Zsuzsa Huszenicza, Brian C. Gilmour, Lise Koll, Hanna Kjelstrup, Hanna Chan, Vibeke Sundvold, Stine Granum, Anne Spurkland
Adapter proteins are flexible and dynamic modulators of cellular signalling that are important for immune cell function. One of these, the T-cell-specific adapter protein (TSAd), interacts with the non-receptor tyrosine kinases Src and Lck of the Src family kinases (SFKs) and Itk of the Tec family kinases (TFKs). Three tyrosine residues in the TSAd C-terminus are phosphorylated by Lck and serve as docking sites for the Src homology 2 (SH2) domains of Src and Lck. The TSAd proline-rich region (PRR) binds to the Src homology 3 (SH3) domains found in Lck, Src and Itk. Despite known interactors, the role TSAd plays in cellular signalling remains largely unknown. TSAd's ability to bind both SFKs and TFKs may point to its function as a general scaffold for both kinase families. Using GST-pulldown as well as peptide array experiments, we found that both the SH2 and SH3 domains of the SFKs Fyn and Hck, as well as the TFKs Tec and Txk, interact with TSAd. This contrasts with Itk, which interacts with TSAd only through its SH3 domain. Although our analysis showed that TSAd is both co-expressed and may interact with Fyn, we were unable to co-precipitate Fyn with TSAd from Jurkat cells, as detected by Western blotting and affinity purification mass spectrometry. This may suggest that TSAd-Fyn interaction in intact cells may be limited by other factors, such as the subcellular localization of the two molecules or the co-expression of competing binding partners.
{"title":"Interaction of T-cell-specific adapter protein with Src- and Tec-family kinases","authors":"Zsuzsa Huszenicza, Brian C. Gilmour, Lise Koll, Hanna Kjelstrup, Hanna Chan, Vibeke Sundvold, Stine Granum, Anne Spurkland","doi":"10.1111/sji.13358","DOIUrl":"https://doi.org/10.1111/sji.13358","url":null,"abstract":"Adapter proteins are flexible and dynamic modulators of cellular signalling that are important for immune cell function. One of these, the T-cell-specific adapter protein (TSAd), interacts with the non-receptor tyrosine kinases Src and Lck of the Src family kinases (SFKs) and Itk of the Tec family kinases (TFKs). Three tyrosine residues in the TSAd C-terminus are phosphorylated by Lck and serve as docking sites for the Src homology 2 (SH2) domains of Src and Lck. The TSAd proline-rich region (PRR) binds to the Src homology 3 (SH3) domains found in Lck, Src and Itk. Despite known interactors, the role TSAd plays in cellular signalling remains largely unknown. TSAd's ability to bind both SFKs and TFKs may point to its function as a general scaffold for both kinase families. Using GST-pulldown as well as peptide array experiments, we found that both the SH2 and SH3 domains of the SFKs Fyn and Hck, as well as the TFKs Tec and Txk, interact with TSAd. This contrasts with Itk, which interacts with TSAd only through its SH3 domain. Although our analysis showed that TSAd is both co-expressed and may interact with Fyn, we were unable to co-precipitate Fyn with TSAd from Jurkat cells, as detected by Western blotting and affinity purification mass spectrometry. This may suggest that TSAd-Fyn interaction in intact cells may be limited by other factors, such as the subcellular localization of the two molecules or the co-expression of competing binding partners.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"9 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139584851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charles W. Armitage, Emily R. Bryan, Logan Trim, Ella Palframan, Lucas Wager, Kenneth W. Beagley, Alison J. Carey
Chlamydia trachomatis infection is the leading cause of bacterial urogenital infection and has been demonstrated to drive inflammation and scarring of the reproductive tract. Recent studies have identified key triggers of proinflammatory adaptive immune responses driven by innate leukocytes and epithelia driving immunopathology. Utilizing chimeric mouse models, we investigated the definitive source and role of IL17 and IL17 signalling receptors during early Chlamydia muridarum infection of the female urogenital tract. Bone marrow transplants from wild-type (WT) and IL17A−/− mice to recipients demonstrated equivocal infection kinetics in the reproductive tract, but interestingly, adoptive transfer of IL17A−/− immune cells to WT recipients resulted in no infertility, suggesting a haematopoietic (as opposed to tissue) source of IL17 driving immunopathology. To further delineate the role of IL17 in immunopathology, we infected WT and IL17 receptor A (IL17RA)−/− female mice and observed a significant reduction in immunopathology in IL17RA−/− mice. WT bone marrow transplants to IL17RA−/− recipient mice prevented hydrosalpinx, suggesting signalling through IL17RA drives immunopathology. Furthermore, early chemical inhibition of IL17 signalling significantly reduced hydrosalpinx, suggesting IL17 acts as an innate driver of disease. Early during the infection, IL17 was produced by γδ T cells in the cervico-vagina, but more importantly, by neutrophils at the site of infertility in the oviducts. Taken together, these data suggest innate production of IL17 by haematopoietic leukocytes drives immunopathology in the epithelia during early C. muridarum infection of the female reproductive tract.
{"title":"Haematopoietic innate interleukin 17A production drives immunopathology in female mouse genital Chlamydia muridarum infection","authors":"Charles W. Armitage, Emily R. Bryan, Logan Trim, Ella Palframan, Lucas Wager, Kenneth W. Beagley, Alison J. Carey","doi":"10.1111/sji.13359","DOIUrl":"https://doi.org/10.1111/sji.13359","url":null,"abstract":"<i>Chlamydia trachomatis</i> infection is the leading cause of bacterial urogenital infection and has been demonstrated to drive inflammation and scarring of the reproductive tract. Recent studies have identified key triggers of proinflammatory adaptive immune responses driven by innate leukocytes and epithelia driving immunopathology. Utilizing chimeric mouse models, we investigated the definitive source and role of IL17 and IL17 signalling receptors during early <i>Chlamydia muridarum</i> infection of the female urogenital tract. Bone marrow transplants from wild-type (WT) and IL17A<sup>−/−</sup> mice to recipients demonstrated equivocal infection kinetics in the reproductive tract, but interestingly, adoptive transfer of IL17A<sup>−/−</sup> immune cells to WT recipients resulted in no infertility, suggesting a haematopoietic (as opposed to tissue) source of IL17 driving immunopathology. To further delineate the role of IL17 in immunopathology, we infected WT and IL17 receptor A (IL17RA)<sup>−/−</sup> female mice and observed a significant reduction in immunopathology in IL17RA<sup>−/−</sup> mice. WT bone marrow transplants to IL17RA<sup>−/−</sup> recipient mice prevented hydrosalpinx, suggesting signalling through IL17RA drives immunopathology. Furthermore, early chemical inhibition of IL17 signalling significantly reduced hydrosalpinx, suggesting IL17 acts as an innate driver of disease. Early during the infection, IL17 was produced by γδ T cells in the cervico-vagina, but more importantly, by neutrophils at the site of infertility in the oviducts. Taken together, these data suggest innate production of IL17 by haematopoietic leukocytes drives immunopathology in the epithelia during early <i>C. muridarum</i> infection of the female reproductive tract.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"32 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139517985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhongling Dai, Zhande Gong, Cui Wang, WeiXiang Long, Duo Liu, Haijun Zhang, Aihua Lei
Group 2 innate lymphoid cells (ILC2s) are a type of innate immune cells that produce a large amount of IL-5 and IL-13 and two cytokines that are crucial for various processes such as allergic airway inflammation, tissue repair and tissue homeostasis. It is known that damaged epithelial-derived alarmins, such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP), are the predominant ILC2 activators that mediate the production of type 2 cytokines. In recent years, abundant studies have found that many factors can regulate ILC2 development and function. Hormones synthesized by the body's endocrine glands or cells play an important role in immune response. Notably, ILC2s express hormone receptors and their proliferation and function can be modulated by multiple hormones during allergic airway inflammation. Here, we summarize the effects of multiple hormones on ILC2-driven allergic airway inflammation and discuss the underlying mechanisms and potential therapeutic significance.
{"title":"The role of hormones in ILC2-driven allergic airway inflammation","authors":"Zhongling Dai, Zhande Gong, Cui Wang, WeiXiang Long, Duo Liu, Haijun Zhang, Aihua Lei","doi":"10.1111/sji.13357","DOIUrl":"https://doi.org/10.1111/sji.13357","url":null,"abstract":"Group 2 innate lymphoid cells (ILC2s) are a type of innate immune cells that produce a large amount of IL-5 and IL-13 and two cytokines that are crucial for various processes such as allergic airway inflammation, tissue repair and tissue homeostasis. It is known that damaged epithelial-derived alarmins, such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP), are the predominant ILC2 activators that mediate the production of type 2 cytokines. In recent years, abundant studies have found that many factors can regulate ILC2 development and function. Hormones synthesized by the body's endocrine glands or cells play an important role in immune response. Notably, ILC2s express hormone receptors and their proliferation and function can be modulated by multiple hormones during allergic airway inflammation. Here, we summarize the effects of multiple hormones on ILC2-driven allergic airway inflammation and discuss the underlying mechanisms and potential therapeutic significance.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"54 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139517811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoqin Wang, Yinsha Miao, Jinghui Shen, Dandan Li, Xinyue Deng, Chengcheng Yang, Yanhong Ji, ZhiJun Dai, Yunfeng Ma
In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8+ T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8+/CD4+ T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.
鉴于某些患者群体对 PD1 抗体治疗的耐药性不断增加，因此亟需进行深入研究。我们的研究采用小鼠 CT26/MUC1 结肠癌模型，评估了 MUC1 DNA 疫苗和 PD1 抗体在克服 PD1 抗药性方面的协同作用。在单独治疗时，PD1 抗体对肿瘤生长没有影响。此外，瘤内 T 细胞比例或 T 细胞功能也没有发生变化。相比之下，单独注射 MUC1 DNA 疫苗可通过提高 IFN-γ 和颗粒酶 B 的产生，显著增强 CD8+ T 细胞的细胞毒性。我们令人信服的证据表明，与单一疗法相比，联合疗法能更有效地抑制肿瘤生长并延长生存期，从而缓解了单药疗法固有的局限性。肿瘤微环境的显著改变推动了疗效的增强，使其向有利于免疫原性的条件倾斜。CD8+/CD4+ T细胞比率的提高以及免疫抑制性MDSC和Treg细胞群的减少都证明了这一点。在机理方面，协同疗法提高了肿瘤中CXCL13的表达水平，从而促进T细胞进入肿瘤环境。总之，我们的研究结果主张将综合疗法作为克服 PD1 抗体耐药性的一种有效机制，利用改善的 T 细胞功能和浸润。这项研究为通过应用创新治疗策略增强抗肿瘤免疫力提供了重要的视角。
{"title":"Unlocking PD-1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression","authors":"Xiaoqin Wang, Yinsha Miao, Jinghui Shen, Dandan Li, Xinyue Deng, Chengcheng Yang, Yanhong Ji, ZhiJun Dai, Yunfeng Ma","doi":"10.1111/sji.13356","DOIUrl":"https://doi.org/10.1111/sji.13356","url":null,"abstract":"In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8<sup>+</sup> T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8<sup>+</sup>/CD4<sup>+</sup> T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"3 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139518034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ke Zhu, Chen Liu, Xiaofang Guo, Xuting Zhang, Jiaxin Xie, Songmiao Xie, Qing Qi, Bin Yang
Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Vascular damage is one of the important features of SSc, which affects the progression and prognosis of the disease. MiR-126-3p is an important microRNA (miRNA) that regulates vascular structure and function, which can be transported through exosomes. However, the role of miR-126-3p in vascular damage in SSc is still unclear. Therefore, we focused on the connection between miR-126-3p and vascular damage in SSc, as well as investigated the potential role of miR-126-3p in vascular damage in SSc. First, this study successfully extracted extracellular vesicles from clinical plasma samples and characterized the exosomes within them. Then, we predicted and screened the target pathway mammalian/mechanistic target of rapamycin (mTOR) and the target gene SLC7A5 of miR-126-3p through online databases. Next, we constructed SSc mice for in vivo studies. The results showed that the expression of miR-126-3p was decreased in the plasma exosomes, while the SLC7A5 expression, autophagy, and lipid peroxidation were increased in the aorta. Luciferase reporter gene assays demonstrated that miR-126-3p can bind to SLC7A5, resulting in a decrease in its expression. In vitro experiments have shown that exosomal miR-126-3p can be internalized by human umbilical vein endothelial cells (HUVECs). The miR-126-3p group exhibited enhanced cell viability and tube formation ability, along with increased expression of the vascular formation marker CD31. Additionally, miR-126-3p downregulated the protein expression of SLC7A5 and LC3 in HUVECs, while upregulating the protein expression of mTOR, P62, PPARγ, and CPT-1. However, the effects of miR-126-3p on HUVECs were counteracted by mTOR inhibitors and enhanced by mTOR activators. The results indicated that exosomal miR-126-3p has the potential to protect against vascular injury in SSc by regulating the SLC7A5/mTOR signalling pathway in HUVECs.
{"title":"Exosomal miR-126-3p: Potential protection against vascular damage by regulating the SLC7A5/mTOR Signalling pathway in human umbilical vein endothelial cells","authors":"Ke Zhu, Chen Liu, Xiaofang Guo, Xuting Zhang, Jiaxin Xie, Songmiao Xie, Qing Qi, Bin Yang","doi":"10.1111/sji.13354","DOIUrl":"https://doi.org/10.1111/sji.13354","url":null,"abstract":"Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Vascular damage is one of the important features of SSc, which affects the progression and prognosis of the disease. MiR-126-3p is an important microRNA (miRNA) that regulates vascular structure and function, which can be transported through exosomes. However, the role of miR-126-3p in vascular damage in SSc is still unclear. Therefore, we focused on the connection between miR-126-3p and vascular damage in SSc, as well as investigated the potential role of miR-126-3p in vascular damage in SSc. First, this study successfully extracted extracellular vesicles from clinical plasma samples and characterized the exosomes within them. Then, we predicted and screened the target pathway mammalian/mechanistic target of rapamycin (mTOR) and the target gene SLC7A5 of miR-126-3p through online databases. Next, we constructed SSc mice for in vivo studies. The results showed that the expression of miR-126-3p was decreased in the plasma exosomes, while the SLC7A5 expression, autophagy, and lipid peroxidation were increased in the aorta. Luciferase reporter gene assays demonstrated that miR-126-3p can bind to SLC7A5, resulting in a decrease in its expression. In vitro experiments have shown that exosomal miR-126-3p can be internalized by human umbilical vein endothelial cells (HUVECs). The miR-126-3p group exhibited enhanced cell viability and tube formation ability, along with increased expression of the vascular formation marker CD31. Additionally, miR-126-3p downregulated the protein expression of SLC7A5 and LC3 in HUVECs, while upregulating the protein expression of mTOR, P62, PPARγ, and CPT-1. However, the effects of miR-126-3p on HUVECs were counteracted by mTOR inhibitors and enhanced by mTOR activators. The results indicated that exosomal miR-126-3p has the potential to protect against vascular injury in SSc by regulating the SLC7A5/mTOR signalling pathway in HUVECs.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"14 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139498207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lianfang Pu, Huiping Wang, Fan Wu, Furun An, Hao Xiao, Yangyang Wang, Xue Liang, Zhimin Zhai
Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in treating relapsed/refractory acute B-cell lymphoblastic leukaemia (R/R B-ALL). However, a subset of patients does not benefit from CAR-T therapy. Our study aims to identify predictive indicators and establish a model to evaluate the feasibility of CAR-T therapy. Fifty-five R/R B-ALL patients and 22 healthy donors were enrolled. Peripheral blood lymphocyte subsets were analysed using flow cytometry. Sensitivity, specificity, accuracy, positive and negative predictive values and receiver operating characteristic (ROC) areas under the curve (AUC) were determined to evaluate the predictive values of the indicators. We identified B lymphocyte, regulatory T cell (Treg) and peripheral blood minimal residual leukaemia cells (B-MRD) as indicators for predicting the success of CAR-T cell preparation with AUC 0.936, 0.857 and 0.914. Furthermore, a model based on CD3+ T count, CD4+ T/CD8+ T ratio, Treg and extramedullary diseases (EMD) was used to predict the response to CAR-T therapy with AUC of 0.938. Notably, a model based on CD4+ T/CD8+ T ratio, B, Treg and EMD were used in predicting the success of CAR-T therapy with AUC 0.966 [0.908–1.000], with specificity (92.59%) and sensitivity (91.67%). In the validated group, the predictive model predicted the success of CAR-T therapy with specificity (90.91%) and sensitivity (100%). We have identified several predictive indicators for CAR-T cell therapy success and a model has demonstrated robust predictive capacity for the success of CAR-T therapy. These results show great potential for guiding informed clinical decisions in the field of CAR-T cell therapy.
嵌合抗原受体 T 细胞（CAR-T）疗法在治疗复发/难治性急性 B 细胞淋巴细胞白血病（R/R B-ALL）方面疗效显著。然而，有一部分患者并不能从CAR-T疗法中获益。我们的研究旨在确定预测指标，并建立一个评估CAR-T疗法可行性的模型。研究共招募了 55 名 R/R B-ALL 患者和 22 名健康供体。使用流式细胞术分析了外周血淋巴细胞亚群。确定了敏感性、特异性、准确性、阳性和阴性预测值以及曲线下接收者操作特征（ROC）面积（AUC），以评估指标的预测值。我们发现 B 淋巴细胞、调节性 T 细胞（Treg）和外周血最小残留白血病细胞（B-MRD）是预测 CAR-T 细胞制备成功与否的指标，其 AUC 分别为 0.936、0.857 和 0.914。此外，基于 CD3+ T 计数、CD4+ T/CD8+ T 比率、Treg 和髓外疾病（EMD）的模型被用来预测 CAR-T 疗法的反应，AUC 为 0.938。值得注意的是，基于 CD4+ T/CD8+ T 比率、B、Treg 和 EMD 的模型用于预测 CAR-T 疗法的成功率，AUC 为 0.966 [0.908-1.000]，特异性（92.59%）和灵敏度（91.67%）均为 0.938。在验证组中，预测模型预测 CAR-T 疗法的成功率为特异性（90.91%）和灵敏度（100%）。我们确定了 CAR-T 细胞疗法成功与否的几个预测指标，并建立了一个模型，该模型对 CAR-T 疗法的成功与否具有很强的预测能力。这些结果表明，CAR-T 细胞疗法在指导临床知情决策方面具有巨大潜力。
{"title":"Predictive model for CAR-T cell therapy success in patients with relapsed/refractory B-cell acute lymphoblastic leukaemia","authors":"Lianfang Pu, Huiping Wang, Fan Wu, Furun An, Hao Xiao, Yangyang Wang, Xue Liang, Zhimin Zhai","doi":"10.1111/sji.13352","DOIUrl":"https://doi.org/10.1111/sji.13352","url":null,"abstract":"Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in treating relapsed/refractory acute B-cell lymphoblastic leukaemia (R/R B-ALL). However, a subset of patients does not benefit from CAR-T therapy. Our study aims to identify predictive indicators and establish a model to evaluate the feasibility of CAR-T therapy. Fifty-five R/R B-ALL patients and 22 healthy donors were enrolled. Peripheral blood lymphocyte subsets were analysed using flow cytometry. Sensitivity, specificity, accuracy, positive and negative predictive values and receiver operating characteristic (ROC) areas under the curve (AUC) were determined to evaluate the predictive values of the indicators. We identified B lymphocyte, regulatory T cell (Treg) and peripheral blood minimal residual leukaemia cells (B-MRD) as indicators for predicting the success of CAR-T cell preparation with AUC 0.936, 0.857 and 0.914. Furthermore, a model based on CD3<sup>+</sup> T count, CD4<sup>+</sup> T/CD8<sup>+</sup> T ratio, Treg and extramedullary diseases (EMD) was used to predict the response to CAR-T therapy with AUC of 0.938. Notably, a model based on CD4<sup>+</sup> T/CD8<sup>+</sup> T ratio, B, Treg and EMD were used in predicting the success of CAR-T therapy with AUC 0.966 [0.908–1.000], with specificity (92.59%) and sensitivity (91.67%). In the validated group, the predictive model predicted the success of CAR-T therapy with specificity (90.91%) and sensitivity (100%). We have identified several predictive indicators for CAR-T cell therapy success and a model has demonstrated robust predictive capacity for the success of CAR-T therapy. These results show great potential for guiding informed clinical decisions in the field of CAR-T cell therapy.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"13 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139498243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Celiac disease (CD) is a common immune-mediated, gluten-sensitive enteropathy that develops in human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 allele carriers due to the dysregulation of gluten-specific T helper cells. Although ingested gluten from cereals was identified as the disease driver in the 1950s, the ultimate cause (or disease trigger) remains unknown. CD is further characterized by the production by intestinal B cells of autoantibodies against tissue transglutaminase 2, an enzyme that can modify gluten peptides by deamidation, thus rendering gluten more recognizable for celiac patient T cells. The celiac intestinal lesion is hallmarked by crypt hyperplasia and villus atrophy, but also by intraepithelial T cells and lamina propria plasma cell infiltration.<span><sup>1, 2</sup></span></p> <p>So far, an accurate CD model in rodents that would unite the features listed above does not exist.<span><sup>3</sup></span> HLA-DQ2 or HLA-DQ8 transgenic, mouse class II knockout models provide appropriate restriction of T helper cells, valuable for the experimental study of cellular and humoral immune responses directed at gluten. But HLA-transgenic mice do not develop disease on gluten-containing diet, or following various additional challenges, while any histological changes in the intestine remain mild and rudimentary.<span><sup>4-7</sup></span> In contrast, Rag1<sup>−/−</sup> mice adoptively transferred with gliadin memory T cells have been described as a CD model with an intestinal phenotype that includes villus atrophy, crypt hyperplasia and mucosal mononuclear cell infiltration.<span><sup>8</sup></span> However, the gluten-sensitive enteropathy in this model depends on the quantitative depletion of regulatory T cells. Consequently, negative control mice on gluten-free diet also show mild-to-moderate (autoimmune) enteropathy.</p> <p>In-depth histological analyses are vital for the development of animal models of human diseases. Since CD primarily affects the proximal small intestine, and is characterized by well-documented histological changes,<span><sup>2</sup></span> thorough histological investigation of at least the entire small intestine, that is, duodenum, jejunum and ileum, is key for the validation of any animal model of human CD.<span><sup>3</sup></span> Non-validated surrogate biomarkers such as immune mediators or anti-gliadin antibodies cannot replace histological parameters. The assessment of architectural changes in the small intestine forms an important part of the histological analysis in CD and its animal models. However, it is well known that villus/crypt (V/C) ratios are notoriously unreliable as sole parameters of intestinal damage for various reasons; they are affected by diets, the age of the animal, and location in the intestinal compartment, as well as technical issues, for example, sampling consistency,<span><sup>9</sup></span> tissue orientation<span><sup>10</sup></span> or compression by luminal content. Intraepithel
{"title":"Concerns about the histological assessment in a mouse model of human celiac disease","authors":"Tobias L. Freitag, Leif C. Andersson, Anja Kipar","doi":"10.1111/sji.13351","DOIUrl":"https://doi.org/10.1111/sji.13351","url":null,"abstract":"<p>Celiac disease (CD) is a common immune-mediated, gluten-sensitive enteropathy that develops in human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 allele carriers due to the dysregulation of gluten-specific T helper cells. Although ingested gluten from cereals was identified as the disease driver in the 1950s, the ultimate cause (or disease trigger) remains unknown. CD is further characterized by the production by intestinal B cells of autoantibodies against tissue transglutaminase 2, an enzyme that can modify gluten peptides by deamidation, thus rendering gluten more recognizable for celiac patient T cells. The celiac intestinal lesion is hallmarked by crypt hyperplasia and villus atrophy, but also by intraepithelial T cells and lamina propria plasma cell infiltration.<span><sup>1, 2</sup></span></p>\u0000<p>So far, an accurate CD model in rodents that would unite the features listed above does not exist.<span><sup>3</sup></span> HLA-DQ2 or HLA-DQ8 transgenic, mouse class II knockout models provide appropriate restriction of T helper cells, valuable for the experimental study of cellular and humoral immune responses directed at gluten. But HLA-transgenic mice do not develop disease on gluten-containing diet, or following various additional challenges, while any histological changes in the intestine remain mild and rudimentary.<span><sup>4-7</sup></span> In contrast, Rag1<sup>−/−</sup> mice adoptively transferred with gliadin memory T cells have been described as a CD model with an intestinal phenotype that includes villus atrophy, crypt hyperplasia and mucosal mononuclear cell infiltration.<span><sup>8</sup></span> However, the gluten-sensitive enteropathy in this model depends on the quantitative depletion of regulatory T cells. Consequently, negative control mice on gluten-free diet also show mild-to-moderate (autoimmune) enteropathy.</p>\u0000<p>In-depth histological analyses are vital for the development of animal models of human diseases. Since CD primarily affects the proximal small intestine, and is characterized by well-documented histological changes,<span><sup>2</sup></span> thorough histological investigation of at least the entire small intestine, that is, duodenum, jejunum and ileum, is key for the validation of any animal model of human CD.<span><sup>3</sup></span> Non-validated surrogate biomarkers such as immune mediators or anti-gliadin antibodies cannot replace histological parameters. The assessment of architectural changes in the small intestine forms an important part of the histological analysis in CD and its animal models. However, it is well known that villus/crypt (V/C) ratios are notoriously unreliable as sole parameters of intestinal damage for various reasons; they are affected by diets, the age of the animal, and location in the intestinal compartment, as well as technical issues, for example, sampling consistency,<span><sup>9</sup></span> tissue orientation<span><sup>10</sup></span> or compression by luminal content. Intraepithel","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"2615 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139498204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vinaya Dulipati, Juha Kotimaa, Mikel Rezola, Mikko Kontiainen, Hanna Jarva, Dag Nyman, Seppo Meri
Lyme borreliosis, caused by Borrelia burgdorferi sensu lato, is the most common tickborne disease. Its neuronal form, neuroborreliosis, comprises 3 to 38% of borreliosis cases in Europe. Borrelia outer surface proteins and virulence factors, OspE and BBK32, have been previously reported to help cause infection by promoting attachment to human host epithelial cells and evading complement attack. We assessed the serological responses to BBK32 and OspE in 19 individuals diagnosed with neuroborreliosis to see whether antibodies that could both target the bacteria and neutralize the virulence mechanisms on the microbial surface emerge. Results evaluate levels of total protein, IgG and the chemokine CXCL13, a determinant for B-cell recruitment during neuroinflammation, in patients' cerebrospinal fluid samples. Antibody levels against BBK32 and OspE correlated with those against VlsE, a well-characterized diagnostic serological marker of the disease. A dual serological profile of the patients was observed. K-means clustering split the cohort into two discrete groups presenting distinct serological and CNS responses. One group contained young patients with low levels of anti-BBK32 and OspE antibodies. The other group showed stronger responses, possibly following prolonged infections or reinfections. Additionally, we assessed anti-ganglioside antibodies that could cause autoimmunity or complement dysregulation but observed that they did not correlate with neuroborreliosis in our patient cohort. The dual nature of antibody responses against the virulence factors BBK32 and OspE in neuroborreliosis patients may suggest the necessity of repeated exposures for efficient immune responses. Better protection could be achieved if the virulence factors were formulated into vaccines.
由常染色体包柔氏包虫病（Borrelia burgdorferi sensu lato）引起的莱姆包虫病是最常见的蜱媒疾病。在欧洲，神经型包虫病占包虫病病例的 3% 至 38%。据报道，包柔氏菌的外表面蛋白和致病因子 OspE 和 BBK32 能促进包柔氏菌附着在人类宿主上皮细胞上并逃避补体攻击，从而帮助引起感染。我们评估了 19 名确诊为神经源性疾病患者对 BBK32 和 OspE 的血清反应，以了解是否出现了既能针对细菌又能中和微生物表面毒力机制的抗体。结果评估了患者脑脊液样本中总蛋白、IgG 和趋化因子 CXCL13（神经炎症期间 B 细胞招募的决定因素）的水平。针对 BBK32 和 OspE 的抗体水平与针对 VlsE 的抗体水平相关，而 VlsE 是一种特征明确的疾病诊断血清学标志物。患者的血清学特征具有双重性。K-means 聚类方法将患者分为两组，分别表现出不同的血清学和中枢神经系统反应。一组是抗BBK32和OspE抗体水平较低的年轻患者。另一组则表现出较强的反应，可能是在长期感染或再次感染后出现的。此外，我们还评估了可能导致自身免疫或补体失调的抗神经节苷脂抗体，但发现在我们的患者队列中，这些抗体与神经源性疾病并不相关。神经源性疾病患者体内针对毒力因子 BBK32 和 OspE 的抗体反应具有双重性，这可能表明需要反复接触才能产生有效的免疫反应。如果将致病因子制成疫苗，就能获得更好的保护。
{"title":"Antibody responses to immunoevasion proteins BBK32 and OspE constitute part of the serological footprint in neuroborreliosis but are insufficient to prevent the disease","authors":"Vinaya Dulipati, Juha Kotimaa, Mikel Rezola, Mikko Kontiainen, Hanna Jarva, Dag Nyman, Seppo Meri","doi":"10.1111/sji.13353","DOIUrl":"https://doi.org/10.1111/sji.13353","url":null,"abstract":"Lyme borreliosis, caused by <i>Borrelia burgdorferi</i> sensu lato, is the most common tickborne disease. Its neuronal form, neuroborreliosis, comprises 3 to 38% of borreliosis cases in Europe. <i>Borrelia</i> outer surface proteins and virulence factors, OspE and BBK32, have been previously reported to help cause infection by promoting attachment to human host epithelial cells and evading complement attack. We assessed the serological responses to BBK32 and OspE in 19 individuals diagnosed with neuroborreliosis to see whether antibodies that could both target the bacteria and neutralize the virulence mechanisms on the microbial surface emerge. Results evaluate levels of total protein, IgG and the chemokine CXCL13, a determinant for B-cell recruitment during neuroinflammation, in patients' cerebrospinal fluid samples. Antibody levels against BBK32 and OspE correlated with those against VlsE, a well-characterized diagnostic serological marker of the disease. A dual serological profile of the patients was observed. K-means clustering split the cohort into two discrete groups presenting distinct serological and CNS responses. One group contained young patients with low levels of anti-BBK32 and OspE antibodies. The other group showed stronger responses, possibly following prolonged infections or reinfections. Additionally, we assessed anti-ganglioside antibodies that could cause autoimmunity or complement dysregulation but observed that they did not correlate with neuroborreliosis in our patient cohort. The dual nature of antibody responses against the virulence factors BBK32 and OspE in neuroborreliosis patients may suggest the necessity of repeated exposures for efficient immune responses. Better protection could be achieved if the virulence factors were formulated into vaccines.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"23 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139421742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Repurposing drugs and adjuvants is an attractive choice of present therapy that reduces the substantial costs, chances of failure, and systemic toxicity. Mycobacterium indicus pranii was originally developed as a leprosy vaccine but later has been found effective against Leishmania donovani infection. To extend our earlier study, here we reported the immunotherapeutic modulation of the splenic and circulatory neutrophils in favour of hosts as neutrophils actually serve as the pro-parasitic portable shelter to extend the Leishmania infection specifically during the early entry into the hosts' circulation. We targeted to disrupt this early pro-parasitic incidence by the therapeutic combination of M. indicus pranii and heat-induced promastigotes against antimony-resistant L. donovani infection. The combination therapy induced the functional expansion of CD11b+Ly6CintLy6Ghi neutrophils both in the post-infected spleen, and also in the circulation of post-treated animals followed by the immediate Leishmania infection. More importantly, the enhanced expression of MHC-II, phagocytic uptake of the parasites by the circulatory neutrophils as well as the oxidative burst were induced that limited the chances of the very early establishment of the infection. The enhanced expression of pro-inflammatory cytokines, like IL-1α and TNF-α indicated resistance to the parasite-mediated takeover of the neutrophils, as these cytokines are critical for the activation of T cell-mediated immunity and host-protective responses. Additionally, the induction of essential transcription factors and cytokines for early granulocytic lineage commitment suggests that the strategy not only contributed to the peripheral activation of the neutrophils but also promoted granulopoiesis in the bone marrow.
{"title":"Activation of neutrophils excels the therapeutic potential of Mycobacterium indicus pranii and heat-induced promastigotes against antimony-resistant Leishmania donovani infection","authors":"Kamalika Roy, Sanhita Ghosh, Mintu Karan, Suman Karmakar, Supriya Nath, Bedanta Das, Sharmistha Paul, Pritam Mandal, Monalisa Ray, Mousumi Das, Soumyadip Mukherjee, Somaditya Dey, Chiranjib Pal","doi":"10.1111/sji.13350","DOIUrl":"https://doi.org/10.1111/sji.13350","url":null,"abstract":"Repurposing drugs and adjuvants is an attractive choice of present therapy that reduces the substantial costs, chances of failure, and systemic toxicity. <i>Mycobacterium indicus pranii</i> was originally developed as a leprosy vaccine but later has been found effective against <i>Leishmania donovani</i> infection. To extend our earlier study, here we reported the immunotherapeutic modulation of the splenic and circulatory neutrophils in favour of hosts as neutrophils actually serve as the pro-parasitic portable shelter to extend the <i>Leishmania</i> infection specifically during the early entry into the hosts' circulation. We targeted to disrupt this early pro-parasitic incidence by the therapeutic combination of <i>M. indicus pranii</i> and heat-induced promastigotes against antimony-resistant <i>L. donovani</i> infection. The combination therapy induced the functional expansion of CD11b<sup>+</sup>Ly6C<sup>int</sup>Ly6G<sup>hi</sup> neutrophils both in the post-infected spleen, and also in the circulation of post-treated animals followed by the immediate <i>Leishmania</i> infection. More importantly, the enhanced expression of MHC-II, phagocytic uptake of the parasites by the circulatory neutrophils as well as the oxidative burst were induced that limited the chances of the very early establishment of the infection. The enhanced expression of pro-inflammatory cytokines, like IL-1α and TNF-α indicated resistance to the parasite-mediated takeover of the neutrophils, as these cytokines are critical for the activation of T cell-mediated immunity and host-protective responses. Additionally, the induction of essential transcription factors and cytokines for early granulocytic lineage commitment suggests that the strategy not only contributed to the peripheral activation of the neutrophils but also promoted granulopoiesis in the bone marrow.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"16 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139411897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2023-08-23DOI: 10.1111/sji.13323
Lasse Melvaer Giil, Silja Hanseth, Ognjen Bojovic, Jan Erik Nordrehaug, Per Magne Ueland, Klaus Meyer, Grethe S Tell
Background: C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations.
Objectives: To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes.
Methods: We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions.
Results: CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use.
Conclusions: Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.
{"title":"The inverse association between the apolipoprotein E ε4 allele and C-reactive protein levels is stronger in persons with obesity and diabetes.","authors":"Lasse Melvaer Giil, Silja Hanseth, Ognjen Bojovic, Jan Erik Nordrehaug, Per Magne Ueland, Klaus Meyer, Grethe S Tell","doi":"10.1111/sji.13323","DOIUrl":"10.1111/sji.13323","url":null,"abstract":"<p><strong>Background: </strong>C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations.</p><p><strong>Objectives: </strong>To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes.</p><p><strong>Methods: </strong>We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions.</p><p><strong>Results: </strong>CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use.</p><p><strong>Conclusions: </strong>Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":" ","pages":"e13323"},"PeriodicalIF":3.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41170126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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