Dwarakanathan Ranganathan, Saskia Leibowitz, George T John, Michelle A Neller, George R Ambalathingal, Leone Beagley, Archana Panikkar, Shannon Best, Jyothy Raju, Hilary Reddiex, Sharad Ratanjee, Monica Suet Ying Ng, Corey Smith, Rajiv Khanna
Objectives
Dysregulation of Epstein–Barr virus (EBV)-specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune-based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.
Methods
Autologous EBV latent antigen-specific CD4+ and CD8+ T cells were expanded in vitro and adoptively transferred to a lupus nephritis patient.
Results
This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti-CD20 antibody, obinutuzumab. The patient showed a reduction in anti-dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti-viral and global T-cell activation.
Conclusion
To our knowledge, this is the first report of the use of EBV-specific adoptive immunotherapy to treat a patient with lupus nephritis.
目的：爱泼斯坦-巴氏病毒（EBV）特异性细胞免疫失调被认为是系统性红斑狼疮（SLE）发病机制的诱因之一。狼疮性肾炎是系统性红斑狼疮总体发病率的主要风险因素。针对EB病毒的免疫策略已被提出作为系统性红斑狼疮和狼疮性肾炎的潜在治疗策略：方法：在体外扩增自体EB病毒潜伏抗原特异性CD4+和CD8+T细胞，并将其收养性转移给狼疮肾炎患者：结果：这种采纳性免疫疗法没有立即产生不良反应，患者随后接受了抗CD20抗体--奥比妥珠单抗的治疗。患者体内的抗dsDNA抗体有所减少，肾小球滤过率也有所改善，但仍然存在肾病。这些观察结果与抗病毒和整体 T 细胞活化的减少相吻合：据我们所知，这是首次报道使用 EBV 特异性免疫疗法治疗狼疮肾炎患者。
{"title":"Autologous Epstein–Barr virus-specific adoptive T-cell therapy in a patient with lupus nephritis","authors":"Dwarakanathan Ranganathan, Saskia Leibowitz, George T John, Michelle A Neller, George R Ambalathingal, Leone Beagley, Archana Panikkar, Shannon Best, Jyothy Raju, Hilary Reddiex, Sharad Ratanjee, Monica Suet Ying Ng, Corey Smith, Rajiv Khanna","doi":"10.1002/cti2.70015","DOIUrl":"10.1002/cti2.70015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Dysregulation of Epstein–Barr virus (EBV)-specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune-based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Autologous EBV latent antigen-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells were expanded <i>in vitro</i> and adoptively transferred to a lupus nephritis patient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti-CD20 antibody, obinutuzumab. The patient showed a reduction in anti-dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti-viral and global T-cell activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>To our knowledge, this is the first report of the use of EBV-specific adoptive immunotherapy to treat a patient with lupus nephritis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).
Methods
This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and in vitro experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64+ macrophages with tumor severity and systemic CRP levels.
Results
A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64+ TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.
Conclusions
The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.
{"title":"The contribution of the CRP/CD64 axis to renal cancer progression by inducing protumor activation of tumor-associated macrophages","authors":"Cheng Pan, Yukio Fujiwara, Hiromu Yano, Toshiki Anami, Yuki Ibe, Lianbo Li, Yuji Miura, Takanobu Motoshima, Shigeyuki Esumi, Junji Yatsuda, Taizo Hibi, Tomomi Kamba, Yoshihiro Komohara","doi":"10.1002/cti2.70013","DOIUrl":"10.1002/cti2.70013","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and <i>in vitro</i> experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64<sup>+</sup> macrophages with tumor severity and systemic CRP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64<sup>+</sup> TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen Tukwasibwe, Savannah Nicole Lewis, Yoweri Taremwa, Kattria van der Ploeg, Kathleen D Press, Maureen Ty, Felistas Namirimu Nankya, Kenneth Musinguzi, Evelyn Nansubuga, Florian Bach, Martin Chamai, Martin Okitwi, Gerald Tumusiime, Annettee Nakimuli, Francesco Colucci, Moses R Kamya, Joaniter I Nankabirwa, Emmanuel Arinaitwe, Bryan Greenhouse, Grant Dorsey, Philip J Rosenthal, Isaac Ssewanyana, Prasanna Jagannathan
Objectives
Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.
Methods
We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.
Results
Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.
Conclusion
This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.
目的 自然杀伤（NK）细胞通过抗体依赖性细胞毒性（ADCC）对抗疟免疫做出了重要贡献，但这一途径的不同成分在促进 NK 细胞活化方面的作用仍不清楚。 方法 我们比较了来自疟疾暴露供体和疟疾免疫供体的 NK 细胞的功能和表型，然后改变了 ADCC 中使用的红细胞遗传背景、恶性疟原虫菌株和疏松血浆，以观察它们对 NK 细胞脱颗粒的影响（通过 CD107a 动员测量）。 结果 与来自对疟疾免疫的北美成年供体的 NK 细胞相比，来自疟疾暴露的乌干达成年供体的自然杀伤细胞的 ADCC 增强，但对细胞因子刺激的促炎反应减弱。疟疾暴露供体的细胞表型反映了这种ADCC特化，Fc受体γ-链在整个区段范围内下调，高度分化的CD56dim和CD56neg种群富集。与野生型红细胞相比，在镰状细胞杂合子红细胞中培养的恶性疟原虫裂殖体的疏松化过程中，NK细胞的脱颗粒反应增强；尽管3D7裂殖体特异性IgG水平相似，但与低传播地区相比，当使用从高传播地区捐献者处收集的疏松化血浆时，NK细胞的脱颗粒反应也增强。然而，与这些试验中通常使用的 3D7 实验室菌株相比，对从临床疟疾感染中分离出来的野外分离的恶性疟原虫裂殖体的去颗粒化反应较低。 结论 这项工作强调了促进 ADCC 效能的重要宿主和寄生虫因素，在设计 ADCC 试验时应考虑到这些因素。
{"title":"Natural killer cell antibody-dependent cellular cytotoxicity to Plasmodium falciparum is impacted by cellular phenotypes, erythrocyte polymorphisms, parasite diversity and intensity of transmission","authors":"Stephen Tukwasibwe, Savannah Nicole Lewis, Yoweri Taremwa, Kattria van der Ploeg, Kathleen D Press, Maureen Ty, Felistas Namirimu Nankya, Kenneth Musinguzi, Evelyn Nansubuga, Florian Bach, Martin Chamai, Martin Okitwi, Gerald Tumusiime, Annettee Nakimuli, Francesco Colucci, Moses R Kamya, Joaniter I Nankabirwa, Emmanuel Arinaitwe, Bryan Greenhouse, Grant Dorsey, Philip J Rosenthal, Isaac Ssewanyana, Prasanna Jagannathan","doi":"10.1002/cti2.70005","DOIUrl":"https://doi.org/10.1002/cti2.70005","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, <i>Plasmodium falciparum</i> strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56<sup>dim</sup> and CD56<sup>neg</sup> populations. NK cell degranulation was enhanced in response to opsonised <i>P. falciparum</i> schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate <i>P. falciparum</i> schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giuseppe Ercoli, Hugh Selway-Clarke, Dena Truijen, Milda Folkmanaite, Tate Oulton, Caitlin Norris-Grey, Rie Nakajima, Philip Felgner, Brendan W Wren, Kevin Tetteh, Nicholas J Croucher, Maria Leandro, Geraldine Cambridge, Jeremy S Brown
Objectives
Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by Streptococcus pneumoniae. Why RA is associated with increased susceptibility to S. pneumoniae is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 S. pneumoniae protein antigens using a novel protein array.
Methods
IgG responses to S. pneumoniae were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an S. pneumoniae protein array. For the RA patients, results were compared before and after B-cell depletion therapy.
Results
Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple S. pneumoniae protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of S. pneumoniae. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of S. pneumoniae in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.
Conclusion
These data show RA is associated with major disruption of naturally acquired adaptive immunity to S. pneumoniae, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.
目的 类风湿性关节炎（RA）患者对感染的易感性增加，其中包括由肺炎链球菌引起的感染。目前尚不清楚 RA 为什么会增加对肺炎链球菌的易感性。本研究旨在使用新型蛋白质阵列评估 RA 和 B 细胞耗竭疗法对 289 种肺炎链球菌蛋白质抗原的天然抗体反应的影响。 方法 采用全细胞酶联免疫吸附试验、流式细胞仪抗溶血试验和肺炎双球菌蛋白阵列分析 RA 患者和疾病对照组（肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS））血清中肺炎双球菌 IgG 反应的特征。对 RA 患者进行了 B 细胞耗竭治疗前后的结果比较。 结果 与特征明确的疾病对照组 ME/CFS 患者相比，RA 患者对多种肺炎双球菌蛋白抗原的抗体反应减弱，对大约一半抗原的 IgG 识别率明显下降，同时这些反应的中位强度也有所降低。多种阵列抗原特异性反应的降低还与肺炎双球菌的IgG蛋白溶解度降低有关。虽然使用利妥昔单抗的 B 细胞耗竭疗法并未降低 RA 组对肺炎双球菌的总体 IgG 识别率，但却明显破坏了个别患者对蛋白质抗原的原有 IgG 反应谱系。 结论 这些数据表明，RA 与对肺炎双球菌的自然获得性适应性免疫的严重破坏有关，这种破坏可通过蛋白抗原阵列进行快速评估，并可能导致 RA 患者肺炎发病率的增加。
{"title":"Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients","authors":"Giuseppe Ercoli, Hugh Selway-Clarke, Dena Truijen, Milda Folkmanaite, Tate Oulton, Caitlin Norris-Grey, Rie Nakajima, Philip Felgner, Brendan W Wren, Kevin Tetteh, Nicholas J Croucher, Maria Leandro, Geraldine Cambridge, Jeremy S Brown","doi":"10.1002/cti2.70012","DOIUrl":"https://doi.org/10.1002/cti2.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by <i>Streptococcus pneumoniae</i>. Why RA is associated with increased susceptibility to <i>S. pneumoniae</i> is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 <i>S. pneumoniae</i> protein antigens using a novel protein array.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>IgG responses to <i>S. pneumoniae</i> were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an <i>S. pneumoniae</i> protein array. For the RA patients, results were compared before and after B-cell depletion therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple <i>S. pneumoniae</i> protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of <i>S. pneumoniae</i>. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of <i>S. pneumoniae</i> in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data show RA is associated with major disruption of naturally acquired adaptive immunity to <i>S. pneumoniae</i>, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenlin Qiu, Xiaoxiao Han, Tong Yu, Lijuan Jiang, Xuefei Wang, Ruizhi Feng, Xiaoru Duan, Yao Teng, Haifeng Yin, Maria I Bokarewa, Guo-Min Deng
Objectives
Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first-line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.
Methods
An SLE IgG-induced inflammation model was used to investigate the anti-inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid-induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow-derived osteoclast cultures.
Results
An SLE IgG-induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti-inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2-related factor 2 and limiting reactive oxygen species formation, which mitigated GC-induced bone loss.
Conclusion
The results indicate that HCQ improved the anti-inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.
{"title":"Inhibitory effect of hydroxychloroquine on glucocorticoid-induced osteoporosis in lupus therapy","authors":"Wenlin Qiu, Xiaoxiao Han, Tong Yu, Lijuan Jiang, Xuefei Wang, Ruizhi Feng, Xiaoru Duan, Yao Teng, Haifeng Yin, Maria I Bokarewa, Guo-Min Deng","doi":"10.1002/cti2.70010","DOIUrl":"https://doi.org/10.1002/cti2.70010","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first-line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An SLE IgG-induced inflammation model was used to investigate the anti-inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid-induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow-derived osteoclast cultures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An SLE IgG-induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti-inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2-related factor 2 and limiting reactive oxygen species formation, which mitigated GC-induced bone loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results indicate that HCQ improved the anti-inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T-cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan-cancer scale. Thus, we aim to reveal its role at the pan-cancer level.
Methods
We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan–Meier survival analysis and multivariate Cox regression analysis. In pan-cancer analysis, we constructed competing endogenous RNA and protein–protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types.
Results
LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43–17.90, P < 0.001) and PFS (HR = 3.44, 95% CI = 1.68–7.10, P < 0.001). In pan-cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune-related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers.
Conclusion
High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan-cancer dimension.
研究目的淋巴细胞活化基因 3（LAG3）是 T 细胞活化过程中的一个抑制受体，是一个不利的预后因素。然而，它对肿瘤的影响尚未在泛癌症范围内得到全面阐明。因此，我们旨在揭示它在泛癌症中的作用：方法：我们对 370 例患者的回顾性队列进行了 IHC 染色。方法：我们对 370 例回顾性患者进行了 IHC 染色，然后使用 Kaplan-Meier 生存分析和多变量 Cox 回归分析评估了 LAG3 的预后作用。在泛癌症分析中，我们构建了竞争内源性RNA和蛋白-蛋白相互作用网络，进行了基因组富集分析，并确定了33种癌症类型中LAG3基因表达与临床特征、肿瘤纯度、突变、肿瘤免疫和药物敏感性等各种因素之间的相关性：结果：LAG3在正常肾组织中的表达高于肿瘤。LAG3基因高表达是OS的独立预后因素（HR = 6.60，95% CI = 2.43-17.90, P P 结论：LAG3基因高表达是OS的独立预后因素：LAG3基因高表达是肾脏肿瘤的一个独立危险因素。在泛癌症维度上，它还是预后、TIME和免疫疗法疗效的生物标志物。
{"title":"Lymphocyte activation gene 3 served as a potential prognostic and immunological biomarker across various cancer types: a clinical and pan-cancer analysis","authors":"Yifan Liu, Yuntao Yao, Xinyue Yang, Maodong Wei, Bingnan Lu, Keqing Dong, Donghao Lyu, Yuanan Li, Wenbin Guan, Runzhi Huang, Guofeng Xu, Xiuwu Pan","doi":"10.1002/cti2.70009","DOIUrl":"10.1002/cti2.70009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T-cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan-cancer scale. Thus, we aim to reveal its role at the pan-cancer level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan–Meier survival analysis and multivariate Cox regression analysis. In pan-cancer analysis, we constructed competing endogenous RNA and protein–protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43–17.90, <i>P</i> < 0.001) and PFS (HR = 3.44, 95% CI = 1.68–7.10, <i>P</i> < 0.001). In pan-cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune-related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan-cancer dimension.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathrin Kläsener, Nadja Herrmann, Liliana Håversen, Timothy Sundell, Martina Sundqvist, Christina Lundqvist, Paul T Manna, Charlotte A Jonsson, Marcella Visentini, Diana Ljung Sass, Sarah McGrath, Kristoffer Grimstad, Alaitz Aranburu, Karin Mellgren, Linda Fogelstrand, Huamei Forsman, Olov Ekwall, Jan Borén, Inger Gjertsson, Michael Reth, Inga-Lill Mårtensson, Alessandro Camponeschi
Objectives
Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells.
Methods
In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway.
Results
Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.
Conclusion
The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.
{"title":"Targeting CD38 with monoclonal antibodies disrupts key survival pathways in paediatric Burkitt's lymphoma malignant B cells","authors":"Kathrin Kläsener, Nadja Herrmann, Liliana Håversen, Timothy Sundell, Martina Sundqvist, Christina Lundqvist, Paul T Manna, Charlotte A Jonsson, Marcella Visentini, Diana Ljung Sass, Sarah McGrath, Kristoffer Grimstad, Alaitz Aranburu, Karin Mellgren, Linda Fogelstrand, Huamei Forsman, Olov Ekwall, Jan Borén, Inger Gjertsson, Michael Reth, Inga-Lill Mårtensson, Alessandro Camponeschi","doi":"10.1002/cti2.70011","DOIUrl":"10.1002/cti2.70011","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p><i>In silico</i> analyses of patient samples, combined with <i>in vitro</i> experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zheng Quan Toh, Jeremy Anderson, Nadia Mazarakis, Leanne Quah, Jill Nguyen, Rachel A Higgins, Lien Anh Ha Do, Yan Yung Ng, Sedi Jalali, Melanie R Neeland, Alissa McMinn, Richard Saffery, Sarah McNab, Jodie McVernon, Adrian Marcato, David P Burgner, Nigel Curtis, Andrew C Steer, Kim Mulholland, Daniel G Pellicci, Nigel W Crawford, Shidan Tosif, Paul V Licciardi
Objectives
The immune response in children elicited by SARS-CoV-2 Omicron infection alone or in combination with COVID-19 vaccination (hybrid immunity) is poorly understood. We examined the humoral and cellular immune response following SARS-CoV-2 Omicron infection in unvaccinated children and children who were previously vaccinated with COVID-19 mRNA vaccine.
Methods
Participants were recruited as part of a household cohort study conducted during the Omicron predominant wave (Jan to July 2022) in Victoria, Australia. Blood samples were collected at 1, 3, 6 and 12 months following COVID-19 diagnosis. Humoral immune responses to SARS-CoV-2 Spike proteins from Wuhan, Omicron BA.1, BA.4/5 and JN.1, as well as cellular immune responses to Wuhan and BA.1 were assessed.
Results
A total of 43 children and 113 samples were included in the analysis. Following Omicron infection, unvaccinated children generated low antibody responses but elicited Spike-specific CD4 and CD8 T-cell responses. In contrast, vaccinated children infected with the Omicron variant mounted robust humoral and cellular immune responses to both ancestral strain and Omicron subvariants. Hybrid immunity persisted for at least 6 months post infection, with cellular immune memory characterised by the generation of Spike-specific polyfunctional CD8 T-cell responses.
Conclusion
SARS-CoV-2 hybrid immunity in children is characterised by persisting SARS-CoV-2 antibodies and robust CD4 and CD8 T-cell activation and polyfunctional responses. Our findings contribute to understanding hybrid immunity in children and may have implications regarding COVID-19 vaccination and SARS-CoV-2 re-infections.
{"title":"Humoral and cellular immune responses in vaccinated and unvaccinated children following SARS-CoV-2 Omicron infection","authors":"Zheng Quan Toh, Jeremy Anderson, Nadia Mazarakis, Leanne Quah, Jill Nguyen, Rachel A Higgins, Lien Anh Ha Do, Yan Yung Ng, Sedi Jalali, Melanie R Neeland, Alissa McMinn, Richard Saffery, Sarah McNab, Jodie McVernon, Adrian Marcato, David P Burgner, Nigel Curtis, Andrew C Steer, Kim Mulholland, Daniel G Pellicci, Nigel W Crawford, Shidan Tosif, Paul V Licciardi","doi":"10.1002/cti2.70008","DOIUrl":"10.1002/cti2.70008","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The immune response in children elicited by SARS-CoV-2 Omicron infection alone or in combination with COVID-19 vaccination (hybrid immunity) is poorly understood. We examined the humoral and cellular immune response following SARS-CoV-2 Omicron infection in unvaccinated children and children who were previously vaccinated with COVID-19 mRNA vaccine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Participants were recruited as part of a household cohort study conducted during the Omicron predominant wave (Jan to July 2022) in Victoria, Australia. Blood samples were collected at 1, 3, 6 and 12 months following COVID-19 diagnosis. Humoral immune responses to SARS-CoV-2 Spike proteins from Wuhan, Omicron BA.1, BA.4/5 and JN.1, as well as cellular immune responses to Wuhan and BA.1 were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 43 children and 113 samples were included in the analysis. Following Omicron infection, unvaccinated children generated low antibody responses but elicited Spike-specific CD4 and CD8 T-cell responses. In contrast, vaccinated children infected with the Omicron variant mounted robust humoral and cellular immune responses to both ancestral strain and Omicron subvariants. Hybrid immunity persisted for at least 6 months post infection, with cellular immune memory characterised by the generation of Spike-specific polyfunctional CD8 T-cell responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>SARS-CoV-2 hybrid immunity in children is characterised by persisting SARS-CoV-2 antibodies and robust CD4 and CD8 T-cell activation and polyfunctional responses. Our findings contribute to understanding hybrid immunity in children and may have implications regarding COVID-19 vaccination and SARS-CoV-2 re-infections.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Fan, Min Xu, Ke Liu, Wanping Yan, Huanyu Wu, Hongliang Dong, Yongfeng Yang, Wei Ye
Objectives
CD8+ T cells play a critical role in the immune dysfunction associated with liver cirrhosis. CD38+HLA-DR+CD8+ T cells, or bystander-activated CD8+ T cells, are involved in tissue injury but their specific contribution to liver cirrhosis remains unclear. This study sought to identify the mechanism for CD38+HLA-DR+CD8+ T cell-mediated pathogenesis during liver cirrhosis.
Methods
The immunophenotype, antigen specificity, cytokine secretion and cytotoxicity-related indicators of CD38+HLA-DR+CD8+ T cells were determined using flow cytometry. The functional properties of these cells were assessed using transcriptome analysis. CD38+HLA-DR+CD8+ T-cell killing was detected using cytotoxicity and antibody-blocking assays.
Results
The proportion of CD38+HLA-DR+CD8+ T cells was significantly elevated in liver cirrhosis patients and correlated with tissue damage. Transcriptome analysis revealed that these cells had innate-like functional characteristics. This CD8+ T-cell population primarily consisted of effector memory T cells and produced a high level of cytotoxicity-related cytokines, granzyme B and perforin. IL-15 promoted CD38+HLA-DR+CD8+ T-cell activation and proliferation, inducing significant TCR-independent cytotoxicity mediated through NKG2D.
Conclusions
CD38+HLA-DR+CD8+ T cells correlated with cirrhosis-related liver injury and contributed to liver damage by signalling through NKG2D in a TCR-independent manner.
目的 CD8+ T细胞在与肝硬化相关的免疫功能失调中起着关键作用。CD38+HLA-DR+CD8+ T细胞或旁观者激活的CD8+ T细胞参与组织损伤，但它们对肝硬化的具体贡献仍不清楚。本研究试图确定 CD38+HLA-DR+CD8+ T 细胞介导的肝硬化发病机制。 方法 使用流式细胞术测定 CD38+HLA-DR+CD8+ T 细胞的免疫表型、抗原特异性、细胞因子分泌和细胞毒性相关指标。转录组分析评估了这些细胞的功能特性。CD38+HLA-DR+CD8+T细胞的杀伤力是通过细胞毒性和抗体阻断试验检测的。 结果 肝硬化患者 CD38+HLA-DR+CD8+ T 细胞的比例明显升高，并与组织损伤相关。转录组分析表明，这些细胞具有类似先天性的功能特征。这种CD8+ T细胞群主要由效应记忆T细胞组成，能产生大量细胞毒性相关细胞因子、颗粒酶B和穿孔素。IL-15 促进了 CD38+HLA-DR+CD8+ T 细胞的活化和增殖，并通过 NKG2D 诱导了显著的 TCR 依赖性细胞毒性。 结论 CD38+HLA-DR+CD8+ T细胞与肝硬化相关的肝损伤有关，并通过NKG2D以一种TCR无关的方式发出信号，导致肝损伤。
{"title":"IL-15-induced CD38+HLA-DR+CD8+ T cells correlate with liver injury via NKG2D in chronic hepatitis B cirrhosis","authors":"Jing Fan, Min Xu, Ke Liu, Wanping Yan, Huanyu Wu, Hongliang Dong, Yongfeng Yang, Wei Ye","doi":"10.1002/cti2.70007","DOIUrl":"https://doi.org/10.1002/cti2.70007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>CD8<sup>+</sup> T cells play a critical role in the immune dysfunction associated with liver cirrhosis. CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T cells, or bystander-activated CD8<sup>+</sup> T cells, are involved in tissue injury but their specific contribution to liver cirrhosis remains unclear. This study sought to identify the mechanism for CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T cell-mediated pathogenesis during liver cirrhosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The immunophenotype, antigen specificity, cytokine secretion and cytotoxicity-related indicators of CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T cells were determined using flow cytometry. The functional properties of these cells were assessed using transcriptome analysis. CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T-cell killing was detected using cytotoxicity and antibody-blocking assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The proportion of CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T cells was significantly elevated in liver cirrhosis patients and correlated with tissue damage. Transcriptome analysis revealed that these cells had innate-like functional characteristics. This CD8<sup>+</sup> T-cell population primarily consisted of effector memory T cells and produced a high level of cytotoxicity-related cytokines, granzyme B and perforin. IL-15 promoted CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T-cell activation and proliferation, inducing significant TCR-independent cytotoxicity mediated through NKG2D.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CD38<sup>+</sup>HLA-DR<sup>+</sup>CD8<sup>+</sup> T cells correlated with cirrhosis-related liver injury and contributed to liver damage by signalling through NKG2D in a TCR-independent manner.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PD-1 plays a crucial role in the immune dysregulation of rheumatoid arthritis (RA), but the specific characteristics of PD-1+CD4+ T cells remain unclear and require further investigation.
Methods
Circulating PD-1+CD4+ T cells from RA patients were analysed using flow cytometry. Plasma levels of soluble PD-1 (sPD-1) were measured using enzyme-linked immunosorbent assay (ELISA). Single-cell RNA sequence data from peripheral blood mononuclear cells (PBMCs) and synovial tissue of patients were obtained from the GEO and the ImmPort databases. Bioinformatics analyses were performed in the R studio to characterise PD-1+CD4+ T cells. Expression of CCR7, KLF2 and IL32 in PD-1+CD4+ T cells was validated by flow cytometry.
Results
RA patients showed an elevated proportion of PD-1+CD4+ T cells in peripheral blood, along with increased plasma sPD-1 levels, which positively correlated with TNF-α and erythrocyte sedimentation rate. Bioinformatic analysis revealed PD-1 expression on CCR7+CD4+ T cells in PBMCs, and on both CCR7+CD4+ T cells and CXCL13+CD4+ T cells in RA synovium. PD-1 was co-expressed with CCR7, KLF2, and IL32 in peripheral CD4+ T cells. In synovium, PD-1+CCR7+CD4+ T cells had higher expression of TNF and LCP2, while PD-1+CXCL13+CD4+ T cells showed elevated levels of ARID5A and DUSP2. PD-1+CD4+ T cells in synovium also appeared to interact with B cells and fibroblasts through BTLA and TNFSF signalling pathways.
Conclusion
This study highlights the increased proportion of PD-1+CD4+ T cells and elevated sPD-1 levels in RA. The transcriptomic profiles and signalling networks of PD-1+CD4+ T cells offer new insights into their role in RA pathogenesis.
目的 PD-1 在类风湿性关节炎（RA）的免疫失调中起着关键作用，但 PD-1+CD4+ T 细胞的具体特征仍不清楚，需要进一步研究。 方法 使用流式细胞术分析 RA 患者循环中的 PD-1+CD4+ T 细胞。使用酶联免疫吸附试验（ELISA）测量血浆中可溶性 PD-1 （sPD-1）的水平。患者外周血单核细胞（PBMC）和滑膜组织的单细胞 RNA 序列数据来自 GEO 和 ImmPort 数据库。在 R studio 中进行了生物信息学分析，以确定 PD-1+CD4+ T 细胞的特征。流式细胞术验证了 PD-1+CD4+ T 细胞中 CCR7、KLF2 和 IL32 的表达。 结果 RA 患者外周血中 PD-1+CD4+ T 细胞比例升高，血浆 sPD-1 水平升高，与 TNF-α 和红细胞沉降率呈正相关。生物信息学分析显示，PD-1在PBMCs中的CCR7+CD4+ T细胞以及RA滑膜中的CCR7+CD4+ T细胞和CXCL13+CD4+ T细胞上都有表达。在外周 CD4+ T 细胞中，PD-1 与 CCR7、KLF2 和 IL32 共同表达。在滑膜中，PD-1+CCR7+CD4+ T 细胞的 TNF 和 LCP2 表达较高，而 PD-1+CXCL13+CD4+ T 细胞的 ARID5A 和 DUSP2 水平升高。滑膜中的 PD-1+CD4+ T 细胞似乎还通过 BTLA 和 TNFSF 信号通路与 B 细胞和成纤维细胞相互作用。 结论 本研究强调了 RA 中 PD-1+CD4+ T 细胞比例的增加和 sPD-1 水平的升高。PD-1+CD4+ T 细胞的转录组特征和信号网络为了解它们在 RA 发病机制中的作用提供了新的视角。
{"title":"Characteristics of PD-1+CD4+ T cells in peripheral blood and synovium of rheumatoid arthritis patients","authors":"Yan-juan Chen, Yong Chen, Ping Chen, Yi-qun Jia, Hua Wang, Xiao-ping Hong","doi":"10.1002/cti2.70006","DOIUrl":"https://doi.org/10.1002/cti2.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>PD-1 plays a crucial role in the immune dysregulation of rheumatoid arthritis (RA), but the specific characteristics of PD-1<sup>+</sup>CD4<sup>+</sup> T cells remain unclear and require further investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Circulating PD-1<sup>+</sup>CD4<sup>+</sup> T cells from RA patients were analysed using flow cytometry. Plasma levels of soluble PD-1 (sPD-1) were measured using enzyme-linked immunosorbent assay (ELISA). Single-cell RNA sequence data from peripheral blood mononuclear cells (PBMCs) and synovial tissue of patients were obtained from the GEO and the ImmPort databases. Bioinformatics analyses were performed in the R studio to characterise PD-1<sup>+</sup>CD4<sup>+</sup> T cells. Expression of CCR7, KLF2 and IL32 in PD-1<sup>+</sup>CD4<sup>+</sup> T cells was validated by flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RA patients showed an elevated proportion of PD-1<sup>+</sup>CD4<sup>+</sup> T cells in peripheral blood, along with increased plasma sPD-1 levels, which positively correlated with TNF-α and erythrocyte sedimentation rate. Bioinformatic analysis revealed <i>PD-1</i> expression on CCR7<sup>+</sup>CD4<sup>+</sup> T cells in PBMCs, and on both CCR7<sup>+</sup>CD4<sup>+</sup> T cells and CXCL13<sup>+</sup>CD4<sup>+</sup> T cells in RA synovium. PD-1 was co-expressed with CCR7, KLF2, and IL32 in peripheral CD4<sup>+</sup> T cells. In synovium, PD-1<sup>+</sup>CCR7<sup>+</sup>CD4<sup>+</sup> T cells had higher expression of <i>TNF</i> and <i>LCP2</i>, while PD-1<sup>+</sup>CXCL13<sup>+</sup>CD4<sup>+</sup> T cells showed elevated levels of <i>ARID5A</i> and <i>DUSP2</i>. PD-1<sup>+</sup>CD4<sup>+</sup> T cells in synovium also appeared to interact with B cells and fibroblasts through BTLA and TNFSF signalling pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study highlights the increased proportion of PD-1<sup>+</sup>CD4<sup>+</sup> T cells and elevated sPD-1 levels in RA. The transcriptomic profiles and signalling networks of PD-1<sup>+</sup>CD4<sup>+</sup> T cells offer new insights into their role in RA pathogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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