera, Gabriela, José Luis Maravillas-Montero, Alexander Vargas-Hernández, Laura Berrón-Ruíz, Emmanuel Ramírez-Sánchez, Marco Antonio Yamazaki-Nakashimada, Francisco Javier Espinosa-Rosales et Leopoldo Santos-Argumedo. « A novel CD40LG deletion causes the hyper-IgM syndrome with normal CD40L expression in a 6-month-old child ». Immunologic Research 62, n^o 1 (10 mars 2015) : 89–94. http://dx.doi.org/10.1007/s12026-015-8638-0.

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Shimoda, Michiko, Anna Bolduc, Mayuko Takezaki, Takeshi Tsubata et Pandelakis Koni. « Excess B cell CD40/CD40L signaling promotes CD4 T cell-mediated encephalomyelitis in mice (44.22) ». Journal of Immunology 186, n^o 1_Supplement (1 avril 2011) : 44.22. http://dx.doi.org/10.4049/jimmunol.186.supp.44.22.

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Abstract To test the pathogenic role of B cells under excess inflammatory CD40/CD40L signaling, experimental autoimmune encephalomyelitis (EAE) was induced in B cell specific CD40L transgenic (CD40LBTg) and C57BL/6 control mice by immunization with MOG35-55 peptide. Clinical symptoms were monitored using a 0-5 scoring system during days 10-30 after induction. Alternatively, MOG-specific CD4 TCR Tg (2D2) mice were crossed onto a CD40LBTg background and the incidence of spontaneous encephalomyelitis monitored at 4-35 weeks of age. Both CD40LBTg and control mice developed EAE with similar kinetics, with disease onset at around day 15-17 and the peak of disease score at around day 21-25. However, CD40LBTg mice showed significantly more severe disease than wild type mice with average peak clinical scores of 3.0 and 1.5, respectively. Higher frequencies of IL-17+ CD4 T cells were also observed in CD40LBTg mice compared to wild type mice at the EAE disease peak. Also, 60% (6/10) of 2D2 CD40LB double Tg mice showed spontaneous encephalomyelitis-like symptoms (severe hind and/or fore limb paralysis) between 4-6 weeks of age, with IL-17+ and IFNγ+ CD4 T cells in spleen and inguinal lymph nodes. Furthermore, even those without apparent EAE symptoms died before 30 weeks of age. None of the 2D2 or CD40LBTg mice showed such symptoms between 4-35 weeks of age. These results support the notion that excess B cell CD40/CD40L signaling promotes MOG-specific pathogenic CD4 T cell response.

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Menéndez, Méndez, Almansa, Ortega, Alonso, Suescun, Ferrando, Feced et Bermejo-Martin. « Simultaneous Depression of Immunological Synapse and Endothelial Injury is Associated with Organ Dysfunction in Community-Acquired Pneumonia ». Journal of Clinical Medicine 8, n^o 9 (6 septembre 2019) : 1404. http://dx.doi.org/10.3390/jcm8091404.

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Rationale: A depressed expression of antigen presentation is, along with endothelial dysfunction, a recognized signature of severe community-acquired pneumonia (CAP). We aimed to evaluate the expression of a number of genes involved in the immunological synapse in non-critically ill CAP patients with or without organ dysfunction and to profile endothelial biomarkers such as proendothelin-1 (proET1) and proadrenomedullin (proADM). Methods: A nested study in a prospective cohort in CAP patients was performed. Expression levels of major histocompatibility complex class II DR alpha (HLA-DRA), CD40 ligand (CD40LG), CD3E, CD28, and inducible T-cell costimulator (ICOS) were quantified by using droplet digital polymerase chain reaction and endothelial biomarkers by immunofluorescence. Results: Ninety-four patients were included, 44.7% of whom had organ failure in one or more organs. A significant decrease in the expression of the five genes with increased levels of proadrenomedullin (proADM) and proendothelin-1 (proET1) was found in CAP with organ failure. The depressed expression of HLA-DRA (odds ratio (OR), 2.94), CD40LG (OR, 3.90), and CD28 (OR, 3.48) was independently associated with organ failure after adjustment for age, Charlson score, and severity. Conclusions. CAP with organ failure showed depressed expression of immunological synapse genes with increased levels of biomarkers denoting endothelial damage. Simultaneous profiling of immunological and endothelial signatures could help in the early identification of organ failure in CAP and in the implementation of personalized treatment.

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Sivagami, S., R. Rathna, S. Nagavignesh, N. V. Ghone et M. Sivanandham. « In silico binding analysis of human CD40 ligand mimetic molecule, 3-(dimethylamino)-1-phenyl-1-propanone hydrochloride (3-DPH), with CD40 receptor molecules of various mammalian species ». Journal of Environmental Biology 42, n^o 2 (1 mars 2021) : 186–91. http://dx.doi.org/10.22438/jeb/42/2/mrn-1440.

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Aim: To investigate the binding of human CD40 ligand (CD40L) mimetic molecule, 3-(dimethylamino)-1-phenyl-1-propanone hydrochloride (3-DPH), with CD40 receptor (CD40R) molecules of Homo sapiens, Cavia porcellus, Cricetulus griseus, Macaca mulatta, Mus musculus, Oryctolagus cuniculus, Papio anubis and Rattus norvegicus species using bioinformatics tool. Methodology: Three-dimensional structures of CD40Rs and CD40Ls for various mammalian species were generated using the published crystal structure of human CD40 receptor-ligand complex by homology modelling using SWISS-MODEL tool. Furthermore, human CD40L mimetic molecule, 3-DPH was docked against the generated CD40R of various mammalian species using AUTODOCK 4.2. Results: Docking studies revealed that documented HIS78 and GLN79 residues of human CD40R were the key interaction residues, which interacted with human CD40L and 3-DPH. The CD40Rs of H. sapiens, C. porcellus, C. griseus, M. mulatta, M. musculus, O. cuniculus, P. anubis, and R. norvegicus bind with 3-DPH with a binding energy -4.67, -5.22, -5.19, -4.62, -4.85, -4.63, -4.51, and -4.86 kcal/mol, respectively. Interpretation: Molecular docking studies provide crucial insight into the binding affinity and interaction of 3-DPH at the active site of CD40R of the respective mammalian species. O. cuniculus and M. musculus species were found to be appropriate animal models for further evaluation of the therapeutic effect of human CD40L mimetic molecule Key words: 3-DPH, Animal model, CD40R, CD40L, Homo sapeins, Molecular docking

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Román-Fernández, I. V., G. A. Sánchez-Zuno, J. R. Padilla-Gutiérrez, S. Cerpa-Cruz, J. Hernández-Bello, Y. Valle, M. G. Ramírez-Dueñas, C. Carrillo et J. F. Muñoz-Valle. « The 3′-UTR (CA)n microsatellite on CD40LG gene as a possible genetic marker for rheumatoid arthritis in Mexican population : impact on CD40LG mRNA expression ». Clinical Rheumatology 37, n^o 2 (30 septembre 2017) : 345–53. http://dx.doi.org/10.1007/s10067-017-3853-9.

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Park, Heiyoung, Theo Heller et Barbara Rehermann. « Transcriptome analysis reveals distinct immune response profiles in HBeAg+ and HBeAg− HBV infection and in HBV/HDV co-infection ». Journal of Immunology 198, n^o 1_Supplement (1 mai 2017) : 158.18. http://dx.doi.org/10.4049/jimmunol.198.supp.158.18.

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Abstract In chronic hepatitis B virus (HBV) infection, HBeAg positivity is associated with an increase in liver inflammation and progression to liver cirrhosis and cancer. Super-infection with hepatitis D virus (HDV) results in more severe liver disease. The causative factors are unknown. To understand the unique immunopathogenesis of HBeAg+ chronic HBV infection and chronic HBV/HDV co-infection, we performed a comparative transcriptome analysis using peripheral blood mononuclear cells of 12 HBV infected patients (6 HBeAg+ vs. 6 HBeAg−), 10 HBV/HDV co-infected patients, and 12 uninfected controls using NanoString human immunology V2 panel. About half of the differentially expressed genes in HBeAg+ versus HBeAg− HBV patients were interferon-stimulated genes (ISGs), and 83% of these ISGs (5/6) were upregulated. Ingenuity Pathway Analysis identified IFNA2 and IFNL1 as the most activated upstream regulators associated with HBeAg+ status. In contrast, only 7 out of 31 differentially expressed genes in chronic HBV/HDV co-infection compared to chronic HBV infection were ISGs, which were either upregulated or downregulated, indicating that IFN-signature is marginally involved in the pathogenesis of chronic HBV/HDV co-infection. Instead, Ingenuity Pathway Analysis identified CD40LG and IL18 as the most activated upstream regulators, and IRF activation by cytosolic pattern receptors and B cell receptor signaling as the top canonical pathways associated with chronic HBV/HDV co-infection. Our data suggest that IFN signaling may play a role in the enhanced liver disease found in chronic HBeAg+ HBV infection, and that CD40LG and IL18 signaling may contribute to unique immunopathogenesis of chronic HDV/HBV co-infection.

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Pérez-Melgosa, Mercedes, Diane Hollenbaugh et Christopher B. Wilson. « Cutting Edge : CD40 Ligand Is a Limiting Factor in the Humoral Response to T Cell-Dependent Antigens ». Journal of Immunology 163, n^o 3 (1 août 1999) : 1123–27. http://dx.doi.org/10.4049/jimmunol.163.3.1123.

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Abstract CD40 ligand (CD40L) plays a crucial role in T cell-dependent B cell responses, but whether its abundance is a limiting factor in their development is unclear. This question was addressed in transgenic mice expressing the murine CD40L gene under the control of the IL-2-promoter (CD40Ltg+). The fraction of activated T cells from the CD40Ltg+ mice with detectable levels of surface CD40L was modestly greater (1.1- to 2-fold) than littermate controls and paralleled an ∼1.8-fold increase in CD40L mRNA abundance. In response to trinitrophenol (TNP)-keyhole limpet hemocyanin and tetanus/diphtheria vaccine, CD40Ltg+ mice developed higher titers of high-affinity IgG and IgG1 Ab than wild-type mice. In contrast, the Ab response of CD40Ltg+ and control mice was similar in response to the T-independent Ag TNP-Ficoll. These results suggest that a modest increment in expression of CD40L accelerates the development of T-dependent responses, and that CD40L plays a limiting role in the induction of high-affinity Ab and Ab-class switching.

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Curinga, Gabrielle, Sarah Leach, Swati Singh, Nick Hubbard, David Hagin, Karen Sommer, Iram Khan et al. « 316. Successful Editing of the CD40LG Locus in Human Hematopoietic Stem Cells ». Molecular Therapy 24 (mai 2016) : S127. http://dx.doi.org/10.1016/s1525-0016(16)33125-2.

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Le Coz, Carole, Melissa Trofa, Camille M. Syrett, Anna Martin, Harumi Jyonouchi, Soma Jyonouchi, Montserrat C. Anguera et Neil Romberg. « CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation ». Journal of Allergy and Clinical Immunology 141, n^o 6 (juin 2018) : 2308–11. http://dx.doi.org/10.1016/j.jaci.2018.02.010.

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Imai, Kohsuke, Mitsunobu Shimadzu, Takeo Kubota, Tomohiro Morio, Takeshi Matsunaga, Young-Dong Park, Akira Yoshioka et Shigeaki Nonoyama. « Female hyper IgM syndrome type 1 with a chromosomal translocation disrupting CD40LG ». Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1762, n^o 3 (mars 2006) : 335–40. http://dx.doi.org/10.1016/j.bbadis.2005.10.003.

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Kim, Hyung Young, Tae Min Um et Hee Ju Park. « A Novel Mutation in CD40LG Gene Causing X-Linked Hyper IgM Syndrome ». Indian Journal of Pediatrics 85, n^o 9 (15 décembre 2017) : 788–89. http://dx.doi.org/10.1007/s12098-017-2526-7.

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Li, Jiayun, Zhikai Wang et Douglas T. Fearon. « CD40 signaling induces type I interferon and immune control in mouse pancreatic cancer lacking the CXCL12-coat ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 241.37. http://dx.doi.org/10.4049/jimmunol.204.supp.241.37.

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Abstract Pancreatic ductal adenocarcinoma (PDA) has a low 5 year survival rate of 8.5% because of its late diagnosis and resistance to the existing therapies. Patients with PDA who are microsatellite stable do not respond to check point blockade immunotherapy due to impaired T cell infiltration, which is mediated by the CXCL12-coat on cancer cells (Wang Z, et al. bioRχiv). In mouse hepatic metastases established with PDA cells from the KPC model of PDA, Krt19-CRISPR/Cas9-edited tumors lacking the CXCL12-coat showed a type I interferon (IFN) response as well as T cell infiltration and activation compared to the control scramble tumors. By RNA FISH, we found that IFNb1 is dominantly produced by CD40+ cells, and not by SiglecH+ plasmacytoid dendritic cells. RNA sequencing data showed up-regulation of Cd40lg in the Krt19-edited tumors compared to the scramble tumors. Administration of antagonistic anti-CD40 antibody prior cancer cells inoculation abolished IFNb1 production, T cell accumulation and activation. To confirm the role of CD40, administration of agonistic anti-CD40 antibody to mice bearing wild type PDA tumors elicited intra-tumoral IFNb1 production in CD11b+ CD11c+ myeloid cells. The T cell infiltration and activation induced by agonistic anti-CD40 antibody treatment sensitized both subcutaneous pancreatic tumors and hepatic metastases to anti-PD1 treatment. These findings indicate that the expression of CD40L elicits an intra-tumoral type I IFN response that is required for immune control of PDA tumors in which CXCR4 signaling is impaired.

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De Maio, Diego Javier Prado, Bitha Narayanan, James La Porta, Usha Ganapathi, Ping Xie et Lori R. Covey. « Activation-dependent post-transcriptional regulation of CD40L mediates B cell development and survival in germinal centers ». Journal of Immunology 206, n^o 1_Supplement (1 mai 2021) : 63.03. http://dx.doi.org/10.4049/jimmunol.206.supp.63.03.

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Abstract We have described a posttranscriptional pathway of induced mRNA stability that occurs at late times of T cell activation and is engaged by the binding of a polypyrimidine tract-binding protein (PTBP1) complex to the 3′UTR of the CD40L transcript. We explored the in vivo role of this pathway by generating a mouse bearing a deletion of the CD40L stability element (termed CD40LΔ5) and found that Tfh cells harboring the stability defect expressed approximately 60% of WT CD40L. Importantly, this decrease in CD40L corresponded to a poorly elaborated germinal center (GC) response which included significantly decreased levels of switched antibodies, antibody-secreting cells, GL7+ B cells and differentiated GC B cell subsets. In contrast, there was little difference in either somatic hypermutation or affinity maturation between B cells from WT compared to CD40LD5 mice. Notably, both the number and percentage of early memory B cells and plasmablasts were significantly decreased indicating that CD40L expression linked to mRNA stability was critical for B cell differentiation. To understand the impact of this stability pathway on gene expression, CD19+ B cells from CD40LD5 immunized mice were transcriptionally profiled using RNAseq and pathways associated with cell survival and proliferation were downregulated and apoptotic pathways upregulated compared to WT B cells. Importantly, the level of AID mRNA was unchanged whereas c-myc expression was significantly reduced in GL7+ B cells. Together these findings reveal that the CD40L stability element plays a critical role in regulating CD40L expression in Tfh cells, which in turn supports the optimal proliferation and cell survival of high affinity GC B cells and the differentiation of B cell subsets.

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Qian, Zuanhao, Zhenglei Zhang et Yingying Wang. « T cell receptor signaling pathway and cytokine-cytokine receptor interaction affect the rehabilitation process after respiratory syncytial virus infection ». PeerJ 7 (12 juin 2019) : e7089. http://dx.doi.org/10.7717/peerj.7089.

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Background Respiratory syncytial virus (RSV) is the main cause of respiratory tract infection, which seriously threatens the health and life of children. This study is conducted to reveal the rehabilitation mechanisms of RSV infection. Methods E-MTAB-5195 dataset was downloaded from EBI ArrayExpress database, including 39 acute phase samples in the acute phase of infection and 21 samples in the recovery period. Using the limma package, differentially expressed RNAs (DE-RNAs) were analyzed. The significant modules were identified using WGCNA package, and the mRNAs in them were conducted with enrichment analysis using DAVID tool. Afterwards, co-expression network for the RNAs involved in the significant modules was built by Cytoscape software. Additionally, RSV-correlated pathways were searched from Comparative Toxicogenomics Database, and then the pathway network was constructed. Results There were 2,489 DE-RNAs between the two groups, including 2,386 DE-mRNAs and 103 DE-lncRNAs. The RNAs in the black, salmon, blue, tan and turquoise modules correlated with stage were taken as RNA set1. Meanwhile, the RNAs in brown, blue, magenta and pink modules related to disease severity were defined as RNA set2. In the pathway networks, CD40LG and RASGRP1 co-expressed with LINC00891/LINC00526/LINC01215 were involved in the T cell receptor signaling pathway, and IL1B, IL1R2, IL18, and IL18R1 co-expressed with BAIAP2-AS1/CRNDE/LINC01503/SMIM25 were implicated in cytokine-cytokine receptor interaction. Conclusion LINC00891/LINC00526/LINC01215 co-expressed with CD40LG and RASGRP1 might affect the rehabilitation process of RSV infection through the T cell receptor signaling pathway. Besides, BAIAP2-AS1/CRNDE/LINC01503/SMIM25 co-expressed with IL1 and IL18 families might function in the clearance process after RSV infection via cytokine-cytokine receptor interaction.

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Hayashi, Tomoko, Savita P. Rao, Pascal R. Meylan, Richard S. Kornbluth et Antonino Catanzaro. « Role of CD40 Ligand in Mycobacterium avium Infection ». Infection and Immunity 67, n^o 7 (1 juillet 1999) : 3558–65. http://dx.doi.org/10.1128/iai.67.7.3558-3565.1999.

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ABSTRACT Mycobacterium avium is a common opportunistic pathogen in immunocompromised patients such as those infected with human immunodeficiency virus. Although M. avium is an intracellular organism replicating predominantly in macrophages, disseminated M. avium infection is seen in AIDS patients with CD4+ cell counts of <50 cells/μl, suggesting a possible involvement of a T cell-macrophage interaction for the elimination of M. avium. To determine whether CD40-CD40 ligand (CD40L) interactions play a role in M. aviuminfection, we studied the ability of CD40L to restrict M. avium replication in human monocyte-derived macrophages (MDM) in vitro. MDM were infected with M. avium and cocultured with CD40L-transfected 293 cells for 7 days. Intracellular growth ofM. avium in these MDM was assessed by colony counting. CD40L-expressing cells inhibited growth of M. avium in MDM by 86.5% ± 4.2% compared to MDM cultured with control cells. These findings were verified by assays using purified, soluble recombinant human CD40L (CD40LT). CD40LT (5 μg/ml) inhibited intracellular growth of M. avium by 76.9% ± 18.0% compared to cells treated with medium alone. Inhibition by CD40LT was reduced by monoclonal antibodies (MAbs) against CD40 and CD40L. The inhibitory effect of CD40LT was not accompanied by enhancement of interleukin-12 (IL-12) production by M. avium-infected MDM, while CD40L-expressing cells stimulated IL-12 production by these cells. Treatment of M. avium-infected mice with MAb against murine CD40L resulted in recovery of larger numbers of organisms (0.8 to 1.0 log) from the spleens, livers, and lungs of these animals compared to infected mice which received normal immunoglobulin G. These results indicate that CD40-CD40L signaling may be an important step in host immune response against M. avium infection.

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Coit, Patrick, Lindsey B. De Lott, Bin Nan, Victor M. Elner et Amr H. Sawalha. « DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis ». Annals of the Rheumatic Diseases 75, n^o 6 (2 juin 2015) : 1196–202. http://dx.doi.org/10.1136/annrheumdis-2014-207116.

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ObjectiveTo investigate the inflammatory response in giant cell arteritis (GCA) by characterising the DNA methylation pattern within the temporal artery microenvironment.MethodsTwelve patients with non-equivocal histological evidence for GCA and 12 age-matched, sex-matched and ethnicity-matched controls with normal biopsies were studied. DNA was extracted from the affected portions of temporal artery tissue in patients with GCA and from histologically confirmed normal arteries in controls. Genome-wide DNA methylation status was evaluated using the Illumina Infinium HumanMethylation450 BeadChip Array. Differentially methylated loci between affected and unaffected arterial tissues were identified, and subsequent bioinformatic analysis performed. Immunohistochemistry was used to examine tissue expression patterns in temporal artery biopsies.ResultsWe identified 1555 hypomethylated CG sites (853 genes) in affected temporal artery tissue from patients with GCA compared with normal controls. Gene ontology enrichment analysis of hypomethylated genes revealed significant representation in T cell activation and differentiation pathways, including both TH1 and TH17 signatures. Our DNA methylation data suggest a role for increased activity of the calcineurin/nuclear factor of activated T cells (NFAT) signalling pathway in GCA, confirmed by immunohistochemistry showing increased expression and nuclear localisation of NFAT1. NFAT signalling downstream targets such as interleukin (IL)-21/IL-21R and CD40L were overexpressed in GCA-affected arteries. Further, proinflammatory genes including TNF, LTA, LTB, CCR7, RUNX3, CD6, CD40LG, IL2, IL6, NLRP1, IL1B, IL18, IL21, IL23R and IFNG were hypomethylated in the cellular milieu of GCA arteries.ConclusionsWe characterised the inflammatory response in GCA-affected arteries using ‘epigenetic immunophenotyping’ and identified molecules and pathways relevant to disease pathogenesis in GCA.

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Reckamp, Karen L., Jasmine A. McQuerry, Isa Mambetsariev, Rebecca Pharaon, Susan E. Yost, Jeremy Fricke, Tamara Mirzapoiazova et al. « Co-stimulatory and co-inhibitory immune markers in solid tumors with MET alterations ». Future Science OA 7, n^o 2 (février 2021) : FSO662. http://dx.doi.org/10.2144/fsoa-2020-0159.

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The implication of MET alterations in solid tumors and the immune microenvironment remains elusive. Formalin-fixed, paraffin-embedded samples of 21 patients with solid tumors harboring MET alterations were used for immunohistochemical staining. Extracted RNA was analyzed with the NanoString nCounter human PanCancer immune profiling panel (NanoString Technologies, Inc., WA, USA). Patients were diagnosed with lung (n = 10), breast (n = 5), genitourinary (n = 3) or colorectal cancer (n = 3). Eleven had a MET missense mutation, four had an exon 14 splice site mutation and six had MET amplification. CD6, CCL19, CD40LG, XCR1, MAGEA1, ATM and CCL19 genes were significantly differentially expressed in MET-altered cancers. MET alterations may have a role in various solid tumors as potential therapeutic targets and combination therapy candidates with immune checkpoint inhibitors.

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Lu, Qianjin, Ailing Wu, Laura Tesmer, Donna Ray, Neda Yousif et Bruce Richardson. « Demethylation of CD40LG on the Inactive X in T Cells from Women with Lupus ». Journal of Immunology 179, n^o 9 (18 octobre 2007) : 6352–58. http://dx.doi.org/10.4049/jimmunol.179.9.6352.

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Trivellin, Giampaolo, et Constantine A. Stratakis. « CD40LG duplications in patients with X-LAG syndrome commonly undergo random X-chromosome inactivation ». Journal of Allergy and Clinical Immunology 143, n^o 4 (avril 2019) : 1659. http://dx.doi.org/10.1016/j.jaci.2018.12.1017.

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Yuan, Manqiu, Jianying Pei, Ruihao Li, Lirong Tian, Xin He et Yanping Li. « CD40LG as a Prognostic Molecular Marker Regulates Tumor Microenvironment Through Immune Process in Breast Cancer ». International Journal of General Medicine Volume 14 (novembre 2021) : 8833–46. http://dx.doi.org/10.2147/ijgm.s336813.

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Kim, Jae Heon, Hee Jo Yang, Sung Sik Choi, Hong J. Lee et Yun Seob Song. « Changes of proapoptotic and antiapoptotic genes affect sensitivity to apoptotic stimuli in impaired contractility due to long term bladder outlet obstruction ». PLOS ONE 17, n^o 12 (27 décembre 2022) : e0279503. http://dx.doi.org/10.1371/journal.pone.0279503.

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Introduction The normal biological process that necessitates cell removal greatly depends on apoptosis. Long term bladder outlet obstruction (BOO) causes damaged smooth muscle cells to undergo apoptosis. However, smooth muscle cell apoptosis that BOO causes is not well known in impaired bladder contractility. Therefore, we designed this study to investigate whether long-term BOO could induce apoptosis activities and to obtain an expression profile of apoptosis related genes. Materials and methods We used 10 Sprague-Dawley six-week-old female rats. We separated them equally into two groups: a sham intervention group (group 1) and an eight-week BOO group (group 2). We conducted cystometric evaluation eight weeks following BOO onset, with processing of bladder tissue for PCR array. Every array comprised 84 genes, which were established to contribute to an apoptosis response, cell differentiation and metabolism, and 12 sequences were established for the regulation of loading and the quality of cDNA. We performed real-time PCR. Changes in gene expression presented as a fold increase/decrease. Alterations of more than two-fold constituted the cut-off determining expression. Results Group 2 had a greater bladder weight and Impaired bladder contractility. Immunofluorescent staining with CAS3, TUNEL showed increased in the BOO group. In comparison to group 1, group 2 exhibited an at least two-fold upregulation in five genes, the Bcl-2 (15.1), Birc5 (5.8), Cd40lg (7.5), Il10 (16.2), and Naip2 (13.2). They also demonstrated at least a two-fold downregulation in the PRLR (-18.1) gene. Genes Bcl2ald, Circ5, Cd40lg, Il10, Naip2, and PRLR were among the genes with activity against apoptosis. TNF, STAT3 and TP53 mediated the effect that genes had on one another. Conclusion This study demonstrated that the relative ratios of pro- and antiapoptotic genes determine bladder cell sensitivity cells to apoptotic stimuli in impaired contractility caused by long term BOO. Although we cannot confirm whether this finding is the result of the decompensated phase of the bladder or the process, the gene expression profiles could explain molecular mechanisms of apoptosis in impaired bladder contractility caused by long-term BOO with further studies.

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McDyer, John F., Mark Dybul, Theresa J. Goletz, Audrey L. Kinter, Elaine K. Thomas, Jay A. Berzofsky, Anthony S. Fauci et Robert A. Seder. « Differential Effects of CD40 Ligand/Trimer Stimulation on the Ability of Dendritic Cells to Replicate and Transmit HIV Infection : Evidence for CC-Chemokine-Dependent and -Independent Mechanisms ». Journal of Immunology 162, n^o 6 (15 mars 1999) : 3711–17. http://dx.doi.org/10.4049/jimmunol.162.6.3711.

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Abstract The role of exogenous stimulation of CD40 by CD40 ligand (CD40L) in dendritic cell (DC) maturation, CC-chemokine production, and CCR5 receptor expression was examined using a soluble trimeric CD40L agonist protein (CD40LT). Stimulation of monocyte-derived DCs with CD40LT enhanced the production of the CC-chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES and diminished surface expression of CCR5. Based on these findings, the functional role of CD40LT stimulation on the ability of DCs to replicate and transmit HIV viral infection was studied. The addition of CD40LT to cocultures of naive CD4+ T cells and autologous DCs (T/DC) infected with the macrophage-tropic isolate, HIVBaL, caused a striking reduction in reverse transcriptase (RT) activity after 10 and 14 days of culture. The addition of a mixture of Abs against CC-chemokines abrogated the decrease in RT activity, demonstrating that the inhibitory effect mediated by CD40LT was CC-chemokine-dependent. In contrast, the presence of CD40LT in T/DC cocultures infected with the T cell-tropic isolate, HIVIIIB, caused an increase in RT activity that was CC-chemokine-independent. Of note, CD40LT stimulation also inhibited RT activity in cultures containing macrophage-tropic virus (HIVBaL)-infected DC only. However, in contrast to the results seen in the T/DC cocultures, CD40LT stimulation inhibited RT activity in cultures of DCs alone in a CC-chemokine-independent manner. Together, these results show that CD40LT stimulation of DCs suppresses HIV replication and transmission to CD4+ T cells by two potentially different mechanisms.

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Apoil, P. A., E. Kuhlein, A. Robert, H. Rubie et A. Blancher. « HIGM syndrome caused by insertion of an AluYb8 element in exon 1 of the CD40LG gene ». Immunogenetics 59, n^o 1 (5 décembre 2006) : 17–23. http://dx.doi.org/10.1007/s00251-006-0175-5.

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Campos-Neto, Antonio, Pamela Ovendale, Teresa Bement, Thelma A. Koppi, William C. Fanslow, Marcos A. Rossi et Mark R. Alderson. « Cutting Edge : CD40 Ligand Is Not Essential for the Development of Cell-Mediated Immunity and Resistance to Mycobacterium tuberculosis ». Journal of Immunology 160, n^o 5 (1 mars 1998) : 2037–41. http://dx.doi.org/10.4049/jimmunol.160.5.2037.

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Abstract It has been proposed that the induction of cellular immunity and resistance to intracellular pathogens is dependent upon CD40 ligand (CD40L). In the present study we show that this proposal is not ubiquitously supported. Mice genetically deficient in CD40L (CD40LKO) were resistant to i.v. infection with Mycobacterium tuberculosis when assessed by survival and bacteriologic burden in the spleen, liver, and lungs. Infected CD40LKO mice developed granulomas that lacked epithelioid cells and were less numerous and markedly smaller than those observed in control mice. Upon stimulation with purified protein derivative of M. tuberculosis,CD4+ T cells from infected CD40LKO mice proliferated and produced high levels of IFN-γ but not IL-4. Finally, spleen cells from CD40LKO mice stimulated with M. tuberculosis produced IL-12, TNF, and nitric oxide levels comparable to those produced by control cells. In contrast to original proposals, these data clearly show that protective Th1 immunity can be achieved against intracellular pathogens (e.g., Mycobacterium) independently of CD40L.

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Nimri, S., D. Atkinson et S. Stutes. « M199 X- LINKED HYPER-IGM SYNDROME WITH CD40LG MUTATION IN A FEMALE PATIENT AND HER MALE SIBLING ». Annals of Allergy, Asthma & ; Immunology 127, n^o 5 (novembre 2021) : S108. http://dx.doi.org/10.1016/j.anai.2021.08.340.

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Chen, Yixiang, Chloé Peubez, Sandrine Jayne, Gabriella Kocsis-Fodor, Martin J. S. Dyer et Salvador Macip. « Differential activation of pro-survival pathways in response to CD40LG/IL4 stimulation in chronic lymphocytic leukaemia cells ». British Journal of Haematology 184, n^o 5 (20 avril 2018) : 867–69. http://dx.doi.org/10.1111/bjh.15197.

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Tsai, Hu-Yuan, Hsin-Hui Yu, Yin-Hsiu Chien, Kuan-Hua Chu, Yu-Lung Lau, Jyh-Hong Lee, Li-Chieh Wang, Bor-Luen Chiang et Yao-Hsu Yang. « X-linked hyper-IgM syndrome with CD40LG mutation : Two case reports and literature review in Taiwanese patients ». Journal of Microbiology, Immunology and Infection 48, n^o 1 (février 2015) : 113–18. http://dx.doi.org/10.1016/j.jmii.2012.07.004.

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Fujisawa, Manabu, Tran B. Nguyen, Yoshiaki Abe, Yasuhito Suehara, Kota Fukumoto, Sakurako Suma, Kensuke Usuki et al. « Germinal Center B Cells Derived from TET2-Mutated Clonal Hematopoiesis Provide a Microenviromental Niche for Tumor Cells in Angioimmunoblastic T-Cell Lymphoma ». Blood 138, Supplement 1 (5 novembre 2021) : 445. http://dx.doi.org/10.1182/blood-2021-149983.

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Abstract Background Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2mutations, whereas the G17V RHOA mutation in TET2-mutated immature cells facilitates development of T follicular helper (T FH)-like tumor cells. Notably, we and others have reported that immune cells derived from ACH with TET2 mutations infiltrate AITL tissues. However, how ACH-derived immune cells function as a microenvironmental niche in AITL remains largely unknown. Objective To elucidate the role of TET2-mutated immune cells in AITL tumorigenesis. Methods The G17V RHOA transgenic mice were crossed with mice lacking Tet2 in all blood cells (Mx-Crex Tet2f/f, A) and in T cells (Cd4-Crex Tet2f/f, B), respectively. Single-cell RNA sequencing (Sc-seq) was performed on >60,000 cells from AITL in mice (AITLm, n=2) and human (AITLh, n=5), and their controls to reveal the immune profiles. We used Seurat and Monocle3 pipelines for analysis of Sc-seq. Whole genome bisulfite sequencing (WGBS) was used to analyze the methylome of germinal center B (GCB) cells in AITLm and control. Results AITLm occurred only in A, but not in B. Then, we intraperitoneally transplanted Cd4 + tumor-containing cells together with various lineages of immune cells sorted from AITLm into nude mice. AITLm developed only when B-lineage cells were cotransplanted with Cd4 + tumor-containing cells. Unsupervised clustering of the Sc-seq data identified 6 T-, 6 B- and 3 myeloid clusters in AITLm. B-cell clusters were annotated into naïve B-, memory B-, GCB-, and plasma clusters along the B-cell differentiation through Geneset variable analysis (GSVA) and trajectory analysis. We found that the aberrant GCB clusters, simultaneously exhibiting DZ-like proliferation markers (Aicda and Mki67) and LZ-like activation markers (Cd40, Cd83) were markedly expanded in AITLm. Geneset Enrichment Analysis (GSEA) revealed that MYC targets and other signaling pathways involved in cell proliferation were highly enriched in the GCB clusters in AITLm. WGBS showed that the number of hypermethylated regions (HyperDMRs) was markedly higher than that of hypomethylated regions (HypoDMRs) at all the regions; promoters, exons, introns, untranslated and intergenic regions. Among HyperDMRs, Atp13a2, Pdzd2, Rapgef4, Irf4 and Egr3 expressions were downregulated in the GCB clusters of Sc-seq in AITLm. Remarkably, the number of BCR clones in GCB of AITLm were significantly less than those in controls. In addition, in AITLm mice, the number of somatic mutations in GCB cells was significantly higher than that in T FH-like tumor cells. Remarkably, we detected unique core histone mutations in the GCB cells of AITLm, including the recurrent p.Ser87Asn Histone3 mutations. Next, In silico network analysis using Sc-seq data between GCB and T FH-like clusters identified that 11 interactions, including Cd40-Cd40lg were significantly enhanced in AITLm compared to controls. Flowcytomeric analysis revealed that cell-surface expression of Cd40 were significantly higher in the GCB cells of AITLm than those of control. Pathologically, the follicular structure was disrupted in AITLm. Consequently, Cd40lg +Cd4 +tumor cells and Cd40 +Cd19 + cells were both diffusely distributed and sometimes localized adjacent to each other. Finally, administration of an anti-Cd40lg antibody prolonged the survival of nude mice transplanted with AITLm. In AITLh with TET2 mutations, unsupervised clustering of Sc-seq identified T-, B-, and myeloid-cell clusters and a cluster characterized by proliferative markers. In B-lineage cells, 9 clusters were re-clustered and annotated to naïve or memory B-, GCB- and plasmablast clusters under the same manner of mouse data. Gene ontology analysis from differential expression genes in each cluster showed that the GCB- and CD40-related genesets were enriched not only in the GCB cluster but also in the naive to memory B clusters. Furthermore, the AITL-B-specific geneset, which referred from genes (CD40, CD83, AICDA, MKI67) highly expressed in the GCB cluster in AITLm was enriched not only in the GCB cluster, but also in the naive to memory B clusters in AITLh. Conclusion This study suggests a new concept that ACH-derived GCB cells with TET2 mutations can undergo independent clonal evolution and function as microenvironmental cells to support tumorigenesis in AITL via the CD40-CD40LG axis. Disclosures Usuki: Astellas Pharma Inc.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding.

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Leal-Calvo, Thyago, Charlotte Avanzi, Mayara Abud Mendes, Andrej Benjak, Philippe Busso, Roberta Olmo Pinheiro, Euzenir Nunes Sarno, Stewart Thomas Cole et Milton Ozório Moraes. « A new paradigm for leprosy diagnosis based on host gene expression ». PLOS Pathogens 17, n^o 10 (25 octobre 2021) : e1009972. http://dx.doi.org/10.1371/journal.ppat.1009972.

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Transcriptional profiling is a powerful tool to investigate and detect human diseases. In this study, we used bulk RNA-sequencing (RNA-Seq) to compare the transcriptomes in skin lesions of leprosy patients or controls affected by other dermal conditions such as granuloma annulare, a confounder for paucibacillary leprosy. We identified five genes capable of accurately distinguishing multibacillary and paucibacillary leprosy from other skin conditions. Indoleamine 2,3-dioxygenase 1 (IDO1) expression alone was highly discriminatory, followed by TLR10, BLK, CD38, and SLAMF7, whereas the HS3ST2 and CD40LG mRNA separated multi- and paucibacillary leprosy. Finally, from the main differentially expressed genes (DEG) and enriched pathways, we conclude that paucibacillary disease is characterized by epithelioid transformation and granuloma formation, with an exacerbated cellular immune response, while multibacillary leprosy features epithelial-mesenchymal transition with phagocytic and lipid biogenesis patterns in the skin. These findings will help catalyze the development of better diagnostic tools and potential host-based therapeutic interventions. Finally, our data may help elucidate host-pathogen interplay driving disease clinical manifestations.

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Wang, Yingying, Yu Xu, Qingquan Hua, Yang Jiang, Peiqiang Liu, Wei Zhang et Rong Xiang. « Novel Prognostic Model Based on Immune Signature for Head and Neck Squamous Cell Carcinoma ». BioMed Research International 2020 (19 octobre 2020) : 1–9. http://dx.doi.org/10.1155/2020/4725314.

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Background. Deciphering the immune characteristics within tumors and identifying the immune signals related to the prognostic factor are helpful for the treatment and management of tumor patients. However, systematic analysis of immune signatures in head and neck squamous cell carcinoma (HNSCC) remains largely unstudied. Methods. A total of 718 immune-related genes were extracted from RNA sequencing data from 519 HNSCC patients in the TCGA database, and survival analysis with integrated bioinformatics analyses was performed to build the final predictive prognosis model. Results. The 178 survival-associated genes ( P < 0.05 ) participated in important immune functions, including immune cell activation and migration. Multivariate regression analysis using 93 genes ( P < 0.01 ), together with survival-associated clinicopathological parameters, identified 35 independent prognostic factors. The most significant 8 independent factors were CD3E, CD40LG, TNFRSF4, CD3G, CD5, ITGA2B, ABCB1, and TNFRSF13b. The final prognostic model achieved outstanding predictive efficiency with the highest AUC of 0.963. Conclusion. Our prognostic model based on the immune signature could effectively predict the prognosis of HNSCC patients, providing novel predictive biomarkers and potential therapeutic targets for HNSCC patients.

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Sun, Liping, Dandan Wang, Yan Xu, Wenxiu Qi et Yanbo Wang. « Evidence of TCM Theory in Treating the Same Disease with Different Methods : Treatment of Pneumonia with Ephedra sinica and Scutellariae Radix as an Example ». Evidence-Based Complementary and Alternative Medicine 2020 (28 novembre 2020) : 1–23. http://dx.doi.org/10.1155/2020/8873371.

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Pneumonia is a serious global health problem and the leading cause of mortality in children. Antibiotics are the main treatment for bacterial pneumonia, but there are serious drug resistance problems. Traditional Chinese medicine (TCM) has been used to treat diseases for thousands of years and has a unique theory. This article takes the treatment of pneumonia with Ephedra sinica as a representative hot medicine and Scutellariae Radix as a representative cold medicine as an example. We explore and explain the theory of treating the same disease with different TCM treatments. Using transcriptomics and network pharmacology methods, GO, KEGG enrichment, and PPI network construction were carried out, demonstrating that Ephedra sinica plays a therapeutic role through the NF-κB and apoptosis signaling pathways targeting PLAU, CD40LG, BLC2L1, CASP7, and CXCL8. The targets of Scutellariae Radix through the IL-17 signaling pathway are MMP9, CXCL8, and MAPK14. Molecular docking technology was also used to verify the results. In short, our results provide evidence for the theory of treating the same disease with different treatments, and we also discuss future directions for traditional Chinese medicine.

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Tsuchiya, Yukako, Taku Naito, Mari Tenno, Mitsuo Maruyama, Haruhiko Koseki, Ichiro Taniuchi et Yoshinori Naoe. « ThPOK represses CXXC5, which induces methylation of histone H3 lysine 9 in Cd40lg promoter by association with SUV39H1 : implications in repression of CD40L expression in CD8+ cytotoxic T cells ». Journal of Leukocyte Biology 100, n^o 2 (19 février 2016) : 327–38. http://dx.doi.org/10.1189/jlb.1a0915-396rr.

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Shimoda, Michiko, Anna Bolduc, Domonica Powell, Yutetsu Ametani, Mayuko Takezaki, Stephen Nutt, Masahito Kamanaka et al. « A critical role of dendritic cells in CD8 T cell IL-10 expression during inflammatory response triggered by CD40-activated B cells (159.16) ». Journal of Immunology 188, n^o 1_Supplement (1 mai 2012) : 159.16. http://dx.doi.org/10.4049/jimmunol.188.supp.159.16.

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Abstract CD40LBTg mice, expressing a CD40 ligand (CD40L) transgene on B cells, represent a model for human diseases where B cells aberrantly express CD40L or receive excess CD40/CD40L signaling under inflammatory conditions. Here, we show that B cells expressing transgenic CD40L are capable of priming CD8 T cells and generate strong antigen-specific cytotoxicity. Adoptively transferred SIINFEKL peptide-loaded B cells from CD40LBTg but not wild type mice were able to activate self-reactive OT-I CD8 T cells upon immunization with OVA plus alum and trigger diabetes in RIP-OVA mice by enhancing the help of endogenous self-reactive CD4 T cells. CD40L expressing B cells also trigger spontaneous activation of splenic CD8 T cells, which rapidly up-regulate PD-1, Blimp-1 and LAG-3 and lose cytotoxicity along with IL-10 expression via interaction with PDL-1hi CD11c+ dendritic cells in T cell zones. Thus, CD11c+ dendritic cells from CD40LBTg mice exhibit regulatory phenotype, which block granzyme B expression and preferentially induce IL-10 expression in activated CD8 T cells. These results demonstrate that constitutive CD40 signaling on B cells under inflammation increases the risk of breaking peripheral CD8 T cell tolerance. However, the presence of CD40-activated B cells results in PDL-1hi CD11c+ dendritic cells, which exhibit a regulatory role to dampen harmful self-reactive cytotoxicity by promoting IL-10 expression in CD8 T cells.

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Zhou, Ying, Jun Yuan, Yujun Pan, Yiping Fei, Xiangning Qiu, Nan Hu, Yongqi Luo et al. « T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus ». Clinical Immunology 132, n^o 3 (septembre 2009) : 362–70. http://dx.doi.org/10.1016/j.clim.2009.05.011.

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Assing, Kristian, Kaspar René Nielsen, Helene Broch Tenstad, Marianne Antonius Jakobsen, Christian Nielsen, Dorthe Grosen et Ulla Birgitte Hartling. « Association between neutropenia and IgG antineutrophil antibodies in a case of CD40LG deficiency due to two novel mutations ». Clinical Case Reports 8, n^o 2 (25 décembre 2019) : 313–16. http://dx.doi.org/10.1002/ccr3.2621.

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Silva, Cláudia Regina Santos, Joice Matos Biselli-Périco, Bruna Lancia Zampieri, Wilson Araujo Silva, Jorge Estefano Santana de Souza, Matheus Carvalho Bürger, Eny Maria Goloni-Bertollo et Érika Cristina Pavarino. « Differential Expression of Inflammation-Related Genes in Children with Down Syndrome ». Mediators of Inflammation 2016 (2016) : 1–8. http://dx.doi.org/10.1155/2016/6985903.

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Objective. The aim of the study was to investigate the expression patterns of a specific set of genes involved in the inflammation process in children with Down Syndrome (DS) and children without the syndrome (control group) to identify differences that may be related to the immune abnormalities observed in DS individuals.Method. RNA samples were obtained from peripheral blood, and gene expression was quantified using the TaqMan® Array Plate Human Inflammation Kit, which facilitated the investigation into 92 inflammation-related genes and four reference genes using real-time polymerase chain reaction (qPCR).Results. Twenty genes showed differential expression in children with DS; 12 were overexpressed (PLA2G2D,CACNA1D,ALOX12,VCAM1,ICAM1,PLCD1,ADRB1,HTR3A,PDE4C,CASP1,PLA2G5,andPLCB4), and eight were underexpressed (LTA4H,BDKRB1,ADRB2,CD40LG,ITGAM,TNFRSF1B,ITGB1,andTBXAS1). After statistically correcting for the false discovery rate, only the genesBDKRB1andLTA4Hshowed differential expression, and both were underexpressed within the DS group.Conclusion. DS children showed differential expression of inflammation-related genes that were not located on chromosome 21 compared with children without DS. TheBDKRB1andLTA4Hgenes may differentiate the case and control groups based on the inflammatory response, which plays an important role in DS pathogenesis.

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Lin, S. C., et J. Stavnezer. « Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter. » Molecular and Cellular Biology 16, n^o 9 (septembre 1996) : 4591–603. http://dx.doi.org/10.1128/mcb.16.9.4591.

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Interaction between CD40 on B cells and CD40 ligand (CD40L) on T cells has been shown to mediate T-cell contact help for B-cell proliferation, differentiation, and immunoglobulin isotype switching. It has recently been shown that cross-linking CD40 on mouse B cells induces germ line gamma1 and epsilon transcripts and that interleukin-4 synergizes with CD40 signaling to further induce these germ line transcripts. Germ line transcripts have been shown to be required for class switch recombination. Here we show that signaling via CD40 increases expression of a transiently transfected luciferase reporter plasmid driven by the germ line Cgamma1 promoter in M12.4.1 B-lymphoma cells. By linker-scanning mutation analysis of the promoter, we have identified a CD40-responsive region (CD40RR) which is able to confer inducibility by CD40L to a minimal c-fos promoter. The CD40RR contains three binding sites for NF-kappaB/Rel proteins which are each required for maximal induction of CD40RR activity by CD40L. Binding of the NF-kappaB/Rel proteins p50, p65, c-Rel, and RelB to the CD40RR is induced by CD40 signaling in M12.4.1 cells and in splenic B cells. Cotransfection of expression plasmids for p50 and p65 or p50 and RelB, but not c-Rel, into M12.4.1 cells transactivates the CD40RR and the germ line gamma1 promoter. These data demonstrate that NF-kappaB Rel proteins activated by CD40 ligation play an important role in induction of the germ line Cgamma1 promoter.

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Callard, R. E., S. H. Smith, J. Herbert, G. Morgan, M. Padayachee, S. Lederman, L. Chess, R. A. Kroczek, W. C. Fanslow et R. J. Armitage. « CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers. » Journal of Immunology 153, n^o 7 (1 octobre 1994) : 3295–306. http://dx.doi.org/10.4049/jimmunol.153.7.3295.

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Abstract Hyper-IgM syndrome is a rare immunodeficiency characterized by low or absent IgG, IgA, and IgE with normal or elevated levels of IgM. It can occur as an acquired or familial disorder with either X-linked or autosomal modes of inheritance. The X-linked form (HIGM1) is a result of mutations in the CD40 ligand (CD40L) gene, but the defect in non-X-linked forms of the disease (HIM) has not been determined. We show here that CD40L expression on activated T cells from non-X-linked patients can be detected by CD40Fc, 5c8 Mab, and anti-TRAP, whereas activated T cells from HIGM1 patients either had no detectable CD40L (Type I), or stained with anti-TRAP but not CD40Fc or 5c8 (Type II). Activated T cells from obligate carriers varied from low to normal expression of CD40L. B cells from HIGM1 and non-X-linked HIM patients proliferated in response to CD40L. Costimulation of B cells from HIGM1, from sporadic HIM, or from non-X-linked HIM patients with CD40L plus IL-2 resulted in some IgM production, but no significant IgG or IgA. Costimulation with CD40L plus IL-10 resulted in significant IgG and/or IgA secretion by B cells from some HIGM1 patients, but consistently failed to stimulate IgG or IgA secretion by B cells from non-X-linked patients. In addition, costimulation with CD40L and IL-4 failed to induce IgE secretion by B cells from one non-X-linked HIM patient, and induced a weak response in another. These results suggest that patients with non-X-linked forms of HIM may have an intrinsic B cell defect preventing heavy chain switching, which is not related to expression of CD40L.

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Wang, Tian-Jiao, Li-Fang Wu, Junguo Chen, Wen Zhu, Hua Wang, Xiao-Lin Liu et Yi-Qun Teng. « X-linked hyper-IgM syndrome complicated with interstitial pneumonia and liver injury : a new mutation locus in the CD40LG gene ». Immunologic Research 67, n^o 4-5 (octobre 2019) : 454–59. http://dx.doi.org/10.1007/s12026-019-09098-4.

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Haebe, Sarah, Tanaya Shree, Anuja Sathe, Grady Day, Debra K. Czerwinski, Susan M. Grimes, HoJoon Lee et al. « Single-cell analysis can define distinct evolution of tumor sites in follicular lymphoma ». Blood 137, n^o 21 (27 mai 2021) : 2869–80. http://dx.doi.org/10.1182/blood.2020009855.

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Abstract Tumor heterogeneity complicates biomarker development and fosters drug resistance in solid malignancies. In lymphoma, our knowledge of site-to-site heterogeneity and its clinical implications is still limited. Here, we profiled 2 nodal, synchronously acquired tumor samples from 10 patients with follicular lymphoma (FL) using single-cell RNA, B-cell receptor (BCR) and T-cell receptor sequencing, and flow cytometry. By following the rapidly mutating tumor immunoglobulin genes, we discovered that BCR subclones were shared between the 2 tumor sites in some patients, but in many patients, the disease had evolved separately with limited tumor cell migration between the sites. Patients exhibiting divergent BCR evolution also exhibited divergent tumor gene-expression and cell-surface protein profiles. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper (Tfh) cell abundance. We further observed enrichment of particular ligand-receptor pairs between tumor and Tfh cells, including CD40 and CD40LG, and a significant correlation between tumor CD40 expression and Tfh proliferation. Our study may explain discordant responses to systemic therapies, underscores the difficulty of capturing a patient’s disease with a single biopsy, and furthers our understanding of tumor-immune networks in FL.

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Kaur, Sukhbir, Duha Awad, Richard P. Finney, Thomas J. Meyer, Satya P. Singh, Margaret C. Cam, Baktiar O. Karim, Andrew C. Warner et David D. Roberts. « CD47-Dependent Regulation of Immune Checkpoint Gene Expression and MYCN mRNA Splicing in Murine CD8 and Jurkat T Cells ». International Journal of Molecular Sciences 24, n^o 3 (30 janvier 2023) : 2612. http://dx.doi.org/10.3390/ijms24032612.

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Elevated expression of CD47 in some cancers is associated with poor survival related to its function as an innate immune checkpoint when expressed on tumor cells. In contrast, elevated CD47 expression in cutaneous melanomas is associated with improved survival. Previous studies implicated protective functions of CD47 expressed by immune cells in the melanoma tumor microenvironment. RNA sequencing analysis of responses induced by CD3 and CD28 engagement on wild type and CD47-deficient Jurkat T lymphoblast cells identified additional regulators of T cell function that were also CD47-dependent in mouse CD8 T cells. MYCN mRNA expression was upregulated in CD47-deficient cells but downregulated in CD47-deficient cells following activation. CD47 also regulated alternative splicing that produces two N-MYC isoforms. The CD47 ligand thrombospondin-1 inhibited expression of these MYCN mRNA isoforms, as well as induction of the oncogenic decoy MYCN opposite strand (MYCNOS) RNA during T cell activation. Analysis of mRNA expression data for melanomas in The Cancer Genome Atlas identified a significant coexpression of MYCN with CD47 and known regulators of CD8 T cell function. Thrombospondin-1 inhibited the induction of TIGIT, CD40LG, and MCL1 mRNAs following T cell activation in vitro. Increased mRNA expression of these T cell transcripts and MYCN in melanomas was associated with improved overall survival.

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