Charles W. Armitage, Connor P. O'Meara, Emily R. Bryan, Avinash Kollipara, Logan K. Trim, Danica Hickey, Alison J. Carey, Wilhelmina M. Huston, Gavin Donnelly, Anusch Yazdani, Richard S. Blumberg, Kenneth W. Beagley
Abstract Chlamydia trachomatis infections are an important sexually transmitted infection that can lead to inflammation, scarring and hydrosalpinx/infertility. However, infections are commonly clinically asymptomatic and do not receive treatment. The underlying cause of asymptomatic immunopathology remains unknown. Here, we demonstrate that IgG produced during male infection enhanced the incidence of immunopathology and infertility in females. Human endocervical cells expressing the neonatal Fc Receptor (FcRn) increased translocation of human IgG‐opsonized C. trachomatis . Using total IgG purified from infected male mice, we opsonized C. muridarum and then infected female mice, mimicking sexual transmission. Following infection, IgG‐opsonized Chlamydia was found to transcytose the epithelial barrier in the uterus, where it was phagocytosed by antigen‐presenting cells (APCs) and trafficked to the draining lymph nodes. APCs then expanded both CD4 + and CD8 + T cell populations and caused significantly more infertility in female mice infected with non‐opsonized Chlamydia . Enhanced phagocytosis of IgG‐opsonized Chlamydia significantly increased pro‐inflammatory signalling and T cell proliferation. As IgG is transcytosed by FcRn, we utilized FcRn −/− mice and observed that shedding kinetics of Chlamydia were only affected in FcRn −/− mice infected with IgG‐opsonized Chlamydia . Depletion of CD8 + T cells in FcRn −/− mice lead to a significant reduction in the incidence of infertility. Taken together, these data demonstrate that IgG seroconversion during male infection can amplify female immunopathology, dependent on FcRn transcytosis, APC differentiation and enhanced CD8 T cell responses.
{"title":"<scp>IgG</scp> exacerbates genital chlamydial pathology in females by enhancing pathogenic <scp>CD8</scp><sup>+</sup> T cell responses","authors":"Charles W. Armitage, Connor P. O'Meara, Emily R. Bryan, Avinash Kollipara, Logan K. Trim, Danica Hickey, Alison J. Carey, Wilhelmina M. Huston, Gavin Donnelly, Anusch Yazdani, Richard S. Blumberg, Kenneth W. Beagley","doi":"10.1111/sji.13331","DOIUrl":"https://doi.org/10.1111/sji.13331","url":null,"abstract":"Abstract Chlamydia trachomatis infections are an important sexually transmitted infection that can lead to inflammation, scarring and hydrosalpinx/infertility. However, infections are commonly clinically asymptomatic and do not receive treatment. The underlying cause of asymptomatic immunopathology remains unknown. Here, we demonstrate that IgG produced during male infection enhanced the incidence of immunopathology and infertility in females. Human endocervical cells expressing the neonatal Fc Receptor (FcRn) increased translocation of human IgG‐opsonized C. trachomatis . Using total IgG purified from infected male mice, we opsonized C. muridarum and then infected female mice, mimicking sexual transmission. Following infection, IgG‐opsonized Chlamydia was found to transcytose the epithelial barrier in the uterus, where it was phagocytosed by antigen‐presenting cells (APCs) and trafficked to the draining lymph nodes. APCs then expanded both CD4 + and CD8 + T cell populations and caused significantly more infertility in female mice infected with non‐opsonized Chlamydia . Enhanced phagocytosis of IgG‐opsonized Chlamydia significantly increased pro‐inflammatory signalling and T cell proliferation. As IgG is transcytosed by FcRn, we utilized FcRn −/− mice and observed that shedding kinetics of Chlamydia were only affected in FcRn −/− mice infected with IgG‐opsonized Chlamydia . Depletion of CD8 + T cells in FcRn −/− mice lead to a significant reduction in the incidence of infertility. Taken together, these data demonstrate that IgG seroconversion during male infection can amplify female immunopathology, dependent on FcRn transcytosis, APC differentiation and enhanced CD8 T cell responses.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"77 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135917847","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}
In a letter dated December 2022, Polykretis and McCullough reported that there had been an increase in sudden cardiac death (SCD) and survived sudden cardiac arrest (SCA) among athletes from 2021 until the date the letter was submitted.1 In the letter, they cited a database purportedly containing 1598 instances of athletes having experienced SCA or SCA during the mentioned timeframe.2 When I examined the database, however, I did not find support for the claim. A number of the cases in the database were unrelated to elite sports as well as SCD or SCA. For example, in some cases, the stated cause of death was suicide. In a different instance, a 70-year-old man reportedly experienced SCD while cycling. The referenced database was clearly disorganized and did not provide evidence of the stated claim. Whether or not there was an increase in SCD and SCA has been the subject of considerable debate, but as far as I am aware no scientific investigation has been conducted.3 This prompted me to look further. In the letter, Polykretis and McCullough compared the data with a systematic review by Bille, Figueiras, Schamasch, et al, who reported that from 1966 to 2004, a total of 1101 athletes under the age of 35 had died as a result of various heart-related conditions. However, such a broad comparison may not be the best approach for assessing whether athletes were at an increased risk of SCA and SCD in 2021 in comparison with pre-COVID data. I would argue that a more appropriate comparison can be drawn if we exclusively focus on cases of SCA and SCD among elite footballers, as this subject has been extensively studied. As elite footballers are in the media spotlight, cases of SCA and SCD are unlikely to be overlooked. Cases occurring at recreational and competitive levels are less likely to receive significant media coverage or be recorded by surveillance systems. The pre-COVID rate of SCA and SCD among footballers was assessed in a prospective, observational study by Egger et al4 known as the FIFA study. Globally, the study found a total of 617 cases of SCD and SCA from 2014 to 2018. A total of 475 died. The study also included a few cases from related sports, including beach soccer, walking football, and futsal. Out of the 617 cases, a total of 95% occurred at the amateur level, which encompassed both recreational and competitive players. It only found 33 cases classified as elite level, amounting to 6.6 cases per year on average. The study was confined to cases during football-specific exercise, such as during training or a match, or within 1 h after cessation of such activity. In the context of this letter, let x denote the number of cases of SCD and SCA in 2021, that is, 10 cases, and let x! = 1 × 2 × 3 × 4 × … × x. Further, let λ be the average rate, namely 6.6 cases. Euler's constant, e ≈ $$ approx $$ 2.71828. It can easily be shown that the 10 cases are not statistically significant, that is, P X ≥ 10 = 0.131 > 0.05 = α $$ Pleft[Xge 10right]=0.131>0.0
在一封日期为2022年12月的信中，Polykretis和McCullough报告说，从2021年到这封信提交之日，运动员中心脏性猝死(SCD)和心脏骤停(SCA)存活的人数有所增加在信中，他们引用了一个据称包含1598名运动员在上述时间段内经历过SCA或SCA的数据库然而，当我检查数据库时，我没有找到支持这种说法的证据。数据库中的许多病例与精英运动以及SCD或SCA无关。例如，在某些案件中，所陈述的死亡原因是自杀。在另一个案例中，据报道，一名70岁的男子在骑车时出现了SCD。所引用的数据库显然杂乱无章，没有提供所述索赔的证据。是否有SCD和SCA的增加一直是一个相当有争议的话题，但据我所知，没有进行过科学调查这促使我进一步研究。在信中，Polykretis和McCullough将这些数据与Bille, Figueiras, Schamasch等人的系统回顾进行了比较，他们报告说，从1966年到2004年，共有1101名35岁以下的运动员死于各种心脏相关疾病。然而，与covid前的数据相比，如此广泛的比较可能不是评估2021年运动员患SCA和SCD风险是否增加的最佳方法。我认为，如果我们只关注精英足球运动员的SCA和SCD病例，可以得出更合适的比较，因为这个主题已经得到了广泛的研究。由于精英足球运动员是媒体关注的焦点，SCA和SCD的案例不太可能被忽视。在娱乐和竞技级别发生的病例不太可能得到媒体的大量报道或被监测系统记录。埃格等人在一项被称为国际足联研究的前瞻性观察研究中评估了足球运动员中SCA和SCD的前冠状病毒感染率。在全球范围内，该研究发现，从2014年到2018年，共有617例SCD和SCA病例。共有475人死亡。这项研究还包括了一些相关运动的案例，包括沙滩足球、步行足球和五人制足球。在617起案件中，共有95起% occurred at the amateur level, which encompassed both recreational and competitive players. It only found 33 cases classified as elite level, amounting to 6.6 cases per year on average. The study was confined to cases during football-specific exercise, such as during training or a match, or within 1 h after cessation of such activity. In the context of this letter, let x denote the number of cases of SCD and SCA in 2021, that is, 10 cases, and let x! = 1 × 2 × 3 × 4 × … × x. Further, let λ be the average rate, namely 6.6 cases. Euler's constant, e ≈ $$ approx $$ 2.71828. It can easily be shown that the 10 cases are not statistically significant, that is, P X ≥ 10 = 0.131 > 0.05 = α $$ Pleft[Xge 10right]=0.131>0.05=alpha $$ , where α is the significance level. It should be pointed out that the data are preliminary and surveillance systems might have picked up additional cases. Furthermore, two potentially relevant cases were excluded due to insufficient corroborating information. If there had been 12 cases or more, then P < 0.05. If evidence eventually emerges that a non-coincidental surge in SCD and SCA took place in 2021, a number of potential causes should be considered. First, as entire football leagues were put to a standstill for long periods in 2020 as a result of lockdowns and restrictions, it is likely that there were significantly fewer cases than the average. If this happened, the cases that under normal circumstances would have taken place in 2020 could have been postponed to 2021, resulting in an increase. Alternatively, myocarditis, which is a major cause of sudden, unexpected death in young adults, may have been induced via a SARS-CoV-2 infection or via mRNA SARS-CoV-2 vaccination. It is well documented that post-viral myocarditis can result in SCD in athletes. However, to my knowledge, there have been no reported cases associated with SARS-CoV-2.5 With respect to vaccination, it should be mentioned that an autopsy-based histopathological characterization of myocarditis found that “myocarditis can be a potentially lethal complication following mRNA-based anti-SARS-CoV-2 vaccination”.6 Moreover, an endomyocardial biopsy-proven case series found that 9 out of 15 pat
{"title":"Were athletes at increased risk of sudden cardiac death and survived sudden cardiac arrest in 2021?","authors":"Søren Roest Korsgaard","doi":"10.1111/sji.13334","DOIUrl":"https://doi.org/10.1111/sji.13334","url":null,"abstract":"In a letter dated December 2022, Polykretis and McCullough reported that there had been an increase in sudden cardiac death (SCD) and survived sudden cardiac arrest (SCA) among athletes from 2021 until the date the letter was submitted.1 In the letter, they cited a database purportedly containing 1598 instances of athletes having experienced SCA or SCA during the mentioned timeframe.2 When I examined the database, however, I did not find support for the claim. A number of the cases in the database were unrelated to elite sports as well as SCD or SCA. For example, in some cases, the stated cause of death was suicide. In a different instance, a 70-year-old man reportedly experienced SCD while cycling. The referenced database was clearly disorganized and did not provide evidence of the stated claim. Whether or not there was an increase in SCD and SCA has been the subject of considerable debate, but as far as I am aware no scientific investigation has been conducted.3 This prompted me to look further. In the letter, Polykretis and McCullough compared the data with a systematic review by Bille, Figueiras, Schamasch, et al, who reported that from 1966 to 2004, a total of 1101 athletes under the age of 35 had died as a result of various heart-related conditions. However, such a broad comparison may not be the best approach for assessing whether athletes were at an increased risk of SCA and SCD in 2021 in comparison with pre-COVID data. I would argue that a more appropriate comparison can be drawn if we exclusively focus on cases of SCA and SCD among elite footballers, as this subject has been extensively studied. As elite footballers are in the media spotlight, cases of SCA and SCD are unlikely to be overlooked. Cases occurring at recreational and competitive levels are less likely to receive significant media coverage or be recorded by surveillance systems. The pre-COVID rate of SCA and SCD among footballers was assessed in a prospective, observational study by Egger et al4 known as the FIFA study. Globally, the study found a total of 617 cases of SCD and SCA from 2014 to 2018. A total of 475 died. The study also included a few cases from related sports, including beach soccer, walking football, and futsal. Out of the 617 cases, a total of 95% occurred at the amateur level, which encompassed both recreational and competitive players. It only found 33 cases classified as elite level, amounting to 6.6 cases per year on average. The study was confined to cases during football-specific exercise, such as during training or a match, or within 1 h after cessation of such activity. In the context of this letter, let x denote the number of cases of SCD and SCA in 2021, that is, 10 cases, and let x! = 1 × 2 × 3 × 4 × … × x. Further, let λ be the average rate, namely 6.6 cases. Euler's constant, e ≈ $$ approx $$ 2.71828. It can easily be shown that the 10 cases are not statistically significant, that is, P X ≥ 10 = 0.131 > 0.05 = α $$ Pleft[Xge 10right]=0.131>0.0","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146517","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}
Axel Rosell, Cecilia Karlström, Joakim S. Dahlin, Daryl Boey, Monika Klimkowska, Kajsa Ax, Charlotte Thålin, Johanna Ungerstedt
Abstract In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit‐DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit‐DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit‐DNA levels in SM patients compared with healthy controls. H3Cit‐DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit‐DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.
{"title":"No indication of aberrant neutrophil extracellular trap release in indolent or advanced systemic mastocytosis","authors":"Axel Rosell, Cecilia Karlström, Joakim S. Dahlin, Daryl Boey, Monika Klimkowska, Kajsa Ax, Charlotte Thålin, Johanna Ungerstedt","doi":"10.1111/sji.13333","DOIUrl":"https://doi.org/10.1111/sji.13333","url":null,"abstract":"Abstract In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit‐DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit‐DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit‐DNA levels in SM patients compared with healthy controls. H3Cit‐DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit‐DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"46 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135250744","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}
Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) has become the first-line treatment for metastatic renal cell carcinoma (RCC), despite the lack of biomarkers. Cyclin-dependent kinase 6 (CDK6) has shown a regulatory role in antitumour response. The study enrolled two cohorts of metastatic RCC treated by IO/TKI (Zhongshan Hospital [ZS]-MRCC, n = 45; JAVELIN-101, n = 726) and two cohorts of localized RCC (ZS-HRRCC, n = 40; TCGA-KIRC, n = 530). CDK6 was evaluated by RNA-sequencing. Progression-free survival (PFS) was the primary endpoint. The prognostic role of CDK6 was evaluated by survival analysis. The correlation between CDK6 and tumour microenvironment was assessed by immunohistochemistry and flow cytometry. The high-CDK6 group displayed a lower response rate (13.6%) than the low-CDK6 group (56.5%) (P = .002). High-CDK6 was associated with poor PFS in both the ZS-MRCC cohort (high-CDK6, median PFS 6.4 months; low-CDK6, median PFS not reached; P = .010) and JAVELIN-101 cohort (high-CDK6, median PFS 10.0 months; low-CDK6, median PFS 13.3 month; P = .033). High-CDK6 was associated with increased PD1+ CD8+ T cells (Spearman's ρ = .47, P < .001) and decreased Granzyme B+ CD8+ T cells (Spearman's ρ = -.35, P = .030). Finally, a random forest score (RFscore) was built by integrating CDK6 and immunologic genes, which was associated with survival benefits of IO/TKI (RFscore-low, TKI vs IO/TKI, HR = 2.47, 95% CI 1.82-3.35, P < .001; RFscore-high, TKI vs IO/TKI, HR = 0.99, 95% CI 0.75-1.32, P = .963). Elevated CDK6 expression indicated resistance and poor PFS under IO/TKI therapy, which was related to exhausted CD8+ T cells. Integrated RFscore could evaluate the benefits of IO/TKI.
{"title":"The prognostic significance of CDK6 expression in renal cell carcinoma treated by immune checkpoint plus tyrosine kinase inhibition.","authors":"Jiajun Wang, Sihong Zhang, Ying Wang, Yanjun Zhu, Xianglai Xu, Jianming Guo","doi":"10.1111/sji.13304","DOIUrl":"10.1111/sji.13304","url":null,"abstract":"<p><p>Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) has become the first-line treatment for metastatic renal cell carcinoma (RCC), despite the lack of biomarkers. Cyclin-dependent kinase 6 (CDK6) has shown a regulatory role in antitumour response. The study enrolled two cohorts of metastatic RCC treated by IO/TKI (Zhongshan Hospital [ZS]-MRCC, n = 45; JAVELIN-101, n = 726) and two cohorts of localized RCC (ZS-HRRCC, n = 40; TCGA-KIRC, n = 530). CDK6 was evaluated by RNA-sequencing. Progression-free survival (PFS) was the primary endpoint. The prognostic role of CDK6 was evaluated by survival analysis. The correlation between CDK6 and tumour microenvironment was assessed by immunohistochemistry and flow cytometry. The high-CDK6 group displayed a lower response rate (13.6%) than the low-CDK6 group (56.5%) (P = .002). High-CDK6 was associated with poor PFS in both the ZS-MRCC cohort (high-CDK6, median PFS 6.4 months; low-CDK6, median PFS not reached; P = .010) and JAVELIN-101 cohort (high-CDK6, median PFS 10.0 months; low-CDK6, median PFS 13.3 month; P = .033). High-CDK6 was associated with increased PD1<sup>+</sup> CD8<sup>+</sup> T cells (Spearman's ρ = .47, P < .001) and decreased Granzyme B<sup>+</sup> CD8<sup>+</sup> T cells (Spearman's ρ = -.35, P = .030). Finally, a random forest score (RFscore) was built by integrating CDK6 and immunologic genes, which was associated with survival benefits of IO/TKI (RFscore-low, TKI vs IO/TKI, HR = 2.47, 95% CI 1.82-3.35, P < .001; RFscore-high, TKI vs IO/TKI, HR = 0.99, 95% CI 0.75-1.32, P = .963). Elevated CDK6 expression indicated resistance and poor PFS under IO/TKI therapy, which was related to exhausted CD8<sup>+</sup> T cells. Integrated RFscore could evaluate the benefits of IO/TKI.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"98 4","pages":"e13304"},"PeriodicalIF":3.7,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10248724","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 : 2023-10-01Epub Date: 2023-07-29DOI: 10.1111/sji.13314
Anran Liu, Songcheng Ying
Aicardi-Goutières syndrome (AGS) is a rare monogenic autoimmune disease that primarily affects the brains of children patients. Its main clinical features include encephalatrophy, basal ganglia calcification, leukoencephalopathy, lymphocytosis and increased interferon-α (IFN-α) levels in the patient's cerebrospinal fluid (CSF) and serum. AGS may be caused by mutations in any one of nine genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11 and RNU7-1) that result in accumulation of self-nucleic acids in the cytoplasm or aberrant sensing of self-nucleic acids. This triggers overproduction of type I interferons (IFNs) and subsequently causes AGS, the prototype of type I interferonopathies. This review describes the discovery history of AGS with various genotypes and provides the latest knowledge of clinical manifestations and causative genes of AGS. The relationship between AGS and type I interferonopathy and potential therapeutic methods for AGS are also discussed in this review.
{"title":"Aicardi-Goutières syndrome: A monogenic type I interferonopathy.","authors":"Anran Liu, Songcheng Ying","doi":"10.1111/sji.13314","DOIUrl":"10.1111/sji.13314","url":null,"abstract":"<p><p>Aicardi-Goutières syndrome (AGS) is a rare monogenic autoimmune disease that primarily affects the brains of children patients. Its main clinical features include encephalatrophy, basal ganglia calcification, leukoencephalopathy, lymphocytosis and increased interferon-α (IFN-α) levels in the patient's cerebrospinal fluid (CSF) and serum. AGS may be caused by mutations in any one of nine genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11 and RNU7-1) that result in accumulation of self-nucleic acids in the cytoplasm or aberrant sensing of self-nucleic acids. This triggers overproduction of type I interferons (IFNs) and subsequently causes AGS, the prototype of type I interferonopathies. This review describes the discovery history of AGS with various genotypes and provides the latest knowledge of clinical manifestations and causative genes of AGS. The relationship between AGS and type I interferonopathy and potential therapeutic methods for AGS are also discussed in this review.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"98 4","pages":"e13314"},"PeriodicalIF":3.7,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195710","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}
T and B lymphocytes are crucial players in cellular and humoral immune responses. The development, activation and differentiation of T and B lymphocytes are regulated by the best characterized PI3K-PI (3,4,5) P3-AKT phosphoinositide signalling pathway. As a branch of the phosphoinositide signalling pathway, the lipid phosphatase INPP4B inhibits AKT activation through degrading the phosphoinositide signalling messenger PI (3,4) P2. However, the role of Inpp4b in T and B lymphocytes remains elusive. Here, we reported that Inpp4b was highly expressed in human and murine T- and B-1 lymphocytes. Despite its higher expression in T lymphocytes, neither T cell development and homeostasis nor in vitro T cell activation and CD4+ T cell differentiation were altered upon loss of Inpp4b. Interestingly, combined direct phenotype analysis of Inpp4b conventional knockout mice and adoptive transfer studies revealed that ablation of Inpp4b intrinsically reduced peritoneal B-1 cells rather B-2 cells. Moreover, Inpp4b deficiency led to impaired thymus independent (TI) and thymus dependent (TD) antigens-induced antibody production. Further in vitro analysis revealed that CD40-mediated B cell proliferation was impaired upon ablation of Inpp4b. Our findings reveal that Inpp4b is required in regulating B-1 cell numbers and B cell-mediated antibody production.
{"title":"Regulation of B-1 cell numbers and B cell-mediated antibody production by Inpp4b.","authors":"Meizhen Xu, Jinfeng Ren, Wenyu Jia, Siyu Wang, Yuting Liu, Xinzhu Chen, Jianhong Shi, Hui Wang","doi":"10.1111/sji.13309","DOIUrl":"10.1111/sji.13309","url":null,"abstract":"<p><p>T and B lymphocytes are crucial players in cellular and humoral immune responses. The development, activation and differentiation of T and B lymphocytes are regulated by the best characterized PI3K-PI (3,4,5) P3-AKT phosphoinositide signalling pathway. As a branch of the phosphoinositide signalling pathway, the lipid phosphatase INPP4B inhibits AKT activation through degrading the phosphoinositide signalling messenger PI (3,4) P2. However, the role of Inpp4b in T and B lymphocytes remains elusive. Here, we reported that Inpp4b was highly expressed in human and murine T- and B-1 lymphocytes. Despite its higher expression in T lymphocytes, neither T cell development and homeostasis nor in vitro T cell activation and CD4<sup>+</sup> T cell differentiation were altered upon loss of Inpp4b. Interestingly, combined direct phenotype analysis of Inpp4b conventional knockout mice and adoptive transfer studies revealed that ablation of Inpp4b intrinsically reduced peritoneal B-1 cells rather B-2 cells. Moreover, Inpp4b deficiency led to impaired thymus independent (TI) and thymus dependent (TD) antigens-induced antibody production. Further in vitro analysis revealed that CD40-mediated B cell proliferation was impaired upon ablation of Inpp4b. Our findings reveal that Inpp4b is required in regulating B-1 cell numbers and B cell-mediated antibody production.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"98 4","pages":"e13309"},"PeriodicalIF":3.7,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10196632","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}
Abstract Uveitis is a devastating intraocular inflammatory disease. The secreted leucine‐rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti‐inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin‐induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor‐kappa B (NF‐κB), phosphorylated NF‐κB, IkappaB‐a (IκB‐a), phosphorylated IκB‐a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose‐like exudates, the production of ICAM‐1, MCP‐1, TNF‐α and IL‐6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF‐κB pathway was found to be activated in EIU. However, the pre‐treatment of rhSlit2 significantly inhibited the production of ICAM‐1, MCP‐1, TNF‐α, and IL‐6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF‐κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU‐related inflammation in Sprague–Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS‐induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF‐κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.
{"title":"Slit2 suppresses <scp>endotoxin‐induced</scp> uveitis by inhibiting the <scp>PI3K</scp>/Akt/<scp>IKK</scp>/<scp>NF‐κB</scp> pathway","authors":"Yong Du, Linbin Zhou, Zijun Wen, Lujia Feng, Shaochong Zhang, Ting Zhang","doi":"10.1111/sji.13319","DOIUrl":"https://doi.org/10.1111/sji.13319","url":null,"abstract":"Abstract Uveitis is a devastating intraocular inflammatory disease. The secreted leucine‐rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti‐inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin‐induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor‐kappa B (NF‐κB), phosphorylated NF‐κB, IkappaB‐a (IκB‐a), phosphorylated IκB‐a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose‐like exudates, the production of ICAM‐1, MCP‐1, TNF‐α and IL‐6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF‐κB pathway was found to be activated in EIU. However, the pre‐treatment of rhSlit2 significantly inhibited the production of ICAM‐1, MCP‐1, TNF‐α, and IL‐6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF‐κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU‐related inflammation in Sprague–Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS‐induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF‐κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"96 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135425677","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}
The data that support the findings of this study are available from the corresponding author upon reasonable request.
支持本研究结果的数据可根据通讯作者的合理要求提供。
{"title":"TREM2 knockout promotes liver cell apoptosis and inflammation in acute liver injury","authors":"Shihua Chao, Shulin Shan, Fuyong Song","doi":"10.1111/sji.13330","DOIUrl":"https://doi.org/10.1111/sji.13330","url":null,"abstract":"The data that support the findings of this study are available from the corresponding author upon reasonable request.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"309 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135816297","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}
Borislav Ignatov, Daniel Sortebech, Thomas Emmanuel, Ekaterina Zhuravleva, Liv Eidsmo
Abstract Specific T cell populations in the skin have been demonstrated as important disease drivers in several dermatoses. Due to the unique skin architecture, these cells are not grouped together in structures but dispersedly spread out throughout the epidermis. Following tissue disruption and isolation, only about 10% of skin T cells are recovered and any in vitro expansion may alter their bona fide phenotype. The Nanostring GeoMx system was developed to address cellular phenotype and protein expression in a tissue spatial context. To do so, regions of interest (ROI) must exceed a certain area threshold (usually 100 μm in diameter) to generate a sufficient signal‐to‐noise ratio. Here, we present an approach that allows for the pooling of numerous smaller ROIs within the skin, enabling T cell and melanocyte phenotyping. Skin samples from healthy individuals and vitiligo patients were analysed using the GeoMx system and several immune profiling panels. A sufficient signal‐to‐noise ratio was achieved by pooling smaller ROIs and analysing them as a single group. While this prevents spatial analysis, this method allows for detailed analysis of cells as a population in the context of their physiological environment, making it possible to investigate in situ phenotype of rare cells in different tissue compartments.
{"title":"Method for high‐plex analysis of immune cells in human skin using the GeoMx system","authors":"Borislav Ignatov, Daniel Sortebech, Thomas Emmanuel, Ekaterina Zhuravleva, Liv Eidsmo","doi":"10.1111/sji.13326","DOIUrl":"https://doi.org/10.1111/sji.13326","url":null,"abstract":"Abstract Specific T cell populations in the skin have been demonstrated as important disease drivers in several dermatoses. Due to the unique skin architecture, these cells are not grouped together in structures but dispersedly spread out throughout the epidermis. Following tissue disruption and isolation, only about 10% of skin T cells are recovered and any in vitro expansion may alter their bona fide phenotype. The Nanostring GeoMx system was developed to address cellular phenotype and protein expression in a tissue spatial context. To do so, regions of interest (ROI) must exceed a certain area threshold (usually 100 μm in diameter) to generate a sufficient signal‐to‐noise ratio. Here, we present an approach that allows for the pooling of numerous smaller ROIs within the skin, enabling T cell and melanocyte phenotyping. Skin samples from healthy individuals and vitiligo patients were analysed using the GeoMx system and several immune profiling panels. A sufficient signal‐to‐noise ratio was achieved by pooling smaller ROIs and analysing them as a single group. While this prevents spatial analysis, this method allows for detailed analysis of cells as a population in the context of their physiological environment, making it possible to investigate in situ phenotype of rare cells in different tissue compartments.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135063698","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}
Abstract Current treatments for hepatocellular carcinoma (HCC) are less effective and prone to recurrence after surgery, so it's needed to seek new ideas for its therapy. Tumour immune microenvironment (TME) is crucial for the pathogenesis, development and metastasis of HCC. Interactions between immune cells and tumour cells significantly impact responses to immunotherapies and patient prognosis. In recent years, immunotherapies for HCC have shown promising potential, but the response rate is still unsatisfactory. Understanding their cross‐talks is helpful for selecting potential therapeutic targets, predicting immunotherapy responses, determining immunotherapy efficacy, identifying prognostic markers and selecting individualized treatment options. In this paper, we reviewed the research advances on the roles of immune cells and multi‐omic research associated with HCC pathogenesis and therapy, and future perspectives on TME.
{"title":"Deciphering the tumour immune microenvironment of hepatocellular carcinoma","authors":"Sha Liu, Man Jia, Rongyang Dai","doi":"10.1111/sji.13327","DOIUrl":"https://doi.org/10.1111/sji.13327","url":null,"abstract":"Abstract Current treatments for hepatocellular carcinoma (HCC) are less effective and prone to recurrence after surgery, so it's needed to seek new ideas for its therapy. Tumour immune microenvironment (TME) is crucial for the pathogenesis, development and metastasis of HCC. Interactions between immune cells and tumour cells significantly impact responses to immunotherapies and patient prognosis. In recent years, immunotherapies for HCC have shown promising potential, but the response rate is still unsatisfactory. Understanding their cross‐talks is helpful for selecting potential therapeutic targets, predicting immunotherapy responses, determining immunotherapy efficacy, identifying prognostic markers and selecting individualized treatment options. In this paper, we reviewed the research advances on the roles of immune cells and multi‐omic research associated with HCC pathogenesis and therapy, and future perspectives on TME.","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135885540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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