T regulatory lymphocytes (Treg) expressing CCR5 exhibit strong suppression activity in various autoimmune disorders. However, there remains a lack of comprehensive understanding regarding their involvement in the development of type 1 diabetes (T1D). In this study, we examined the role of the CCR5/CCL5 axis in regulating inflammatory response and its impact on regulatory T cells in type 1 diabetes (T1D). We hypothesize that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of T1D through modulation of Treg-dependent immune responses. We analyzed the expression levels of CCR5 on Tregs isolated from individuals with T1D, as well as the plasma concentration of its main ligands. We found that Tregs from T1D patients exhibited decreased expression of CCR5 compared to healthy controls. Additionally, we observed a correlation between the expression levels of CCR5 on Tregs and their immunosuppressive function in T1D patients. Our results indicate the impaired migratory capacity of CCR5 + Tregs, suggesting a possible link between the dysregulation of the CCR5/CCL5 axis and impaired immune regulation in T1D. In line with previous studies, our findings support the notion that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of type 1 diabetes (T1D) by modulating Treg-dependent immune responses. The decreased expression of CCR5 on Tregs in T1D patients suggests a potential impairment in the migratory capacity of these cells, which could compromise their ability to suppress autoreactive T cells and maintain immune homeostasis. Furthermore, our study highlights the importance of CCR5 as a biomarker for identifying dysfunctional Tregs in T1D.
{"title":"Exploring CCR5 + T regulatory cell subset dysfunction in type 1 diabetes patients: implications for immune regulation.","authors":"Ławrynowicz Urszula, Juhas Ulana, Słomiński Bartosz, Okońska Maja, Myśliwiec Małgorzata, Ryba-Stanisławowska Monika","doi":"10.1007/s12026-024-09508-2","DOIUrl":"10.1007/s12026-024-09508-2","url":null,"abstract":"<p><p>T regulatory lymphocytes (Treg) expressing CCR5 exhibit strong suppression activity in various autoimmune disorders. However, there remains a lack of comprehensive understanding regarding their involvement in the development of type 1 diabetes (T1D). In this study, we examined the role of the CCR5/CCL5 axis in regulating inflammatory response and its impact on regulatory T cells in type 1 diabetes (T1D). We hypothesize that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of T1D through modulation of Treg-dependent immune responses. We analyzed the expression levels of CCR5 on Tregs isolated from individuals with T1D, as well as the plasma concentration of its main ligands. We found that Tregs from T1D patients exhibited decreased expression of CCR5 compared to healthy controls. Additionally, we observed a correlation between the expression levels of CCR5 on Tregs and their immunosuppressive function in T1D patients. Our results indicate the impaired migratory capacity of CCR5 + Tregs, suggesting a possible link between the dysregulation of the CCR5/CCL5 axis and impaired immune regulation in T1D. In line with previous studies, our findings support the notion that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of type 1 diabetes (T1D) by modulating Treg-dependent immune responses. The decreased expression of CCR5 on Tregs in T1D patients suggests a potential impairment in the migratory capacity of these cells, which could compromise their ability to suppress autoreactive T cells and maintain immune homeostasis. Furthermore, our study highlights the importance of CCR5 as a biomarker for identifying dysfunctional Tregs in T1D.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1061-1070"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer remains the most common malignant carcinoma among women globally and is resistant to several therapeutic agents. There is a need for novel targets to improve the prognosis of patients with breast cancer. Bioinformatics analyses were conducted to explore potentially relevant prognostic genes in breast cancer using The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases. Gene subtypes were categorized by machine learning algorithms. The machine learning-related breast cancer (MLBC) score was evaluated through principal component analysis (PCA) of clinical patients' pathological statuses and subtypes. Immune cell infiltration was analyzed using the xCell and CIBERSORT algorithms. Kyoto Encyclopedia of Genes and Genomes enrichment analysis elucidated regulatory pathways related to speedy/RINGO cell cycle regulator family member C (SPDYC) in breast cancer. The biological functions and lipid metabolic status of breast cancer cell lines were validated via quantitative real-time polymerase chain reaction (RT‒qPCR) assays, western blotting, CCK-8 assays, PI‒Annexin V fluorescence staining, transwell assays, wound healing assays, and Oil Red O staining. Key differentially expressed genes (DEGs) in breast cancer from the TCGA and GEO databases were screened and utilized to establish the MLBC score. Moreover, the MLBC score we established was negatively correlated with poor prognosis in breast cancer patients. Furthermore, the impacts of SPDYC on the tumor immune microenvironment and lipid metabolism in breast cancer were revealed and validated. SPDYC is closely related to activated dendritic cells and macrophages and is simultaneously correlated with the immune checkpoints CD47, cytotoxic T lymphocyte antigen-4 (CTLA-4), and poliovirus receptor (PVR). SPDYC strongly correlated with C-C motif chemokine ligand 7 (CCL7), a chemokine that influences breast cancer patient prognosis. A significant relationship was discovered between key genes involved in lipid metabolism and SPDYC, such as ELOVL fatty acid elongase 2 (ELOVL2), malic enzyme 1 (ME1), and squalene epoxidase (SQLE). Potent inhibitors targeting SPDYC in breast cancer were also discovered, including JNK inhibitor VIII, AICAR, and JW-7-52-1. Downregulation of SPDYC expression in vitro decreased proliferation, increased the apoptotic rate, decreased migration, and reduced lipid droplets. SPDYC possibly influences the tumor immune microenvironment and regulates lipid metabolism in breast cancer. Hence, this study identified SPDYC as a pivotal biomarker for developing therapeutic strategies for breast cancer.
{"title":"SPDYC serves as a prognostic biomarker related to lipid metabolism and the immune microenvironment in breast cancer.","authors":"Xinxin Chen, Haojie Peng, Zhentao Zhang, Changnian Yang, Yingqi Liu, Yanzhen Chen, Fei Yu, Shanshan Wu, Lixue Cao","doi":"10.1007/s12026-024-09505-5","DOIUrl":"10.1007/s12026-024-09505-5","url":null,"abstract":"<p><p>Breast cancer remains the most common malignant carcinoma among women globally and is resistant to several therapeutic agents. There is a need for novel targets to improve the prognosis of patients with breast cancer. Bioinformatics analyses were conducted to explore potentially relevant prognostic genes in breast cancer using The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases. Gene subtypes were categorized by machine learning algorithms. The machine learning-related breast cancer (MLBC) score was evaluated through principal component analysis (PCA) of clinical patients' pathological statuses and subtypes. Immune cell infiltration was analyzed using the xCell and CIBERSORT algorithms. Kyoto Encyclopedia of Genes and Genomes enrichment analysis elucidated regulatory pathways related to speedy/RINGO cell cycle regulator family member C (SPDYC) in breast cancer. The biological functions and lipid metabolic status of breast cancer cell lines were validated via quantitative real-time polymerase chain reaction (RT‒qPCR) assays, western blotting, CCK-8 assays, PI‒Annexin V fluorescence staining, transwell assays, wound healing assays, and Oil Red O staining. Key differentially expressed genes (DEGs) in breast cancer from the TCGA and GEO databases were screened and utilized to establish the MLBC score. Moreover, the MLBC score we established was negatively correlated with poor prognosis in breast cancer patients. Furthermore, the impacts of SPDYC on the tumor immune microenvironment and lipid metabolism in breast cancer were revealed and validated. SPDYC is closely related to activated dendritic cells and macrophages and is simultaneously correlated with the immune checkpoints CD47, cytotoxic T lymphocyte antigen-4 (CTLA-4), and poliovirus receptor (PVR). SPDYC strongly correlated with C-C motif chemokine ligand 7 (CCL7), a chemokine that influences breast cancer patient prognosis. A significant relationship was discovered between key genes involved in lipid metabolism and SPDYC, such as ELOVL fatty acid elongase 2 (ELOVL2), malic enzyme 1 (ME1), and squalene epoxidase (SQLE). Potent inhibitors targeting SPDYC in breast cancer were also discovered, including JNK inhibitor VIII, AICAR, and JW-7-52-1. Downregulation of SPDYC expression in vitro decreased proliferation, increased the apoptotic rate, decreased migration, and reduced lipid droplets. SPDYC possibly influences the tumor immune microenvironment and regulates lipid metabolism in breast cancer. Hence, this study identified SPDYC as a pivotal biomarker for developing therapeutic strategies for breast cancer.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1030-1050"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418772","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}
Background: The cause of food allergy (FA) is still a mystery. Telomerases are involved in the regulation of immune responses. This study aims to gain an understanding of the contribution of telomerase reverse transcriptase (TERT) to the pathogenesis of FA.
Methods: A murine FA model was established with ovalbumin as the specific antigen. The role of TERT in regulating dendritic cell (DC) immune tolerogenic functions was evaluated in this murine model.
Results: We observed that the Tert promoter was at demethylation status and the Tert expression was elevated in DCs of FA mice. The Tert expression in DCs had a positive correlation with the FA response. TERT prevented the induction of Il10 expression in DCs. The immune tolerogenic functions of DCs were diminished by TERT. The immune tolerogenic functions of DC were restored by CpG by boosting the Tert promoter methylation. Administration of CpG promoted the therapeutic effects of allergen specific immunotherapy in FA mice.
Conclusions: Low levels of Il10 expression and high levels of Tert expression were observed in intestinal DCs of FA mice. CpG exposure restored the expression of Il10 and increased the therapeutic benefits of allergen-specific immunotherapy.
背景:食物过敏症(FA)的病因至今仍是一个谜。端粒酶参与调节免疫反应。本研究旨在了解端粒酶逆转录酶(TERT)对食物过敏症发病机制的贡献:方法:以卵清蛋白为特异性抗原建立了小鼠FA模型。方法:以卵清蛋白为特异性抗原建立了小鼠FA模型,评估了TERT在调节树突状细胞(DC)免疫耐受功能中的作用:结果:我们观察到,在 FA 小鼠的 DC 中,Tert 启动子处于去甲基化状态,Tert 表达升高。Tert在DCs中的表达与FA反应呈正相关。TERT阻止了Il10在DCs中的诱导表达。TERT削弱了DCs的免疫耐受功能。CpG通过促进Tert启动子甲基化恢复了DC的免疫耐受功能。CpG能促进过敏原特异性免疫疗法对FA小鼠的治疗效果:结论:在 FA 小鼠的肠道 DC 中观察到低水平的 Il10 表达和高水平的 Tert 表达。结论:在 FA 小鼠的肠道直流细胞中观察到了低水平的 Il10 表达和高水平的 Tert 表达,CpG 暴露可恢复 Il10 的表达并提高过敏原特异性免疫疗法的治疗效果。
{"title":"Regulation of Tert methylation alleviates food allergy via regulating the Tert-IL10 signal pathway.","authors":"Haotao Zeng, Lingzhi Xu, Jiangqi Liu, Lihua Mo, Minyao Li, Shuo Song, Xuejie Xu, Shihan Miao, Miao Zhao, Pingchang Yang","doi":"10.1007/s12026-024-09504-6","DOIUrl":"10.1007/s12026-024-09504-6","url":null,"abstract":"<p><strong>Background: </strong>The cause of food allergy (FA) is still a mystery. Telomerases are involved in the regulation of immune responses. This study aims to gain an understanding of the contribution of telomerase reverse transcriptase (TERT) to the pathogenesis of FA.</p><p><strong>Methods: </strong>A murine FA model was established with ovalbumin as the specific antigen. The role of TERT in regulating dendritic cell (DC) immune tolerogenic functions was evaluated in this murine model.</p><p><strong>Results: </strong>We observed that the Tert promoter was at demethylation status and the Tert expression was elevated in DCs of FA mice. The Tert expression in DCs had a positive correlation with the FA response. TERT prevented the induction of Il10 expression in DCs. The immune tolerogenic functions of DCs were diminished by TERT. The immune tolerogenic functions of DC were restored by CpG by boosting the Tert promoter methylation. Administration of CpG promoted the therapeutic effects of allergen specific immunotherapy in FA mice.</p><p><strong>Conclusions: </strong>Low levels of Il10 expression and high levels of Tert expression were observed in intestinal DCs of FA mice. CpG exposure restored the expression of Il10 and increased the therapeutic benefits of allergen-specific immunotherapy.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1018-1029"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733981","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 : 2024-10-01Epub Date: 2024-08-30DOI: 10.1007/s12026-024-09518-0
Maurizio Benucci, Ilaria Di Girolamo, Antonino Di Girolamo, Francesca Li Gobbi, Arianna Damiani, Serena Guiducci, Barbara Lari, Valentina Grossi, Maria Infantino, Mariangela Manfredi
In the recent EULAR recommendations, ultrasound examination is now recommended as a first-line imaging test in all patients with suspected giant cell arteritis (GCA) and the axillary arteries should be included in the standard exam. As an alternative to ultrasound evaluation, cranial and extracranial arteries can be examined using FDG-PET or MRI. The aim of our study was to observe in a retrospective case series whether there is a correlation between biomarkers and imaging activity in a population of patients followed in real life with GCA treated with prednisone (PDN) and tocilizumab (TCZ). We retrospectively enrolled 68 patients with newly diagnosed GCA between January 2020 and September 2021, followed in real life, who were examined at the Rheumatology Unit of the San Giovanni di Dio Hospital, Florence, Italy. Patients were evaluated at T0-T3-T6-T12-T18-T24 for the following blood tests: ESR, CRP, fibrinogen, platelet count, serum amyloid A (SAA), IL-6, and circulating calprotectin (MRP). Ultrasound examination of the temporal arteries and axillary arteries was assessed at T0 within 7 days of starting treatment with high-dose glucocorticoids and subsequently at T3-T6-T12-T18-T24. A scale from 0 to 3 with semi-quantitative tools (SUV max) was assessed at T0-T12-T24. The evaluation of the correlation coefficient between laboratory and imaging variables has shown that SAA and MRP have the most powerful correlation with the PET score (0.523 and 0.64), and MRP also has an excellent correlation coefficient with the Halo score (0.658). The evaluation of the ROC curves shows for a PET score 3 and SAA values higher than 26 mg/L, sensitivity of 81.5% and specificity of 84.1%, and for a PET score 3 and MRP values higher than 2.3 mcg/mL, sensitivity of 100% and specificity of 76.8%. In this study, we demonstrated that SAA and MRP can be useful as promising tools to detect GCA activity. The study demonstrates a good correlation between the two biomarkers and the imaging activity evaluated by the Halo and PET scores.
{"title":"Predictive biomarkers of response to tocilizumab in giant cell arteritis (GCA): correlations with imaging activity.","authors":"Maurizio Benucci, Ilaria Di Girolamo, Antonino Di Girolamo, Francesca Li Gobbi, Arianna Damiani, Serena Guiducci, Barbara Lari, Valentina Grossi, Maria Infantino, Mariangela Manfredi","doi":"10.1007/s12026-024-09518-0","DOIUrl":"10.1007/s12026-024-09518-0","url":null,"abstract":"<p><p>In the recent EULAR recommendations, ultrasound examination is now recommended as a first-line imaging test in all patients with suspected giant cell arteritis (GCA) and the axillary arteries should be included in the standard exam. As an alternative to ultrasound evaluation, cranial and extracranial arteries can be examined using FDG-PET or MRI. The aim of our study was to observe in a retrospective case series whether there is a correlation between biomarkers and imaging activity in a population of patients followed in real life with GCA treated with prednisone (PDN) and tocilizumab (TCZ). We retrospectively enrolled 68 patients with newly diagnosed GCA between January 2020 and September 2021, followed in real life, who were examined at the Rheumatology Unit of the San Giovanni di Dio Hospital, Florence, Italy. Patients were evaluated at T0-T3-T6-T12-T18-T24 for the following blood tests: ESR, CRP, fibrinogen, platelet count, serum amyloid A (SAA), IL-6, and circulating calprotectin (MRP). Ultrasound examination of the temporal arteries and axillary arteries was assessed at T0 within 7 days of starting treatment with high-dose glucocorticoids and subsequently at T3-T6-T12-T18-T24. A scale from 0 to 3 with semi-quantitative tools (SUV max) was assessed at T0-T12-T24. The evaluation of the correlation coefficient between laboratory and imaging variables has shown that SAA and MRP have the most powerful correlation with the PET score (0.523 and 0.64), and MRP also has an excellent correlation coefficient with the Halo score (0.658). The evaluation of the ROC curves shows for a PET score 3 and SAA values higher than 26 mg/L, sensitivity of 81.5% and specificity of 84.1%, and for a PET score 3 and MRP values higher than 2.3 mcg/mL, sensitivity of 100% and specificity of 76.8%. In this study, we demonstrated that SAA and MRP can be useful as promising tools to detect GCA activity. The study demonstrates a good correlation between the two biomarkers and the imaging activity evaluated by the Halo and PET scores.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1154-1160"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107008","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 : 2024-10-01Epub Date: 2024-06-06DOI: 10.1007/s12026-024-09496-3
Irán Flores-Sotelo, Natalia Juárez, Marisol I González, Auraamellaly Chávez, Danielle T Vannan, Bertus Eksteen, Luis I Terrazas, José L Reyes
The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3-/-) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3-/- mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3-/- macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3-/- mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3-/- mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15.
{"title":"Endogenous innate sensor NLRP3 is a key component in peritoneal macrophage dynamics required for cestode establishment.","authors":"Irán Flores-Sotelo, Natalia Juárez, Marisol I González, Auraamellaly Chávez, Danielle T Vannan, Bertus Eksteen, Luis I Terrazas, José L Reyes","doi":"10.1007/s12026-024-09496-3","DOIUrl":"10.1007/s12026-024-09496-3","url":null,"abstract":"<p><p>The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3<sup>-/-</sup>) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3<sup>-/-</sup> mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3<sup>-/-</sup> macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3<sup>-/-</sup> mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3<sup>-/-</sup> mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"948-963"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease. Elevated serum immunoglobulin G (IgG) levels, autoantibodies, and histopathological interface hepatitis are the hallmarks of AIH. Autoantibodies and pathological findings, clinical and biochemical features, typical immunoglobulin levels, and exclusion of other diseases are used to diagnose the condition. Gamma-delta (γδ) T cells are a unique population of unconventional T cells with γ and δ glycoprotein chains. γδ T cells have been shown to play a crucial role in autoimmune diseases by producing interleukin (IL)-17. However, its role in AIH remains to be further elucidated. In this study, we aimed to examine the role of γδ T cells and IL-17 in the pathogenesis of AIH, by working on biopsy samples. Paraffin blocks of 18 patients with type 1 AIH and 18 control liver tissues were analyzed. qRT-PCR assessed IL-17 gene expression. Immunofluorescence double staining of CD3+TCRγδ+ was performed to reveal tissue-resident γδ T cells' role in AIH. When comparing AIH to the control, there was a substantial increase in the ratio of CD3+TCRγδ+ cells in total inflammatory cells (p = 0.01). IL-17 gene expression was lowered in AIH when compared to the control (p = 0.01). This study provides evidence for the involvement of γδ T cells and IL-17 in the pathogenesis of AIH. The ratio of γδ T cells and IL-17 gene expression showed a significant difference in AIH suggesting a potential role for γδ T cells in driving liver inflammation in A fIH.
{"title":"Investigation of the relationship of tissue-resident γδ T cells and IL-17 gene expression with the pathogenesis of autoimmune hepatitis.","authors":"Nurullah Yucel, Gulam Hekimoglu, Sevinc Keser, Selma Erhan, Gamze Yesilay, Gulizar Hocaoglu, Muzaffer Seker","doi":"10.1007/s12026-024-09515-3","DOIUrl":"10.1007/s12026-024-09515-3","url":null,"abstract":"<p><p>Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease. Elevated serum immunoglobulin G (IgG) levels, autoantibodies, and histopathological interface hepatitis are the hallmarks of AIH. Autoantibodies and pathological findings, clinical and biochemical features, typical immunoglobulin levels, and exclusion of other diseases are used to diagnose the condition. Gamma-delta (γδ) T cells are a unique population of unconventional T cells with γ and δ glycoprotein chains. γδ T cells have been shown to play a crucial role in autoimmune diseases by producing interleukin (IL)-17. However, its role in AIH remains to be further elucidated. In this study, we aimed to examine the role of γδ T cells and IL-17 in the pathogenesis of AIH, by working on biopsy samples. Paraffin blocks of 18 patients with type 1 AIH and 18 control liver tissues were analyzed. qRT-PCR assessed IL-17 gene expression. Immunofluorescence double staining of CD3<sup>+</sup>TCRγδ<sup>+</sup> was performed to reveal tissue-resident γδ T cells' role in AIH. When comparing AIH to the control, there was a substantial increase in the ratio of CD3<sup>+</sup>TCRγδ<sup>+</sup> cells in total inflammatory cells (p = 0.01). IL-17 gene expression was lowered in AIH when compared to the control (p = 0.01). This study provides evidence for the involvement of γδ T cells and IL-17 in the pathogenesis of AIH. The ratio of γδ T cells and IL-17 gene expression showed a significant difference in AIH suggesting a potential role for γδ T cells in driving liver inflammation in A fIH.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"895-901"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633414","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 : 2024-10-01Epub Date: 2024-05-29DOI: 10.1007/s12026-024-09497-2
Lada Rumora, Ivona Markelić, Iva Hlapčić, Andrea Hulina Tomašković, Marija Fabijanec, Feđa Džubur, Miroslav Samaržija, Andrea Vukić Dugac
The interplay between purinergic receptors as well as pattern recognition receptors like Toll-like receptors (TLRs) and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) might have a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to determine and compare the concentrations of the damage-associated molecular patterns (DAMPs) heat shock protein 70 (Hsp70) and adenosine triphosphate (ATP), and gene expression of their respective receptors as well as NLRP3 inflammasome-related molecules in the peripheral blood of patients with end-stage COPD before and 1 year after lung transplantation (LT). Lung function was assessed by spirometry and diffusion capacity for carbon monoxide (DLCO). Quantitative polymerase chain reaction (qPCR) was applied for detection of TLR2, TLR4, P2X7R, P2Y2R, IL1B, CASP1, and NLRP3 expression. High-sensitivity ELISA kits were used for extracellular (e) Hsp70 and IL-1β, and luminescence assay for eATP measurements. Concentrations of eHsp70 and eATP as well as IL-1β were significantly increased in the plasma of end-stage COPD patients and significantly decreased after LT. In addition, TLR4, P2Y2R, IL1B, CASP1, and NLRP3 expression was up-regulated in COPD patients before LT, while it was significantly suppressed after LT. In conclusion, it could be assumed that NLRP3 inflammasome is activated in the peripheral blood of end-stage COPD patients and that eHsp70 and eATP could be responsible for its activation through triggering their receptors. On the other hand, previously enhanced pro-inflammatory reactions seem to be suppressed to the healthy population levels in lung recipients without allograft rejection.
{"title":"Assessment of NLRP3 inflammasome activation in patients with chronic obstructive pulmonary disease before and after lung transplantation.","authors":"Lada Rumora, Ivona Markelić, Iva Hlapčić, Andrea Hulina Tomašković, Marija Fabijanec, Feđa Džubur, Miroslav Samaržija, Andrea Vukić Dugac","doi":"10.1007/s12026-024-09497-2","DOIUrl":"10.1007/s12026-024-09497-2","url":null,"abstract":"<p><p>The interplay between purinergic receptors as well as pattern recognition receptors like Toll-like receptors (TLRs) and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) might have a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to determine and compare the concentrations of the damage-associated molecular patterns (DAMPs) heat shock protein 70 (Hsp70) and adenosine triphosphate (ATP), and gene expression of their respective receptors as well as NLRP3 inflammasome-related molecules in the peripheral blood of patients with end-stage COPD before and 1 year after lung transplantation (LT). Lung function was assessed by spirometry and diffusion capacity for carbon monoxide (DLCO). Quantitative polymerase chain reaction (qPCR) was applied for detection of TLR2, TLR4, P2X7R, P2Y2R, IL1B, CASP1, and NLRP3 expression. High-sensitivity ELISA kits were used for extracellular (e) Hsp70 and IL-1β, and luminescence assay for eATP measurements. Concentrations of eHsp70 and eATP as well as IL-1β were significantly increased in the plasma of end-stage COPD patients and significantly decreased after LT. In addition, TLR4, P2Y2R, IL1B, CASP1, and NLRP3 expression was up-regulated in COPD patients before LT, while it was significantly suppressed after LT. In conclusion, it could be assumed that NLRP3 inflammasome is activated in the peripheral blood of end-stage COPD patients and that eHsp70 and eATP could be responsible for its activation through triggering their receptors. On the other hand, previously enhanced pro-inflammatory reactions seem to be suppressed to the healthy population levels in lung recipients without allograft rejection.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"964-974"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-12DOI: 10.1007/s12026-024-09510-8
Jill R Schofield, Jill Brook, Denise Calaprice-Whitty
Dysautonomia is an abnormal clinical state with multiple etiologies, including autoimmunity. Antiphospholipid antibodies (aPL) are among the autoantibodies that have been associated with autonomic dysfunction. We have observed that an elevated total serum IgM appears to be associated with the presence of aPL in dysautonomia patients. This is a retrospective study analyzing the clinical characteristics of 45 consecutive patients with cardiac autonomic dysfunction and a persistently elevated total serum IgM. 93% of patients were female with a mean age of 32.7 years. Most patients had severely disabling disease, with a mean Karnofsky-like functional ability score of 42% (normal 100%). 93% of patients tested persistently positive for one or more aPL and all patients tested persistently positive for aPL and/or Sjogren's antibodies. No patient had lupus specific antibodies. One third of patients experienced one or more thrombotic events and 58% of patients attempting pregnancy experienced pregnancy morbidity. Lastly, 78% of aPL-positive patients treated with antithrombotic therapy experienced 50 to 100% improvement in one or more symptoms (e.g., migraine, cognitive dysfunction) recognized to be responsive to antithrombotic therapy in a subset of aPL-positive patients and 73% of patients treated with and tolerating immune modulatory therapy experienced a positive response. We propose total serum IgM as a reliable and inexpensive test that can be used to identify dysautonomia patients at risk for persistent aPL-positivity. These patients are important to identify as they have a significant risk for thrombosis and pregnancy morbidity and often experience significant symptomatic improvement with antithrombotic therapy and/or immune modulatory therapy.
{"title":"Elevated total serum IgM predicts the presence of antiphospholipid antibodies in dysautonomia patients.","authors":"Jill R Schofield, Jill Brook, Denise Calaprice-Whitty","doi":"10.1007/s12026-024-09510-8","DOIUrl":"10.1007/s12026-024-09510-8","url":null,"abstract":"<p><p>Dysautonomia is an abnormal clinical state with multiple etiologies, including autoimmunity. Antiphospholipid antibodies (aPL) are among the autoantibodies that have been associated with autonomic dysfunction. We have observed that an elevated total serum IgM appears to be associated with the presence of aPL in dysautonomia patients. This is a retrospective study analyzing the clinical characteristics of 45 consecutive patients with cardiac autonomic dysfunction and a persistently elevated total serum IgM. 93% of patients were female with a mean age of 32.7 years. Most patients had severely disabling disease, with a mean Karnofsky-like functional ability score of 42% (normal 100%). 93% of patients tested persistently positive for one or more aPL and all patients tested persistently positive for aPL and/or Sjogren's antibodies. No patient had lupus specific antibodies. One third of patients experienced one or more thrombotic events and 58% of patients attempting pregnancy experienced pregnancy morbidity. Lastly, 78% of aPL-positive patients treated with antithrombotic therapy experienced 50 to 100% improvement in one or more symptoms (e.g., migraine, cognitive dysfunction) recognized to be responsive to antithrombotic therapy in a subset of aPL-positive patients and 73% of patients treated with and tolerating immune modulatory therapy experienced a positive response. We propose total serum IgM as a reliable and inexpensive test that can be used to identify dysautonomia patients at risk for persistent aPL-positivity. These patients are important to identify as they have a significant risk for thrombosis and pregnancy morbidity and often experience significant symptomatic improvement with antithrombotic therapy and/or immune modulatory therapy.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1086-1091"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971038","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 : 2024-10-01Epub Date: 2024-07-03DOI: 10.1007/s12026-024-09500-w
Judith W Heutz, Agnes E M Looijen, Jac H S A M Kuijpers, Marco W J Schreurs, Annette H M van der Helm-van Mil, Pascal H P de Jong
The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (< 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in 'quick-attained and persistent remission' rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice.
{"title":"The prognostic value of IgA anti-citrullinated protein antibodies and rheumatoid factor in an early arthritis population with a treat-to-target approach.","authors":"Judith W Heutz, Agnes E M Looijen, Jac H S A M Kuijpers, Marco W J Schreurs, Annette H M van der Helm-van Mil, Pascal H P de Jong","doi":"10.1007/s12026-024-09500-w","DOIUrl":"10.1007/s12026-024-09500-w","url":null,"abstract":"<p><p>The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (< 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in 'quick-attained and persistent remission' rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"982-990"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-07-17DOI: 10.1007/s12026-024-09517-1
Rabab El Hawary, Safa Meshaal, Sohilla Lotfy, Dalia Abd Elaziz, Alia S Eldash, Aya Erfan, Radwa Alkady, Rania Darwish, Mai Saad, Engy Chohayeb, Nermeen Galal, Aisha M Elmarsafy
Inborn errors of the CARD11-BCL10-MALT1 (CBM) signalosome have recently been shown to underlie severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) with variable immunological and clinical phenotypes, and patients usually present with recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. In the present study, we describe the clinical and immunological characteristics of an Egyptian patient with a mutation in the MALT1 gene. The patient suffered from an itchy exfoliative skin rash and eczematous lesions over his face and flexural surface of the limbs. He also had dental enamel erosion, repeated attacks of diarrhea, and pneumonia. He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation. DOCK8 expression on the lymphocytes by flow cytometry was normal. Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene (c.762dup in exon 5 of 17; p.Ile255TyrfsTer10); this variant is likely pathogenic, thus supporting the genetic diagnosis of immunodeficiency-12 (IMD12). Although the presence of eczema, recurrent sinopulmonary, and staphylococcal infections are suggestive of DOCK8 deficiency, they are also a finding in CARD11 and MALT1 deficiency. Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases. Early diagnosis will also enable the proper patient management by hematopoietic stem cell transplantation (HSCT) prior to the establishment of infections and pulmonary damage leading to a better outcome.
最近的研究表明,CARD11-BCL10-MALT1(CBM)信号体的先天性错误是导致重症联合免疫缺陷症(SCID)和联合免疫缺陷症(CID)的原因,其免疫学和临床表型各不相同,患者通常表现为反复的细菌、病毒和真菌感染、牙周病、肠病、皮炎和发育不良。在本研究中,我们描述了一名埃及 MALT1 基因突变患者的临床和免疫学特征。该患者面部和四肢屈侧出现瘙痒性皮疹和湿疹。他还患有牙釉质侵蚀、反复腹泻和肺炎。他的血清 IgE 升高,B 淋巴细胞和 T 淋巴细胞亚群计数正常,但 B 细胞成熟停滞。流式细胞术显示淋巴细胞中的 DOCK8 表达正常。下一代测序发现,MALT1基因存在一个新的同源变异(c.762dup,位于17的第5外显子;p.Ile255TyrfsTer10);该变异很可能是致病性的,因此支持免疫缺陷-12(IMD12)的基因诊断。虽然湿疹、反复鼻窦肺部感染和葡萄球菌感染的出现提示了 DOCK8 缺乏症,但它们也是 CARD11 和 MALT1 缺乏症的发现。因此,只要排除了 DOCK 8,就必须进行分子诊断,因为这可能会发现更多的患者,从而更好地了解和报告该病的表型和自然史,尤其是因为有记录的病例很少。早期诊断还能在感染和肺损伤形成之前,通过造血干细胞移植(HSCT)对患者进行适当治疗,从而获得更好的预后。
{"title":"A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review.","authors":"Rabab El Hawary, Safa Meshaal, Sohilla Lotfy, Dalia Abd Elaziz, Alia S Eldash, Aya Erfan, Radwa Alkady, Rania Darwish, Mai Saad, Engy Chohayeb, Nermeen Galal, Aisha M Elmarsafy","doi":"10.1007/s12026-024-09517-1","DOIUrl":"10.1007/s12026-024-09517-1","url":null,"abstract":"<p><p>Inborn errors of the CARD11-BCL10-MALT1 (CBM) signalosome have recently been shown to underlie severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) with variable immunological and clinical phenotypes, and patients usually present with recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. In the present study, we describe the clinical and immunological characteristics of an Egyptian patient with a mutation in the MALT1 gene. The patient suffered from an itchy exfoliative skin rash and eczematous lesions over his face and flexural surface of the limbs. He also had dental enamel erosion, repeated attacks of diarrhea, and pneumonia. He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation. DOCK8 expression on the lymphocytes by flow cytometry was normal. Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene (c.762dup in exon 5 of 17; p.Ile255TyrfsTer10); this variant is likely pathogenic, thus supporting the genetic diagnosis of immunodeficiency-12 (IMD12). Although the presence of eczema, recurrent sinopulmonary, and staphylococcal infections are suggestive of DOCK8 deficiency, they are also a finding in CARD11 and MALT1 deficiency. Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases. Early diagnosis will also enable the proper patient management by hematopoietic stem cell transplantation (HSCT) prior to the establishment of infections and pulmonary damage leading to a better outcome.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1147-1153"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626661","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}