Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2300023
Fernando Gutierrez, Quiyana M Murphy, Brianna K Swartwout, Kaitlin A Read, Michael R Edwards, Leila Abdelhamid, Xavier Cabana-Puig, James C Testerman, Tian Xu, Ran Lu, Pavly Amin, Thomas E Cecere, Christopher M Reilly, Kenneth J Oestreich, Stanca M Ciupe, Xin M Luo
Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.
{"title":"TCDD and CH223191 Alter T Cell Balance but Fail to Induce Anti-Inflammatory Response in Adult Lupus Mice.","authors":"Fernando Gutierrez, Quiyana M Murphy, Brianna K Swartwout, Kaitlin A Read, Michael R Edwards, Leila Abdelhamid, Xavier Cabana-Puig, James C Testerman, Tian Xu, Ran Lu, Pavly Amin, Thomas E Cecere, Christopher M Reilly, Kenneth J Oestreich, Stanca M Ciupe, Xin M Luo","doi":"10.4049/immunohorizons.2300023","DOIUrl":"10.4049/immunohorizons.2300023","url":null,"abstract":"<p><p>Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139731250","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}
Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2400010
Michael Asamoah-Boaheng, Brian Grunau, Mohammad Ehsanul Karim, Iryna Kayda, Justin Yap, Katherine Bessai, David M Goldfarb
Recent research has highlighted the Omicron variant's capacity to evade immune protection conferred by wild-type (WT) mRNA vaccines. Despite this observation, the potential involvement of antigenic sin phenomena remains unclear. Our hypothesis posited that a greater number of prior WT vaccine doses might lead to reduced anti-Omicron neutralization Abs following Omicron infection. To investigate this, we analyzed blood samples from human participants in the COVID-19 Occupational Risk, Seroprevalence, and Immunity among Paramedics (CORSIP) study who had received at least one WT mRNA vaccine before contracting Omicron. The exposure variable was the number of WT mRNA vaccines administered, and the outcome was the angiotensin-converting enzyme 2 (ACE-2) percent inhibition specific to the BA.4/BA.5 Omicron Ag. Contrary to expectations, our findings revealed that more WT-based vaccines were associated with an enhanced Omicron-specific immune response.
{"title":"Investigating the Antibody Imprinting Hypothesis among Canadian Paramedics after SARS-CoV-2 Omicron Variant Circulation.","authors":"Michael Asamoah-Boaheng, Brian Grunau, Mohammad Ehsanul Karim, Iryna Kayda, Justin Yap, Katherine Bessai, David M Goldfarb","doi":"10.4049/immunohorizons.2400010","DOIUrl":"10.4049/immunohorizons.2400010","url":null,"abstract":"<p><p>Recent research has highlighted the Omicron variant's capacity to evade immune protection conferred by wild-type (WT) mRNA vaccines. Despite this observation, the potential involvement of antigenic sin phenomena remains unclear. Our hypothesis posited that a greater number of prior WT vaccine doses might lead to reduced anti-Omicron neutralization Abs following Omicron infection. To investigate this, we analyzed blood samples from human participants in the COVID-19 Occupational Risk, Seroprevalence, and Immunity among Paramedics (CORSIP) study who had received at least one WT mRNA vaccine before contracting Omicron. The exposure variable was the number of WT mRNA vaccines administered, and the outcome was the angiotensin-converting enzyme 2 (ACE-2) percent inhibition specific to the BA.4/BA.5 Omicron Ag. Contrary to expectations, our findings revealed that more WT-based vaccines were associated with an enhanced Omicron-specific immune response.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934695","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}
Pub Date : 2024-02-01DOI: 10.4049/immunohorizons.2300074
Tristan L A White, Ye Jin, Sean D A Roberts, Matthew J Gable, Penelope A Morel
hnRNP A1 is an important RNA-binding protein that influences many stages of RNA processing, including transcription, alternative splicing, mRNA nuclear export, and RNA stability. However, the role of hnRNP A1 in immune cells, specifically CD4+ T cells, remains unclear. We previously showed that Akt phosphorylation of hnRNP A1 was dependent on TCR signal strength and was associated with Treg differentiation. To explore the impact of hnRNP A1 phosphorylation by Akt on CD4+ T cell differentiation, our laboratory generated a mutant mouse model, hnRNP A1-S199A (A1-MUT) in which the major Akt phosphorylation site on hnRNP A1 was mutated to alanine using CRISPR Cas9 technology. Immune profiling of A1-MUT mice revealed changes in the numbers of Tregs in the mesenteric lymph node. We found no significant differences in naive CD4+ T cell differentiation into Th1, Th2, Th17, or T regulatory cells (Tregs) in vitro. In vivo, Treg differentiation assays using OTII-A1-Mut CD4+ T cells exposed to OVA food revealed migration and homing defects in the A1-MUT but no change in Treg induction. A1-MUT mice were immunized with NP- keyhole limpet hemocyanin, and normal germinal center development, normal numbers of NP-specific B cells, and no change in Tfh numbers were observed. In conclusion, Akt phosphorylation of hnRNP A1 S199 does not play a role in CD4+ T cell fate or function in the models tested. This hnRNP A1-S199A mouse model should be a valuable tool to study the role of Akt phosphorylation of hnRNP A1-S199 in different cell types or other mouse models of human disease.
{"title":"Phosphorylation of hnRNP A1-Serine 199 Is Not Required for T Cell Differentiation and Function.","authors":"Tristan L A White, Ye Jin, Sean D A Roberts, Matthew J Gable, Penelope A Morel","doi":"10.4049/immunohorizons.2300074","DOIUrl":"10.4049/immunohorizons.2300074","url":null,"abstract":"<p><p>hnRNP A1 is an important RNA-binding protein that influences many stages of RNA processing, including transcription, alternative splicing, mRNA nuclear export, and RNA stability. However, the role of hnRNP A1 in immune cells, specifically CD4+ T cells, remains unclear. We previously showed that Akt phosphorylation of hnRNP A1 was dependent on TCR signal strength and was associated with Treg differentiation. To explore the impact of hnRNP A1 phosphorylation by Akt on CD4+ T cell differentiation, our laboratory generated a mutant mouse model, hnRNP A1-S199A (A1-MUT) in which the major Akt phosphorylation site on hnRNP A1 was mutated to alanine using CRISPR Cas9 technology. Immune profiling of A1-MUT mice revealed changes in the numbers of Tregs in the mesenteric lymph node. We found no significant differences in naive CD4+ T cell differentiation into Th1, Th2, Th17, or T regulatory cells (Tregs) in vitro. In vivo, Treg differentiation assays using OTII-A1-Mut CD4+ T cells exposed to OVA food revealed migration and homing defects in the A1-MUT but no change in Treg induction. A1-MUT mice were immunized with NP- keyhole limpet hemocyanin, and normal germinal center development, normal numbers of NP-specific B cells, and no change in Tfh numbers were observed. In conclusion, Akt phosphorylation of hnRNP A1 S199 does not play a role in CD4+ T cell fate or function in the models tested. This hnRNP A1-S199A mouse model should be a valuable tool to study the role of Akt phosphorylation of hnRNP A1-S199 in different cell types or other mouse models of human disease.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139708871","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}
Pub Date : 2024-01-01DOI: 10.4049/immunohorizons.2300089
Kristina Ottens, Jalyn Schneider, Anne B Satterthwaite
Mice deficient in Lyn, a tyrosine kinase that limits B cell activation, develop a lupus-like autoimmune disease characterized by the accumulation of splenic plasma cells and the production of autoantibodies. Lyn-/- mice have reduced numbers of marginal zone (MZ) B cells, a B cell subset that is enriched in autoreactivity and prone to plasma cell differentiation. We hypothesized that this is due to unchecked terminal differentiation of this potentially pathogenic B cell subpopulation. However, impairing MZ B cell development in Lyn-/- mice did not reduce plasma cell accumulation or autoantibodies, and preventing plasma cell differentiation did not restore MZ B cell numbers. Instead, Lyn-/- mice accumulated B-1a cells when plasma cell differentiation was impaired. Similar to MZ B cells, B-1a cells tend to be polyreactive or weakly autoreactive and are primed for terminal differentiation. Our results implicate B-1a cells, but not MZ B cells, as contributors to the autoreactive plasma cell pool in Lyn-/- mice.
Lyn是一种限制B细胞活化的酪氨酸激酶,缺乏Lyn的小鼠会患上一种狼疮样自身免疫性疾病,其特征是脾浆细胞聚集和自身抗体的产生。Lyn-/-小鼠的边缘区(MZ)B细胞数量减少,这种B细胞亚群富含自体活性,容易向浆细胞分化。我们推测这是由于这一潜在致病性 B 细胞亚群的末端分化未得到控制所致。然而,损害Lyn-/-小鼠的MZ B细胞发育并不能减少浆细胞积累或自身抗体,阻止浆细胞分化也不能恢复MZ B细胞的数量。相反,当浆细胞分化受损时,Lyn-/-小鼠会积累B-1a细胞。与 MZ B 细胞类似,B-1a 细胞也倾向于多反应性或弱自反应性,并为终末分化做好了准备。我们的研究结果表明,B-1a 细胞而非 MZ B 细胞是 Lyn-/- 小鼠自反应性浆细胞池的贡献者。
{"title":"B-1a Cells, but Not Marginal Zone B Cells, Are Implicated in the Accumulation of Autoreactive Plasma Cells in Lyn-/- Mice.","authors":"Kristina Ottens, Jalyn Schneider, Anne B Satterthwaite","doi":"10.4049/immunohorizons.2300089","DOIUrl":"10.4049/immunohorizons.2300089","url":null,"abstract":"<p><p>Mice deficient in Lyn, a tyrosine kinase that limits B cell activation, develop a lupus-like autoimmune disease characterized by the accumulation of splenic plasma cells and the production of autoantibodies. Lyn-/- mice have reduced numbers of marginal zone (MZ) B cells, a B cell subset that is enriched in autoreactivity and prone to plasma cell differentiation. We hypothesized that this is due to unchecked terminal differentiation of this potentially pathogenic B cell subpopulation. However, impairing MZ B cell development in Lyn-/- mice did not reduce plasma cell accumulation or autoantibodies, and preventing plasma cell differentiation did not restore MZ B cell numbers. Instead, Lyn-/- mice accumulated B-1a cells when plasma cell differentiation was impaired. Similar to MZ B cells, B-1a cells tend to be polyreactive or weakly autoreactive and are primed for terminal differentiation. Our results implicate B-1a cells, but not MZ B cells, as contributors to the autoreactive plasma cell pool in Lyn-/- mice.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378949","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}
Pub Date : 2024-01-01DOI: 10.4049/immunohorizons.2300060
Cameron W Paterson, Katherine T Fay, Ching-Wen Chen, Nathan J Klingensmith, Melissa B Gutierrez, Zhe Liang, Craig M Coopersmith, Mandy L Ford
Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.
长期酗酒会增加败血症的发病率和死亡率。慢性酒精中毒和败血症的特点都是免疫失调,包括 T 细胞共抑制分子的过度表达。我们试图利用一种慢性酒精摄入并随后进行盲肠结扎和穿刺的小鼠模型来描述 CTLA-4 在慢性酒精暴露的败血症中的作用。结果表明,与饮酒假对照组或饮水败血症小鼠相比,从饮酒败血症小鼠体内分离出的 CD4+ T 细胞中 CTLA-4 表达增加。此外,检查点抑制 CTLA-4 能提高饮酒败血症小鼠的败血症存活率,但不能提高饮水败血症小鼠的存活率。在药物性 CTLA-4 阻断后,以及在 CD4+ T 细胞中条件性 Ctla4 缺失后,对这些动物体内 T 细胞分区的研究表明,CTLA-4 的缺乏促进了效应调节性 T 细胞的活化和增殖,并促进了常规效应记忆 CD4+ T 细胞的生成。这些数据强调了CTLA-4在慢性酒精暴露情况下介导败血症死亡过程中的重要作用,并可能为未来开发针对这一患者群体的靶向疗法提供参考。
{"title":"CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.","authors":"Cameron W Paterson, Katherine T Fay, Ching-Wen Chen, Nathan J Klingensmith, Melissa B Gutierrez, Zhe Liang, Craig M Coopersmith, Mandy L Ford","doi":"10.4049/immunohorizons.2300060","DOIUrl":"10.4049/immunohorizons.2300060","url":null,"abstract":"<p><p>Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139473040","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}
Pub Date : 2024-01-01DOI: 10.4049/immunohorizons.2300110
Ya Wang, Yunhuan Gao, Xiaomin Su, Yang Hao, Yuan Zhang, Rongcun Yang
Inflammasome NLRC4 (NLR family CARD domain containing 4) can protect mucosal barriers such as intestine from invading bacterial pathogens. However, it was incompletely clear how NLRC4 was activated in intestinal epithelial cells. In this study, we demonstrated that LNCGM1082 could mediate the activation of NLRC4 via binding NLRC4 with protein kinase C (PKC)δ. LNCGM1082 knockout (KO) mice had reduced resistance against Salmonella Typhimurium infection, as well as impaired expulsion of infected gut epithelial cells and release of IL-18 upon exposure to S. Typhimurium. Similar to NLRC4 KO and PKCδ knockdown gut organoids, there also was impaired expulsion of gut epithelial cells and release of IL-18 in LNCGM1082 KO gut organoids. Furthermore, there also was reduced activation of caspase-1 and caspase-8 in these LNCGM1082 KO, NLRC4 KO, and PKCδ knockdown gut organoids upon exposure to S. Typhimurium. Our results show that LNCGM1082 in the ICEs plays a critical role in mediating activation of NLRC4 through binding NLRC4 and PKCδ and promoting expulsion of infected epithelial cells and release of IL-18 upon exposure to bacteria such as S. Typhimurium.
炎症小体 NLRC4(NLR 家族 CARD 含域 4)可以保护肠道等粘膜屏障免受细菌病原体的入侵。然而,NLRC4如何在肠上皮细胞中被激活尚不完全清楚。在这项研究中,我们证实了LNCGM1082可通过将NLRC4与蛋白激酶C(PKC)δ结合来介导NLRC4的活化。LNCGM1082基因敲除(KO)小鼠对鼠伤寒沙门氏菌感染的抵抗力下降,受感染肠道上皮细胞的排出和IL-18的释放也受到影响。与 NLRC4 KO 和 PKCδ 敲除的肠道器官组织类似,LNCGM1082 KO 的肠道器官组织中肠道上皮细胞的排出和 IL-18 的释放也受到影响。此外,LNCGM1082 KO、NLRC4 KO和PKCδ敲除的肠道器官组织在接触鼠伤寒杆菌后,caspase-1和caspase-8的活化也有所降低。我们的研究结果表明,ICEs中的LNCGM1082通过与NLRC4和PKCδ结合,在介导NLRC4的活化方面起着关键作用,并在暴露于伤寒杆菌等细菌时促进受感染上皮细胞的排出和IL-18的释放。
{"title":"LNCGM1082 in Gut Epithelial Cells Promotes Expulsion of Infected Epithelial Cells and Release of IL-18.","authors":"Ya Wang, Yunhuan Gao, Xiaomin Su, Yang Hao, Yuan Zhang, Rongcun Yang","doi":"10.4049/immunohorizons.2300110","DOIUrl":"10.4049/immunohorizons.2300110","url":null,"abstract":"<p><p>Inflammasome NLRC4 (NLR family CARD domain containing 4) can protect mucosal barriers such as intestine from invading bacterial pathogens. However, it was incompletely clear how NLRC4 was activated in intestinal epithelial cells. In this study, we demonstrated that LNCGM1082 could mediate the activation of NLRC4 via binding NLRC4 with protein kinase C (PKC)δ. LNCGM1082 knockout (KO) mice had reduced resistance against Salmonella Typhimurium infection, as well as impaired expulsion of infected gut epithelial cells and release of IL-18 upon exposure to S. Typhimurium. Similar to NLRC4 KO and PKCδ knockdown gut organoids, there also was impaired expulsion of gut epithelial cells and release of IL-18 in LNCGM1082 KO gut organoids. Furthermore, there also was reduced activation of caspase-1 and caspase-8 in these LNCGM1082 KO, NLRC4 KO, and PKCδ knockdown gut organoids upon exposure to S. Typhimurium. Our results show that LNCGM1082 in the ICEs plays a critical role in mediating activation of NLRC4 through binding NLRC4 and PKCδ and promoting expulsion of infected epithelial cells and release of IL-18 upon exposure to bacteria such as S. Typhimurium.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378950","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}
Pub Date : 2024-01-01DOI: 10.4049/immunohorizons.2300073
Joshua J Baty, Heather A Bruns
Immunology is inherently interdisciplinary. Understanding how the immune system functions requires knowledge from several scientific disciplines, including molecular biology, cellular biology, genetics, and biochemistry. Furthermore, immunology is conceptually complex, requiring the identification of a plethora of immune components and mastery of a large volume of new vocabulary. These attributes can pose challenges to student learning in the undergraduate immunology classroom. Team-based learning (TBL) is a pedagogical method used to increase student engagement in learning, improve student collaboration, and develop communication skills. In a variety of educational settings, TBL activities have been shown to foster a deeper understanding of complex topics, increase student confidence in course content, and improve learning outcomes. In this study, we examined differences in the impact of traditional lecture versus TBL activities on student learning outcomes for four different topics presented in an undergraduate adaptive immunity course composed largely of academically high-performing students. We matched content across two student cohorts, delivered via team-based learning methodology (T cell development and Ab-mediated functions) and traditional lecture (B cell development and T cell effector functions). Student learning was assessed using content questions across a range of Bloom's taxonomy levels, which demonstrated that the TBL activities did not improve examination performance over lecture-based learning in this course. However, students found this learning tool to be valuable, indicating that the TBL activities assisted with preparation for examinations and provided a necessary opportunity to address misconceptions.
免疫学本身就是一门跨学科的学科。要了解免疫系统如何发挥作用,需要多个科学学科的知识,包括分子生物学、细胞生物学、遗传学和生物化学。此外,免疫学在概念上也很复杂,需要识别大量的免疫成分并掌握大量的新词汇。这些特点都会给学生在本科免疫学课堂上的学习带来挑战。基于团队的学习(TBL)是一种教学方法,用于提高学生的学习参与度、加强学生合作和培养沟通技能。在各种教育环境中,TBL 活动已被证明能促进学生加深对复杂主题的理解,增强学生对课程内容的信心,并提高学习效果。在本研究中,我们考察了传统讲授与 TBL 活动对学生学习成果的影响差异。在一门本科生自适应免疫课程中,学生主要由学习成绩优异的学生组成,讲授了四个不同的主题。我们对两组学生的学习内容进行了匹配,分别通过团队学习法(T 细胞发育和 Ab 介导的功能)和传统讲授法(B 细胞发育和 T 细胞效应器功能)进行授课。学生的学习情况通过布卢姆分类学中不同级别的内容问题进行评估,结果表明,在这门课程中,与讲授式学习相比,TBL活动并没有提高考试成绩。不过,学生们认为这种学习工具很有价值,表明 TBL 活动有助于备考,并为解决误解提供了必要的机会。
{"title":"Assessment of the Effectiveness of Team-based Learning Activities on Learning Outcomes in the Undergraduate Immunology Classroom.","authors":"Joshua J Baty, Heather A Bruns","doi":"10.4049/immunohorizons.2300073","DOIUrl":"10.4049/immunohorizons.2300073","url":null,"abstract":"<p><p>Immunology is inherently interdisciplinary. Understanding how the immune system functions requires knowledge from several scientific disciplines, including molecular biology, cellular biology, genetics, and biochemistry. Furthermore, immunology is conceptually complex, requiring the identification of a plethora of immune components and mastery of a large volume of new vocabulary. These attributes can pose challenges to student learning in the undergraduate immunology classroom. Team-based learning (TBL) is a pedagogical method used to increase student engagement in learning, improve student collaboration, and develop communication skills. In a variety of educational settings, TBL activities have been shown to foster a deeper understanding of complex topics, increase student confidence in course content, and improve learning outcomes. In this study, we examined differences in the impact of traditional lecture versus TBL activities on student learning outcomes for four different topics presented in an undergraduate adaptive immunity course composed largely of academically high-performing students. We matched content across two student cohorts, delivered via team-based learning methodology (T cell development and Ab-mediated functions) and traditional lecture (B cell development and T cell effector functions). Student learning was assessed using content questions across a range of Bloom's taxonomy levels, which demonstrated that the TBL activities did not improve examination performance over lecture-based learning in this course. However, students found this learning tool to be valuable, indicating that the TBL activities assisted with preparation for examinations and provided a necessary opportunity to address misconceptions.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139514336","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}
Pub Date : 2024-01-01DOI: 10.4049/immunohorizons.2400001
Zion T McCoy, Myrna G Serrano, Laahirie Edupuganti, Katherine M Spaine, David J Edwards, Gregory A Buck, Kimberly K Jefferson
Sneathia vaginalis is a Gram-negative vaginal species that is associated with pregnancy complications. It produces cytopathogenic toxin A (CptA), a pore-forming toxin. To determine whether CptA is expressed in vivo and to examine the mucosal Ab response to the toxin, we examined human midvaginal swab samples obtained during pregnancy for IgM, IgA, and IgG Abs with CptA affinity. This subcohort study included samples from 93 pregnant people. S. vaginalis relative abundance was available through 16S rRNA survey. There were 22 samples from pregnancies that resulted in preterm birth in which S. vaginalis relative abundance was <0.005%, 22 samples from pregnancies that resulted in preterm birth with S. vaginalis ≥0.005%, 24 samples from pregnancies that resulted in term birth with S. vaginalis <0.005%, and 25 samples from pregnancies that resulted in term birth with S. vaginalis ≥0.005%. IgM, IgA, and IgG with affinity for CptA were assessed by ELISA. The capacity for the samples to neutralize CptA was quantified by hemolysis assay. All three Ab isotypes were detectable within different subsets of the samples. There was no significant association between relative abundance of S. vaginalis and the presence of any Ab isotype. The majority of vaginal swab samples containing detectable levels of anti-CptA Abs neutralized the hemolytic activity of CptA, with the strongest correlation between IgA and neutralizing activity. These results demonstrate that S. vaginalis produces CptA in vivo and that CptA is recognized by the host immune defenses, resulting in the production of Abs with toxin-neutralizing ability.
{"title":"Antibody Response to the Sneathia vaginalis Cytopathogenic Toxin A during Pregnancy.","authors":"Zion T McCoy, Myrna G Serrano, Laahirie Edupuganti, Katherine M Spaine, David J Edwards, Gregory A Buck, Kimberly K Jefferson","doi":"10.4049/immunohorizons.2400001","DOIUrl":"10.4049/immunohorizons.2400001","url":null,"abstract":"<p><p>Sneathia vaginalis is a Gram-negative vaginal species that is associated with pregnancy complications. It produces cytopathogenic toxin A (CptA), a pore-forming toxin. To determine whether CptA is expressed in vivo and to examine the mucosal Ab response to the toxin, we examined human midvaginal swab samples obtained during pregnancy for IgM, IgA, and IgG Abs with CptA affinity. This subcohort study included samples from 93 pregnant people. S. vaginalis relative abundance was available through 16S rRNA survey. There were 22 samples from pregnancies that resulted in preterm birth in which S. vaginalis relative abundance was <0.005%, 22 samples from pregnancies that resulted in preterm birth with S. vaginalis ≥0.005%, 24 samples from pregnancies that resulted in term birth with S. vaginalis <0.005%, and 25 samples from pregnancies that resulted in term birth with S. vaginalis ≥0.005%. IgM, IgA, and IgG with affinity for CptA were assessed by ELISA. The capacity for the samples to neutralize CptA was quantified by hemolysis assay. All three Ab isotypes were detectable within different subsets of the samples. There was no significant association between relative abundance of S. vaginalis and the presence of any Ab isotype. The majority of vaginal swab samples containing detectable levels of anti-CptA Abs neutralized the hemolytic activity of CptA, with the strongest correlation between IgA and neutralizing activity. These results demonstrate that S. vaginalis produces CptA in vivo and that CptA is recognized by the host immune defenses, resulting in the production of Abs with toxin-neutralizing ability.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10832334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139565300","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}
Despite treatment advances, acute kidney injury (AKI)-related mortality rates are still high in hospitalized adults, often due to sepsis. Sepsis and AKI could synergistically worsen the outcomes of critically ill patients. TLR4 signaling and mitochondrial antiviral signaling protein (MAVS) signaling are innate immune responses essential in kidney diseases, but their involvement in sepsis-associated AKI (SA-AKI) remains unclear. We studied the role of MAVS in kidney injury related to the TLR4 signaling pathway using a murine LPS-induced AKI model in wild-type and MAVS-knockout mice. We confirmed the importance of M1 macrophage in SA-AKI through in vivo assessment of inflammatory responses. The TLR4 signaling pathway was upregulated in activated bone marrow-derived macrophages, in which MAVS helped maintain the LPS-suppressed TLR4 mRNA level. MAVS regulated redox homeostasis via NADPH oxidase Nox2 and mitochondrial reverse electron transport in macrophages to alleviate the TLR4 signaling response to LPS. Hypoxia-inducible factor 1α (HIF-1α) and AP-1 were key regulators of TLR4 transcription and connected MAVS-dependent reactive oxygen species signaling with the TLR4 pathway. Inhibition of succinate dehydrogenase could partly reduce inflammation in LPS-treated bone marrow-derived macrophages without MAVS. These findings highlight the renoprotective role of MAVS in LPS-induced AKI by regulating reactive oxygen species generation-related genes and maintaining redox balance. Controlling redox homeostasis through MAVS signaling may be a promising therapy for SA-AKI.
{"title":"Protective Role of MAVS Signaling for Murine Lipopolysaccharide-Induced Acute Kidney Injury.","authors":"Trang Anh Thi Tran, Yasunori Iwata, Linh Thuy Hoang, Shinji Kitajima, Shiori Yoneda-Nakagawa, Megumi Oshima, Norihiko Sakai, Tadashi Toyama, Yuta Yamamura, Hiroka Yamazaki, Akinori Hara, Miho Shimizu, Keisuke Sako, Taichiro Minami, Takahiro Yuasa, Keisuke Horikoshi, Daiki Hayashi, Sho Kajikawa, Takashi Wada","doi":"10.4049/immunohorizons.2300069","DOIUrl":"10.4049/immunohorizons.2300069","url":null,"abstract":"<p><p>Despite treatment advances, acute kidney injury (AKI)-related mortality rates are still high in hospitalized adults, often due to sepsis. Sepsis and AKI could synergistically worsen the outcomes of critically ill patients. TLR4 signaling and mitochondrial antiviral signaling protein (MAVS) signaling are innate immune responses essential in kidney diseases, but their involvement in sepsis-associated AKI (SA-AKI) remains unclear. We studied the role of MAVS in kidney injury related to the TLR4 signaling pathway using a murine LPS-induced AKI model in wild-type and MAVS-knockout mice. We confirmed the importance of M1 macrophage in SA-AKI through in vivo assessment of inflammatory responses. The TLR4 signaling pathway was upregulated in activated bone marrow-derived macrophages, in which MAVS helped maintain the LPS-suppressed TLR4 mRNA level. MAVS regulated redox homeostasis via NADPH oxidase Nox2 and mitochondrial reverse electron transport in macrophages to alleviate the TLR4 signaling response to LPS. Hypoxia-inducible factor 1α (HIF-1α) and AP-1 were key regulators of TLR4 transcription and connected MAVS-dependent reactive oxygen species signaling with the TLR4 pathway. Inhibition of succinate dehydrogenase could partly reduce inflammation in LPS-treated bone marrow-derived macrophages without MAVS. These findings highlight the renoprotective role of MAVS in LPS-induced AKI by regulating reactive oxygen species generation-related genes and maintaining redox balance. Controlling redox homeostasis through MAVS signaling may be a promising therapy for SA-AKI.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139089747","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}
Pub Date : 2024-01-01DOI: 10.4049/immunohorizons.2300101
Kenneth K Y Ting, Pei Yu, Mudia Iyayi, Riley Dow, Sharon J Hyduk, Eric Floro, Hisham Ibrahim, Saraf Karim, Chanele K Polenz, Daniel A Winer, Minna Woo, Jonathan Rocheleau, Jenny Jongstra-Bilen, Myron I Cybulsky
The accumulation of lipid and the formation of macrophage foam cells is a hallmark of atherosclerosis, a chronic inflammatory disease. To better understand the role of macrophage lipid accumulation in inflammation during atherogenesis, we studied early molecular events that follow the accumulation of oxidized low-density lipoprotein (oxLDL) in cultured mouse macrophages. We previously showed that oxLDL accumulation downregulates the inflammatory response in conjunction with downregulation of late-phase glycolysis. In this study, we show that within hours after LPS stimulation, macrophages with accumulated oxLDL maintain early-phase glycolysis but selectively downregulate activation of AKT2, one of three AKT isoforms. The inhibition of AKT2 activation reduced LPS-induced ATP citrate lyase activation, acetyl-CoA production, and acetylation of histone 3 lysine 27 (H3K27ac) in certain inflammatory gene promoters. In contrast to oxLDL, multiple early LPS-induced signaling pathways were inhibited in macrophages with accumulated cholesterol, including TBK1, AKT1, AKT2, MAPK, and NF-κB, and early-phase glycolysis. The selective inhibition of LPS-induced AKT2 activation was dependent on the generation of mitochondrial oxygen radicals during the accumulation of oxLDL in macrophages prior to LPS stimulation. This is consistent with increased oxidative phosphorylation, fatty acid synthesis, and oxidation pathways found by comparative transcriptomic analyses of oxLDL-loaded versus control macrophages. Our study shows a functional connection between oxLDL accumulation, inactivation of AKT2, and the inhibition of certain inflammatory genes through epigenetic changes that occur soon after LPS stimulation, independent of early-phase glycolysis.
{"title":"Oxidized Low-Density Lipoprotein Accumulation in Macrophages Impairs Lipopolysaccharide-Induced Activation of AKT2, ATP Citrate Lyase, Acetyl-Coenzyme A Production, and Inflammatory Gene H3K27 Acetylation.","authors":"Kenneth K Y Ting, Pei Yu, Mudia Iyayi, Riley Dow, Sharon J Hyduk, Eric Floro, Hisham Ibrahim, Saraf Karim, Chanele K Polenz, Daniel A Winer, Minna Woo, Jonathan Rocheleau, Jenny Jongstra-Bilen, Myron I Cybulsky","doi":"10.4049/immunohorizons.2300101","DOIUrl":"10.4049/immunohorizons.2300101","url":null,"abstract":"<p><p>The accumulation of lipid and the formation of macrophage foam cells is a hallmark of atherosclerosis, a chronic inflammatory disease. To better understand the role of macrophage lipid accumulation in inflammation during atherogenesis, we studied early molecular events that follow the accumulation of oxidized low-density lipoprotein (oxLDL) in cultured mouse macrophages. We previously showed that oxLDL accumulation downregulates the inflammatory response in conjunction with downregulation of late-phase glycolysis. In this study, we show that within hours after LPS stimulation, macrophages with accumulated oxLDL maintain early-phase glycolysis but selectively downregulate activation of AKT2, one of three AKT isoforms. The inhibition of AKT2 activation reduced LPS-induced ATP citrate lyase activation, acetyl-CoA production, and acetylation of histone 3 lysine 27 (H3K27ac) in certain inflammatory gene promoters. In contrast to oxLDL, multiple early LPS-induced signaling pathways were inhibited in macrophages with accumulated cholesterol, including TBK1, AKT1, AKT2, MAPK, and NF-κB, and early-phase glycolysis. The selective inhibition of LPS-induced AKT2 activation was dependent on the generation of mitochondrial oxygen radicals during the accumulation of oxLDL in macrophages prior to LPS stimulation. This is consistent with increased oxidative phosphorylation, fatty acid synthesis, and oxidation pathways found by comparative transcriptomic analyses of oxLDL-loaded versus control macrophages. Our study shows a functional connection between oxLDL accumulation, inactivation of AKT2, and the inhibition of certain inflammatory genes through epigenetic changes that occur soon after LPS stimulation, independent of early-phase glycolysis.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139405670","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}