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Comparison of B Cell Variable Region Gene Segment Characteristics in Neuro-autoantibodies. 神经自身抗体中 B 细胞可变区基因片段特征的比较
ImmunoHorizons Pub Date : 2024-10-01 DOI: 10.4049/immunohorizons.2400037
Hend Abd El Baky, Nadav I Weinstock, Gull Zareen Khan Sial, Mark D Hicar
{"title":"Comparison of B Cell Variable Region Gene Segment Characteristics in Neuro-autoantibodies.","authors":"Hend Abd El Baky, Nadav I Weinstock, Gull Zareen Khan Sial, Mark D Hicar","doi":"10.4049/immunohorizons.2400037","DOIUrl":"10.4049/immunohorizons.2400037","url":null,"abstract":"<p><p>Autoimmune pediatric neurologic diseases have variable phenotypes and presentations, making diagnosis challenging. The pathologic mechanisms are also distinct, including cell-mediated and Ab-mediated autoimmunity, paraneoplastic syndromes, and postinfectious processes. In recent years a number of studies have described the characteristics of the autoantibodies involved in a number of these diseases. Some of the described Abs use a restricted set of variable gene segments. We sought to compare the Ab characteristics of autoantibodies related to some of the more common disorders to discover whether specific Ab signatures are universally associated with neuroautoimmune diseases. We initially performed a literature review to summarize the Ab characteristics of autoantibodies related to some of the more common disorders, including N-methyl-d-aspartate receptor (NMDAR) and leucine-rich, glioma-inactivated 1 (LGI-1). Next, we performed data analysis from selected studies that sequenced Ig genes to further characterize NMDAR and LGI-1 autoantibodies including CDR3 length distribution, variable gene sequence usage, and isotype use. We found that CDR3 length of NMDAR autoantibodies was normally distributed whereas the CDR3 length distribution of LGI-1 autoantibodies was skewed, suggesting that there is no global structural restriction on types of autoantibodies that can cause encephalitis. We also found that IgG1-IgG3 were the main NMDAR autoantibody isotypes detected, while IgG4 was the major isotype used in autoantibodies from LGI-1 encephalitis. These findings are useful for our understanding of autoimmune encephalitis and will help facilitate better diagnosis and treatment of these conditions in the future.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 10","pages":"740-748"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chemokine Receptor CCR2 Is Protective toward Outer Hair Cells in Chronic Suppurative Otitis Media. 趋化因子受体 CCR2 对慢性化脓性中耳炎患者的外耳道毛细胞具有保护作用
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400064
Ankur Gupta, Viktoria Schiel, Ritwija Bhattacharya, Kourosh Eftekharian, Anping Xia, Peter L Santa Maria
{"title":"Chemokine Receptor CCR2 Is Protective toward Outer Hair Cells in Chronic Suppurative Otitis Media.","authors":"Ankur Gupta, Viktoria Schiel, Ritwija Bhattacharya, Kourosh Eftekharian, Anping Xia, Peter L Santa Maria","doi":"10.4049/immunohorizons.2400064","DOIUrl":"10.4049/immunohorizons.2400064","url":null,"abstract":"<p><p>Chronic suppurative otitis media (CSOM) is a neglected disease that afflicts 330 million people worldwide and is the most common cause of permanent hearing loss among children in the developing world. Previously, we discovered that outer hair cell (OHC) loss occurred in the basal turn of the cochlea and that macrophages are the major immune cells associated with OHC loss in CSOM. Macrophage-associated cytokines are upregulated. Specifically, CCL-2, an important member of the MCP family, is elevated over time following middle ear infection. CCR2 is a common receptor of the MCP family and the unique receptor of CCL2. CCR2 knockout mice (CCR2-/-) have been used extensively in studies of monocyte activation in neurodegenerative diseases. In the present study, we investigated the effect of CCR2 deletion on the cochlear immune response and OHC survival in CSOM. The OHC survival rate was 84 ± 12.5% in the basal turn of CCR2+/+ CSOM cochleae, compared with was 63 ± 19.9% in the basal turn of CCR2-/- CSOM cochleae (p ≤ 0.05). Macrophage numbers were significantly reduced in CCR2-/- CSOM cochleae compared with CCR2+/+ CSOM cochleae (p ≤ 0.001). In addition, CCL7 was upregulated, whereas IL-33 was downregulated, in CCR2-/- CSOM cochleae. Finally, the permeability of the blood-labyrinth barrier in the stria vascularis remained unchanged in CCR2-/- CSOM compared with CCR2+/+ CSOM. Taken together, the data suggest that CCR2 plays a protective role through cochlear macrophages in the CSOM cochlea.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"688-694"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Improving Reliability of Immunological Assays by Defining Minimal Criteria for Cell Fitness. 通过定义细胞适宜性的最低标准来提高免疫测定的可靠性
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2300095
Sabine Ivison, Gabrielle Boucher, Grace Zheng, Rosa V Garcia, Rita Kohen, Alain Bitton, John D Rioux, Megan K Levings
{"title":"Improving Reliability of Immunological Assays by Defining Minimal Criteria for Cell Fitness.","authors":"Sabine Ivison, Gabrielle Boucher, Grace Zheng, Rosa V Garcia, Rita Kohen, Alain Bitton, John D Rioux, Megan K Levings","doi":"10.4049/immunohorizons.2300095","DOIUrl":"10.4049/immunohorizons.2300095","url":null,"abstract":"<p><p>Human PBMC-based assays are often used as biomarkers for the diagnosis and prognosis of disease, as well as for the prediction and tracking of response to biological therapeutics. However, the development and use of PBMC-based biomarker assays is often limited by poor reproducibility. Complex immunological assays can be further complicated by variation in cell handling before analysis, especially when using cryopreserved cells. Variation in postthaw viability is further increased if PBMC isolation and cryopreservation are done more than a few hours after collection. There is currently a lack of evidence-based standards for the minimal PBMC viability or \"fitness\" required to ensure the integrity and reproducibility of immune cell-based assays. In this study, we use an \"induced fail\" approach to examine the effect of thawed human PBMC fitness on four flow cytometry-based assays. We found that cell permeability-based viability stains at the time of thawing did not accurately quantify cell fitness, whereas a combined measurement of metabolic activity and early apoptosis markers did. Investigation of the impact of different types and levels of damage on PBMC-based assays revealed that only when cells were >60-70% live and apoptosis negative did biomarker values cease to be determined by cell fitness rather than the inherent biology of the cells. These data show that, to reproducibly measure immunological biomarkers using cryopreserved PBMCs, minimal acceptable standards for cell fitness should be incorporated into the assay protocol.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"622-634"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142157051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Estimates of Sequences with Ultralong and Short CDR3s in the Bovine IgM B Cell Receptor Repertoire Using the Long-read Oxford Nanopore MinION Platform. 使用长读数牛津纳米孔 MinION 平台估算牛 IgM B 细胞受体序列中的超长和短 CDR3 序列。
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400050
Tess E Altvater-Hughes, Harold P Hodgins, Douglas C Hodgins, Natasha B Gallo, Gabhan I Chalmers, Nicole D Ricker, Bonnie A Mallard
{"title":"Estimates of Sequences with Ultralong and Short CDR3s in the Bovine IgM B Cell Receptor Repertoire Using the Long-read Oxford Nanopore MinION Platform.","authors":"Tess E Altvater-Hughes, Harold P Hodgins, Douglas C Hodgins, Natasha B Gallo, Gabhan I Chalmers, Nicole D Ricker, Bonnie A Mallard","doi":"10.4049/immunohorizons.2400050","DOIUrl":"10.4049/immunohorizons.2400050","url":null,"abstract":"<p><p>Cattle produce Abs with an H chain ultralong CDR3 (40-70 aa). These Abs have been shown to have features such as broad neutralization of viruses and are investigated as human therapeutics. A common issue in sequencing the bovine BCR repertoire is the sequence length required to capture variable (V) and isotype gene information. This study aimed to assess the use of Oxford Nanopore Technologies' MinION platform to perform IgM BCR repertoire sequencing to assess variation in the percentage of ultralong CDR3s among dairy cattle. Blood was collected from nine Holstein heifers. B cells were isolated using magnetic bead-based separation, RNA was extracted, and IgM+ transcripts were amplified using PCR and sequenced using a MinION R10.4 flow cell. The distribution of CDR3 lengths was trimodal, and the percentage of ultralong CDR3s ranged among animals from 2.32 to 20.13% in DNA sequences and 1.56% to 17.02% in productive protein sequences. V segment usage varied significantly among heifers. Segment IGHV1-7, associated with ultralong CDR3s, was used in 5.8-24.2% of sequences; usage was positively correlated with ultralong CDR3 production (r = 0.99, p < 0.01). To our knowledge, this is the first study to sequence the bovine BCR repertoire using Oxford Nanopore Technologies and demonstrates the potential for cost-efficient long-read repertoire sequencing in cattle without assembly. Findings from this study support literature describing the distribution of length and percentage of ultralong CDR3s. Future studies will investigate changes in the bovine BCR repertoire associated with age, antigenic exposure, and genetics.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"635-651"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142157050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model. 通过受控人体感染模型探究皮肤对分枝杆菌的免疫力
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400053
E Chandler Church, Emma Bishop, Andrew Fiore-Gartland, Krystle K Q Yu, Ming Chang, Richard M Jones, Justin K Brache, Lamar Ballweber Fleming, Jolie M Phan, Mohau S Makatsa, Jack Heptinstall, Kelvin Chiong, One Dintwe, Anneta Naidoo, Valentin Voillet, Koshlan Mayer-Blackwell, Gift Nwanne, Erica Andersen-Nissen, Jay C Vary, Georgia D Tomaras, M Juliana McElrath, David R Sherman, Sean C Murphy, James G Kublin, Chetan Seshadri
{"title":"Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model.","authors":"E Chandler Church, Emma Bishop, Andrew Fiore-Gartland, Krystle K Q Yu, Ming Chang, Richard M Jones, Justin K Brache, Lamar Ballweber Fleming, Jolie M Phan, Mohau S Makatsa, Jack Heptinstall, Kelvin Chiong, One Dintwe, Anneta Naidoo, Valentin Voillet, Koshlan Mayer-Blackwell, Gift Nwanne, Erica Andersen-Nissen, Jay C Vary, Georgia D Tomaras, M Juliana McElrath, David R Sherman, Sean C Murphy, James G Kublin, Chetan Seshadri","doi":"10.4049/immunohorizons.2400053","DOIUrl":"10.4049/immunohorizons.2400053","url":null,"abstract":"<p><p>Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"695-711"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
α-Hemolysin from Staphylococcus aureus Changes the Epigenetic Landscape of Th17 Cells. 来自金黄色葡萄球菌的α-溶血素改变了 Th17 细胞的表观遗传景观
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400061
Joanna Pastwińska, Iwona Karwaciak, Kaja Karaś, Anna Sałkowska, Katarzyna Chałaśkiewicz, Dominik Strapagiel, Marta Sobalska-Kwapis, Jarosław Dastych, Marcin Ratajewski
{"title":"α-Hemolysin from Staphylococcus aureus Changes the Epigenetic Landscape of Th17 Cells.","authors":"Joanna Pastwińska, Iwona Karwaciak, Kaja Karaś, Anna Sałkowska, Katarzyna Chałaśkiewicz, Dominik Strapagiel, Marta Sobalska-Kwapis, Jarosław Dastych, Marcin Ratajewski","doi":"10.4049/immunohorizons.2400061","DOIUrl":"10.4049/immunohorizons.2400061","url":null,"abstract":"<p><p>The human body harbors a substantial population of bacteria, which may outnumber host cells. Thus, there are multiple interactions between both cell types. Given the common presence of Staphylococcus aureus in the human body and the role of Th17 cells in controlling this pathogen on mucous membranes, we sought to investigate the effect of α-hemolysin, which is produced by this bacterium, on differentiating Th17 cells. RNA sequencing analysis revealed that α-hemolysin influences the expression of signature genes for Th17 cells as well as genes involved in epigenetic regulation. We observed alterations in various histone marks and genome methylation levels via whole-genome bisulfite sequencing. Our findings underscore how bacterial proteins can significantly influence the transcriptome, epigenome, and phenotype of human Th17 cells, highlighting the intricate and complex nature of the interaction between immune cells and the microbiota.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"606-621"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Human ACE2 Gene Replacement Mice Support SARS-CoV-2 Viral Replication and Nonlethal Disease Progression. 人类 ACE2 基因替代小鼠支持 SARS-CoV-2 病毒复制和非致命性疾病进展。
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400030
Joshua M Thiede, Jenna K Dick, Nicholas N Jarjour, Venkatramana D Krishna, Lily Qian, Jules Sangala, Kellie Benzow, Kul Karanjeet, Shine Chin, Orion Rainwater, Maxim C-J Cheeran, Kristin A Hogquist, Stephen C Jameson, Geoffrey T Hart, Tyler D Bold, Michael D Koob
{"title":"Human ACE2 Gene Replacement Mice Support SARS-CoV-2 Viral Replication and Nonlethal Disease Progression.","authors":"Joshua M Thiede, Jenna K Dick, Nicholas N Jarjour, Venkatramana D Krishna, Lily Qian, Jules Sangala, Kellie Benzow, Kul Karanjeet, Shine Chin, Orion Rainwater, Maxim C-J Cheeran, Kristin A Hogquist, Stephen C Jameson, Geoffrey T Hart, Tyler D Bold, Michael D Koob","doi":"10.4049/immunohorizons.2400030","DOIUrl":"10.4049/immunohorizons.2400030","url":null,"abstract":"<p><p>Many mouse models of SARS-CoV-2 infection involve expression of the human ACE2 protein, the entry receptor for SARS-CoV-2 Spike protein, in mouse tissues. However, most of these models suffer from nonphysiological regulation of ACE2 expression, which can lead to atypically severe infections and aberrant sites of viral replication. In this report, we developed and characterized an ACE2 gene replacement (ACE2-GR) mouse strain in which the mouse Ace2 genomic locus was replaced by the entire human ACE2 gene locus, and we investigated the ability of these animals to respond to SARS-CoV-2 infection. We show that ACE2-GR mice support SARS-CoV-2 viral replication, but, in stark contrast to the widely used K18-hACE2 transgenic model, this infection leads to a mild disease with no detectable involvement of the CNS. Thus, ACE2-GR mice provide a novel, to our knowledge, model to explore immune responses and long-term consequences of SARS-CoV-2 infection.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"712-720"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HDAC6 Deletion Decreases Pristane-induced Inflammation. HDAC6 缺失可减少普利斯坦诱导的炎症
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400028
Dao Xu, Xin M Luo, Christopher M Reilly
{"title":"HDAC6 Deletion Decreases Pristane-induced Inflammation.","authors":"Dao Xu, Xin M Luo, Christopher M Reilly","doi":"10.4049/immunohorizons.2400028","DOIUrl":"10.4049/immunohorizons.2400028","url":null,"abstract":"<p><p>Systemic lupus erythematosus is an autoimmune disease characterized by excessive inflammation and production of pathogenic Abs. Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase. It has been reported that selective HDAC6 inhibition decreases inflammation in lupus mouse models. In this study, sex- and age-matched wild-type (WT) and HDAC6-/- mice on the C57BL/6 background were administered 0.5 ml of pristane or PBS i.p. at 8-12 wk of age and were euthanized 10 d later. At sacrifice, body weight and spleen weight were measured, sera were collected, and splenocytes and peritoneal cells were harvested for flow cytometry. We found pristane administration increased the spleen weight with no difference between WT and HDAC6-/- mice. Pristane administration promoted the population of CD11b+Ly6C++ inflammatory monocytes and CD11b+Ly6G+ neutrophils. Peritoneal recruitment of these inflammatory monocytes and neutrophils was significantly decreased in HDAC6-/- mice compared with the WT mice. Flow cytometry results showed that the number of CD69+ T and B cells was increased in HDAC6-/- mice. Pristane administration also induced the IFN signature genes as determined by RT-qPCR. Furthermore, IFN signature genes were not affected in HDAC6-/- mice compared with the WT mice. In vitro studies in J774A.1 cells revealed that the selective HDAC6 inhibitor (ACY-738) increased acetylation of NF-κB while increasing Stat1 phosphorylation, which resulted in inducible NO synthase production in LPS/IFN-γ-stimulated cells. Taken together, these results demonstrate that although HDAC6 inhibition may inhibit some inflammatory pathways, others remain unaffected.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"668-678"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells. 布鲁顿酪氨酸激酶抑制可减轻炎症反应,并对小鼠和人类髓系细胞的吞噬能力和细胞代谢产生不同影响。
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400045
Rochelle Y Benoit, Jennifer L Zagrodnik, Samantha J Carew, Craig S Moore
{"title":"Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells.","authors":"Rochelle Y Benoit, Jennifer L Zagrodnik, Samantha J Carew, Craig S Moore","doi":"10.4049/immunohorizons.2400045","DOIUrl":"10.4049/immunohorizons.2400045","url":null,"abstract":"<p><p>Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"652-667"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
B Cells Influence Encephalitogenic T Cell Frequency to Myelin Oligodendrocyte Glycoprotein (MOG)38-49 during Full-length MOG Protein-Induced Demyelinating Disease. 在全长 MOG 蛋白诱导的脱髓鞘疾病中,B 细胞影响致脑 T 细胞对髓鞘少突胶质细胞蛋白 (MOG)38-49 的频率。
ImmunoHorizons Pub Date : 2024-09-01 DOI: 10.4049/immunohorizons.2400069
Michael A Faust, Lisa Gibbs, Juan M Oviedo, Douglas H Cornwall, Keke C Fairfax, Zemin Zhou, Tracey J Lamb, Brian D Evavold
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