Pub Date : 2024-09-01Epub Date: 2024-06-07DOI: 10.1111/sji.13392
Thomas Skovhus Prior, Nils Hoyer, Jesper Rømhild Davidsen, Saher Burhan Shaker, Malthe Pallesgaard Hundahl, Søren Lomholt, Bent Winding Deleuran, Elisabeth Bendstrup, Tue Wenzel Kragstrup
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis in the lungs. Activated fibroblasts play a central role in fibrogenesis and express fibroblast activation protein α. A truncated, soluble form (sFAP) can be measured in blood and is a potential novel biomarker of disease activity. The aim was to study the association between sFAP and clinical, radiological, and histopathological measures of disease severity, progression, and survival in a prospective, multicentre, real-world cohort of patients with IPF. Patients with IPF were recruited from the tertiary interstitial lung disease centres in Denmark and followed for up to 3 years. Baseline serum levels of sFAP were measured by ELISA in patients with IPF and compared to healthy controls. Pulmonary function tests, 6-minute walk test and quality of life measures were performed at baseline and during follow-up. The study included 149 patients with IPF. Median sFAP in IPF was 49.6 ng/mL (IQR: 43.1-61.6 ng/mL) and in healthy controls 73.8 ng/mL (IQR: 62.1-92.0 ng/mL). Continuous sFAP was not associated with disease severity, progression or survival (p > 0.05). After dichotomization of sFAP below or above mean sFAP + 2 SD for healthy controls, higher levels of sFAP were associated with lower FVC % predicted during follow-up (p < 0.01). Higher than normal serum levels of sFAP were associated with longitudinal changes in FVC % predicted, but sFAP did not show clear associations with other baseline or longitudinal parameters. As such, sFAP has limited use as a biomarker of disease progression or survival in patients with IPF.
{"title":"Fibroblast activation protein and disease severity, progression, and survival in idiopathic pulmonary fibrosis.","authors":"Thomas Skovhus Prior, Nils Hoyer, Jesper Rømhild Davidsen, Saher Burhan Shaker, Malthe Pallesgaard Hundahl, Søren Lomholt, Bent Winding Deleuran, Elisabeth Bendstrup, Tue Wenzel Kragstrup","doi":"10.1111/sji.13392","DOIUrl":"10.1111/sji.13392","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis in the lungs. Activated fibroblasts play a central role in fibrogenesis and express fibroblast activation protein α. A truncated, soluble form (sFAP) can be measured in blood and is a potential novel biomarker of disease activity. The aim was to study the association between sFAP and clinical, radiological, and histopathological measures of disease severity, progression, and survival in a prospective, multicentre, real-world cohort of patients with IPF. Patients with IPF were recruited from the tertiary interstitial lung disease centres in Denmark and followed for up to 3 years. Baseline serum levels of sFAP were measured by ELISA in patients with IPF and compared to healthy controls. Pulmonary function tests, 6-minute walk test and quality of life measures were performed at baseline and during follow-up. The study included 149 patients with IPF. Median sFAP in IPF was 49.6 ng/mL (IQR: 43.1-61.6 ng/mL) and in healthy controls 73.8 ng/mL (IQR: 62.1-92.0 ng/mL). Continuous sFAP was not associated with disease severity, progression or survival (p > 0.05). After dichotomization of sFAP below or above mean sFAP + 2 SD for healthy controls, higher levels of sFAP were associated with lower FVC % predicted during follow-up (p < 0.01). Higher than normal serum levels of sFAP were associated with longitudinal changes in FVC % predicted, but sFAP did not show clear associations with other baseline or longitudinal parameters. As such, sFAP has limited use as a biomarker of disease progression or survival in patients with IPF.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288531","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}
Mahsa Eshkevar Vakili, Niloofar Mashhadi, Mohammad Reza Ataollahi, Seppo Meri, Dieter Kabelitz, Kurosh Kalantar
Hepatitis B (HB) infection is a major global health problem. There is limited knowledge about HB vaccination-induced immune memory responses. We compared the frequency of CD8+ memory T cell subsets between responders (RSs) and non-responders (NRs) to HB vaccination. Blood samples were collected from RSs and NRs. PBMCs were cultured in the presence of Hepatitis B surface antigens (HBsAg) and PHA for 48 h to restimulate CD8+ memory T cells and T cell memory subsets were detected by flow cytometry using memory cell markers. The frequency of TEM, TCM, and TCMhi was significantly higher in responders compared to non-responders (p = 0.024, 0.022, and 0.047, respectively). Additionally, we report a positive correlation between the frequency of TEM cells in RSs with age and anti-HBsAb level (p = 0.03 and rs = 0.5; p = 0.01 and rs = 0.06). Responders display a higher level of CD8+ T cell-mediated immunity. Therefore, we suggest a possible defect in the formation of immunological CD8+ memory T cells in NRs and it may reduce antibody production compared to the RSs, although more experiments are needed.
乙型肝炎(HB)感染是一个重大的全球性健康问题。人们对 HB 疫苗接种诱导的免疫记忆反应了解有限。我们比较了乙肝疫苗接种应答者(RSs)和非应答者(NRs)的 CD8+ 记忆 T 细胞亚群的频率。我们采集了 RSs 和 NRs 的血样。在乙肝表面抗原(HBsAg)和 PHA 存在下培养 PBMC 48 小时,以重新刺激 CD8+ 记忆 T 细胞,并使用记忆细胞标记物通过流式细胞术检测 T 细胞记忆亚群。与非应答者相比,应答者的 TEM、TCM 和 TCM hi 的频率明显更高(p = 0.024、0.022 和 0.047)。此外,我们还发现,RSs 中 TEM 细胞的频率与年龄和抗-HBsAb 水平呈正相关(p = 0.03 和 rs = 0.5;p = 0.01 和 rs = 0.06)。应答者的 CD8+ T 细胞介导的免疫水平更高。因此,我们认为 NRs 的免疫 CD8+ 记忆 T 细胞的形成可能存在缺陷,与 RSs 相比,它可能会减少抗体的产生,尽管还需要更多的实验。
{"title":"Hepatitis B vaccine responders show higher frequencies of CD8<sup>+</sup> effector memory and central memory T cells compared to non-responders.","authors":"Mahsa Eshkevar Vakili, Niloofar Mashhadi, Mohammad Reza Ataollahi, Seppo Meri, Dieter Kabelitz, Kurosh Kalantar","doi":"10.1111/sji.13402","DOIUrl":"https://doi.org/10.1111/sji.13402","url":null,"abstract":"<p><p>Hepatitis B (HB) infection is a major global health problem. There is limited knowledge about HB vaccination-induced immune memory responses. We compared the frequency of CD8<sup>+</sup> memory T cell subsets between responders (RSs) and non-responders (NRs) to HB vaccination. Blood samples were collected from RSs and NRs. PBMCs were cultured in the presence of Hepatitis B surface antigens (HBsAg) and PHA for 48 h to restimulate CD8<sup>+</sup> memory T cells and T cell memory subsets were detected by flow cytometry using memory cell markers. The frequency of T<sub>EM</sub>, T<sub>CM</sub>, and T<sub>CM</sub> <sup>hi</sup> was significantly higher in responders compared to non-responders (p = 0.024, 0.022, and 0.047, respectively). Additionally, we report a positive correlation between the frequency of T<sub>EM</sub> cells in RSs with age and anti-HBsAb level (p = 0.03 and r<sub>s</sub> = 0.5; p = 0.01 and r<sub>s</sub> = 0.06). Responders display a higher level of CD8<sup>+</sup> T cell-mediated immunity. Therefore, we suggest a possible defect in the formation of immunological CD8<sup>+</sup> memory T cells in NRs and it may reduce antibody production compared to the RSs, although more experiments are needed.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073760","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}
Abel Lissom, Rosette Megnekou, Thibau Flaurant Tchouangueu, Loveline Ngu, Jean Claude Djontu, Herve Fotso Ouambo, Carrie Sanders, Jules Colince Tchadji, Carole Stephanie Sake, Salomon Bonsi Tchuandom, Swapnil Bawage, Arinze Stanley Okoli, Chae Gyu Park, Alain Bopda Waffo, Nchinda Wapimewah Godwin
Malaria blood-stage parasite is a critical pathogenic stage responsible for serious adverse outcomes in pregnant women and their neonates. Immunoglobulin G (IgG) antibody responses specific to various asexual blood-stage antigens were well reported in non-pregnant individuals. However, little is still known during placental malaria. To assess the antibody responses specific to Plasmodium falciparum-derived MSP3 and UB05 malaria vaccine candidates in mother-neonate couples, mother's peripheral blood and neonate's cord blood samples were collected at delivery. After malaria diagnostic, plasma levels of IgG and IgG subclass responses specific to UB05, MSP3 and UB05-MSP3 were determined using ELISA. As outcomes, both mothers and neonates had significantly higher IgG responses to UB05 and UB05-MSP3 compared to anti-MSP3 IgG (p < 0.05), irrespective of malaria status. Significant negative correlations were observed between IgG levels specific to the three antigens and parasitaemia (p < 0.01). Anti-UB05 and anti-UB05-MSP3 IgG levels in neonates showed a significant positive correlation with the corresponding mothers' antibodies (rs = 0.25 with p = 0.04; rs = 0.31 with p = 0.01, respectively). UB05MSP3-specific IgG3 and IgG1 subclass responses were significantly higher than the IgG4 subclass (p < 0.01). The neonates IgG1 and IgG3 levels positively correlated with the corresponding antibody subclasses of mothers. These findings suggest an association between UB05 and UB05-MSP3-specific antibody responses and malaria control during pregnancy. Maternal-foetal transfer of MSP3 and UB05-specific IgG occurs during pregnancy, suggesting the interest in the future malaria vaccination strategies in pregnant women to generate early protective immunity in baby against malaria.
{"title":"Specific antibody responses to Qβ-displayed Plasmodium falciparum-derived UB05 and MSP3 proteins in mother-neonate couples.","authors":"Abel Lissom, Rosette Megnekou, Thibau Flaurant Tchouangueu, Loveline Ngu, Jean Claude Djontu, Herve Fotso Ouambo, Carrie Sanders, Jules Colince Tchadji, Carole Stephanie Sake, Salomon Bonsi Tchuandom, Swapnil Bawage, Arinze Stanley Okoli, Chae Gyu Park, Alain Bopda Waffo, Nchinda Wapimewah Godwin","doi":"10.1111/sji.13404","DOIUrl":"https://doi.org/10.1111/sji.13404","url":null,"abstract":"<p><p>Malaria blood-stage parasite is a critical pathogenic stage responsible for serious adverse outcomes in pregnant women and their neonates. Immunoglobulin G (IgG) antibody responses specific to various asexual blood-stage antigens were well reported in non-pregnant individuals. However, little is still known during placental malaria. To assess the antibody responses specific to Plasmodium falciparum-derived MSP3 and UB05 malaria vaccine candidates in mother-neonate couples, mother's peripheral blood and neonate's cord blood samples were collected at delivery. After malaria diagnostic, plasma levels of IgG and IgG subclass responses specific to UB05, MSP3 and UB05-MSP3 were determined using ELISA. As outcomes, both mothers and neonates had significantly higher IgG responses to UB05 and UB05-MSP3 compared to anti-MSP3 IgG (p < 0.05), irrespective of malaria status. Significant negative correlations were observed between IgG levels specific to the three antigens and parasitaemia (p < 0.01). Anti-UB05 and anti-UB05-MSP3 IgG levels in neonates showed a significant positive correlation with the corresponding mothers' antibodies (r<sub>s</sub> = 0.25 with p = 0.04; r<sub>s</sub> = 0.31 with p = 0.01, respectively). UB05MSP3-specific IgG3 and IgG1 subclass responses were significantly higher than the IgG4 subclass (p < 0.01). The neonates IgG1 and IgG3 levels positively correlated with the corresponding antibody subclasses of mothers. These findings suggest an association between UB05 and UB05-MSP3-specific antibody responses and malaria control during pregnancy. Maternal-foetal transfer of MSP3 and UB05-specific IgG occurs during pregnancy, suggesting the interest in the future malaria vaccination strategies in pregnant women to generate early protective immunity in baby against malaria.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000626","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}
Fengjiao Huang, Lijuan Zhang, Yingying Zhou, Shuiying Zhao, Jiao Wang
This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4+ T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4+ T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4+ T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4+ T cells of HC subjects increased the percentage of Th17 cells and upregulated p-IκBα, p50, p65, c-Rel protein expressions, and NF-κB inhibitor BAY11-7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin-related modifier 1 (SUMO-1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO-1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL-21 levels and secretion, and IL-21 neutralizing antibody reversed this effect. IL-21 level was decreased after p65 interference in CD4+ T cells of HC subjects. p65 interacts with IL-21 promoter region. In conclusion, NrCAM binds to SUMO-1 and increases phosphorylation of IκBα, leading to activation of NF-κB pathway, which promotes Th17 cell differentiation.
本研究旨在探讨神经元细胞粘附分子(NrCAM)调控Th17细胞分化在巴塞杜氏病(GD)发病机制中的分子机制。研究人员从巴塞杜氏病患者和健康对照组(HC)的外周血单核细胞中分离出了幼稚的CD4+ T细胞。在CD4+ T细胞向Th17细胞分化的过程中,GD组的NrCAM水平有所提高。干扰 GD 患者 CD4+ T 细胞中的 NrCAM 会降低 Th17 细胞的比例。在 HC 受试者的 CD4+ T 细胞中过表达 NrCAM 会增加 Th17 细胞的比例,并上调 p-IκBα、p50、p65 和 c-Rel 蛋白的表达,NF-κB 抑制剂 BAY11-7082 可部分逆转 NrCAM 的作用。NrCAM的过表达促进了IκBα的降解,而泛素相关小修饰物1(SUMO-1)的过表达抑制了IκBα的降解。NrCAM的过表达减少了IκBα与SUMO-1的结合。在HC组Th17细胞分化过程中,NrCAM过表达增加了IL-21的水平和分泌,IL-21中和抗体逆转了这一效应。p65与IL-21启动子区域相互作用。总之,NrCAM与SUMO-1结合并增加IκBα的磷酸化,导致NF-κB通路的激活,从而促进Th17细胞的分化。
{"title":"NrCAM activates the NF-κB signalling pathway by competitively binding to SUMO-1 and promotes Th17 cell differentiation in Graves' disease.","authors":"Fengjiao Huang, Lijuan Zhang, Yingying Zhou, Shuiying Zhao, Jiao Wang","doi":"10.1111/sji.13401","DOIUrl":"https://doi.org/10.1111/sji.13401","url":null,"abstract":"<p><p>This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4<sup>+</sup> T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4<sup>+</sup> T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4<sup>+</sup> T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4<sup>+</sup> T cells of HC subjects increased the percentage of Th17 cells and upregulated p-IκBα, p50, p65, c-Rel protein expressions, and NF-κB inhibitor BAY11-7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin-related modifier 1 (SUMO-1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO-1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL-21 levels and secretion, and IL-21 neutralizing antibody reversed this effect. IL-21 level was decreased after p65 interference in CD4<sup>+</sup> T cells of HC subjects. p65 interacts with IL-21 promoter region. In conclusion, NrCAM binds to SUMO-1 and increases phosphorylation of IκBα, leading to activation of NF-κB pathway, which promotes Th17 cell differentiation.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000625","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}
Antigen presenting cells sometimes require T cell "help" to kill and decompose microbes they capture, especially when those microbes resist effector molecules including nitric oxide and reactive oxygen species. Pathogens are more likely to resist those effectors, shared by the innate and adaptive immune systems, than are commensals. Does such resistance alert the immune system to the danger posed by those pathogens? Several lines of evidence suggest this occurs. Mouse studies showed a surprising exacerbation, not alleviation of experimental autoimmune encephalomyelitis, by suppression of nitric oxide production, but only when the suppression was applied to animals undergoing vaccination with myelin. In contrast, animals receiving T cells activated by vaccination without suppression of nitric oxide benefitted from reduced autoimmune cytotoxicity when nitric oxide production was suppressed after adoptive transfer. Vaccinia and adenovirus suppress nitric oxide production and have been successful vaccine platforms, also consistent with the above phagolysosomal resistance hypothesis. The hypothesis solves a long-standing quandary-how can nitric oxide protect against both infection and autoimmunity, especially autoimmune diseases for which it seems a major effector? The importance of physical linkage between epitopes, first proposed in Bretscher's Two-Step, Two-Signal theory dependent on B cells, is extended to include phagolysosomal resistance in general, plus a corollary proposition that the immune system detects resistance to dissociation of high-affinity pathogenic ligands from host binding sites to make neutralizing antibodies.
抗原递呈细胞有时需要 T 细胞的 "帮助 "来杀死和分解它们捕获的微生物,尤其是当这些微生物抵制一氧化氮和活性氧等效应分子时。病原体比共生体更有可能抵抗先天性免疫系统和适应性免疫系统共有的这些效应分子。这种抵抗是否会提醒免疫系统注意这些病原体带来的危险?一些证据表明会出现这种情况。小鼠研究显示,抑制一氧化氮的产生会令人惊讶地加剧而非缓解实验性自身免疫性脑脊髓炎,但只有在动物接种髓鞘疫苗时才会出现这种情况。与此相反,当一氧化氮的产生在采用性转移后受到抑制时,接受疫苗激活的 T 细胞的动物会从自身免疫细胞毒性的降低中获益,而不抑制一氧化氮的产生。疫苗素和腺病毒抑制一氧化氮的产生,并已成为成功的疫苗平台,这也与上述吞噬体抗性假说相一致。该假说解决了一个长期存在的难题--一氧化氮如何既能抵御感染,又能抵御自身免疫,尤其是自身免疫疾病,而一氧化氮似乎是自身免疫疾病的主要效应因子?布雷舍尔(Bretscher)的 "两步双信号理论"(Two-Step, Two-Signal theory)首次提出了表位间物理联系的重要性,并将其扩展到一般的吞噬体抗性,以及免疫系统检测高亲和性致病配体与宿主结合位点解离的抗性以产生中和抗体的必然命题。
{"title":"Phagolysosomal resistance hypothesized to be a danger signal.","authors":"Christopher A Forden","doi":"10.1111/sji.13400","DOIUrl":"https://doi.org/10.1111/sji.13400","url":null,"abstract":"<p><p>Antigen presenting cells sometimes require T cell \"help\" to kill and decompose microbes they capture, especially when those microbes resist effector molecules including nitric oxide and reactive oxygen species. Pathogens are more likely to resist those effectors, shared by the innate and adaptive immune systems, than are commensals. Does such resistance alert the immune system to the danger posed by those pathogens? Several lines of evidence suggest this occurs. Mouse studies showed a surprising exacerbation, not alleviation of experimental autoimmune encephalomyelitis, by suppression of nitric oxide production, but only when the suppression was applied to animals undergoing vaccination with myelin. In contrast, animals receiving T cells activated by vaccination without suppression of nitric oxide benefitted from reduced autoimmune cytotoxicity when nitric oxide production was suppressed after adoptive transfer. Vaccinia and adenovirus suppress nitric oxide production and have been successful vaccine platforms, also consistent with the above phagolysosomal resistance hypothesis. The hypothesis solves a long-standing quandary-how can nitric oxide protect against both infection and autoimmunity, especially autoimmune diseases for which it seems a major effector? The importance of physical linkage between epitopes, first proposed in Bretscher's Two-Step, Two-Signal theory dependent on B cells, is extended to include phagolysosomal resistance in general, plus a corollary proposition that the immune system detects resistance to dissociation of high-affinity pathogenic ligands from host binding sites to make neutralizing antibodies.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976462","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}
Autoimmune cytopenias are a heterogeneous group of disorders characterized by immune-mediated destruction of haematopoietic cell lines. Effective and well-tolerated treatment options for relapsed-refractory immune cytopenias are limited. In this study, the aim was to evaluate the efficacy and safety of sirolimus in this disease group within the paediatric age group. The study enrolled patients in the paediatric age group who used sirolimus with a diagnosis of immune cytopenia between December 2010 and December 2020, followed at six centres in Turkey. Of the 17 patients, five (29.4%) were treated for autoimmune haemolytic anaemia (AIHA), six (35.2%) for immune thrombocytopenic purpura (ITP) and six (35.2%) for Evans syndrome (ES). The mean response time was 2.7 months (range, 0-9 months). Complete response (CR) and partial response (PR) were obtained in 13 of 17 patients (76.4%) and nonresponse (NR) in four patients (23.5%). Among the 13 patients who achieved CR, three of them were NR in the follow-up and two of them had remission with low-dose steroid and sirolimus. Thus, overall response rate (ORR) was achieved in 12 of 17 patients (70.5%). In conclusion, sirolimus may be an effective and safe option in paediatric patients with relapsed-refractory immune cytopenia.
{"title":"Sirolimus is effective and safe in childhood relapsed-refractory autoimmune cytopenias: A multicentre study.","authors":"Sultan Okur Acar, Neryal Tahta, Işık Odaman Al, Melek Erdem, Salih Gözmen, Tuba Hilkay Karapınar, Burcu Kılınç, Tiraje Celkan, Serap Kirkiz, Ülker Koçak, Hale Ören, Ayşen Türedi Yıldırım, Esra Arslantaş, Aylin Canbolat Ayhan, Yeşim Oymak","doi":"10.1111/sji.13376","DOIUrl":"10.1111/sji.13376","url":null,"abstract":"<p><p>Autoimmune cytopenias are a heterogeneous group of disorders characterized by immune-mediated destruction of haematopoietic cell lines. Effective and well-tolerated treatment options for relapsed-refractory immune cytopenias are limited. In this study, the aim was to evaluate the efficacy and safety of sirolimus in this disease group within the paediatric age group. The study enrolled patients in the paediatric age group who used sirolimus with a diagnosis of immune cytopenia between December 2010 and December 2020, followed at six centres in Turkey. Of the 17 patients, five (29.4%) were treated for autoimmune haemolytic anaemia (AIHA), six (35.2%) for immune thrombocytopenic purpura (ITP) and six (35.2%) for Evans syndrome (ES). The mean response time was 2.7 months (range, 0-9 months). Complete response (CR) and partial response (PR) were obtained in 13 of 17 patients (76.4%) and nonresponse (NR) in four patients (23.5%). Among the 13 patients who achieved CR, three of them were NR in the follow-up and two of them had remission with low-dose steroid and sirolimus. Thus, overall response rate (ORR) was achieved in 12 of 17 patients (70.5%). In conclusion, sirolimus may be an effective and safe option in paediatric patients with relapsed-refractory immune cytopenia.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-15DOI: 10.1111/sji.13374
Kirstine Kløve-Mogensen, Rudi Steffensen, Tania Nicole Masmas, Andreas Glenthøj, Christina Friis Jensen, Paul Ratcliffe, Petter Höglund, Henrik Hasle, Kaspar René Nielsen, Thure Mors Haunstrup
Autoimmune neutropenia (AIN) in early childhood is characterized by chronic neutropenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg-associated genes, IL-2, IL-10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL-2 -330T>G (rs2069762), +114G>T (rs2069763) and IVS3-116 A>G (rs2069772), four SNPs in IL-10 -3575T>A (rs1800890), -1082G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) and three SNPs in FOXP3 -3499 A>G (rs3761547), -3279 C>A (rs3761548) and -924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL-2 IVS3-116 GG (p = 0.0081, OR = 0.35 [0.15-0.80]), IL-10 -3575 TT (p = 0.0078, OR = 1.71 [1.16-2.54]) and IL-10 -1082 AA (p = 0.014, OR = 1.76 [1.14-2.72]) in all patients and FOXP3 -924 (p = 0.0005, A OR = 0.41 [0.25-0.68] and G OR = 2.42 [1.46-4.01]) in male patients. None of the associations were linked to antibody specificity. Disease-associated haplotypes were observed in IL-2 and FOXP3. IL-2 -330T/+114 T/IVS3-116A was associated with anti-FcγRIIIb-positive patients (p = 0.012, OR = 2.07 [1.18-3.62]). FOXP3 -3499A/-3279C/-924A was associated with anti-HNA-1a-positive male patients (p = 0.016, OR = 0.41 [0.20-0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti-FcγRIIIb-positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg-associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic-evolving Tregs.
{"title":"Genetic polymorphisms in IL-2, IL-10 and FOXP3 are associated with autoimmune neutropenia in early childhood and autoantibody specificity in a Danish cohort.","authors":"Kirstine Kløve-Mogensen, Rudi Steffensen, Tania Nicole Masmas, Andreas Glenthøj, Christina Friis Jensen, Paul Ratcliffe, Petter Höglund, Henrik Hasle, Kaspar René Nielsen, Thure Mors Haunstrup","doi":"10.1111/sji.13374","DOIUrl":"10.1111/sji.13374","url":null,"abstract":"<p><p>Autoimmune neutropenia (AIN) in early childhood is characterized by chronic neutropenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg-associated genes, IL-2, IL-10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL-2 -330T>G (rs2069762), +114G>T (rs2069763) and IVS3-116 A>G (rs2069772), four SNPs in IL-10 -3575T>A (rs1800890), -1082G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) and three SNPs in FOXP3 -3499 A>G (rs3761547), -3279 C>A (rs3761548) and -924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL-2 IVS3-116 GG (p = 0.0081, OR = 0.35 [0.15-0.80]), IL-10 -3575 TT (p = 0.0078, OR = 1.71 [1.16-2.54]) and IL-10 -1082 AA (p = 0.014, OR = 1.76 [1.14-2.72]) in all patients and FOXP3 -924 (p = 0.0005, A OR = 0.41 [0.25-0.68] and G OR = 2.42 [1.46-4.01]) in male patients. None of the associations were linked to antibody specificity. Disease-associated haplotypes were observed in IL-2 and FOXP3. IL-2 -330T/+114 T/IVS3-116A was associated with anti-FcγRIIIb-positive patients (p = 0.012, OR = 2.07 [1.18-3.62]). FOXP3 -3499A/-3279C/-924A was associated with anti-HNA-1a-positive male patients (p = 0.016, OR = 0.41 [0.20-0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti-FcγRIIIb-positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg-associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic-evolving Tregs.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-15DOI: 10.1111/sji.13375
Masoud H Manjili, Saeed H Manjili
Our understanding of the immune response is far from complete, missing out on more detailed explanations that could be provided by molecular insights. To bridge this gap, we introduce the quantum model of T-cell activation. This model suggests that the transfer of energy during protein phosphorylation within T cells is not a continuous flow but occurs in discrete bursts, or 'quanta', of phosphates. This quantized energy transfer is mediated by oscillating cycles of receptor phosphorylation and dephosphorylation, initiated by dynamic 'catch-slip' pulses in the peptide-major histocompatibility complex-T-cell receptor (pMHC-TcR) interactions. T-cell activation is predicated upon achieving a critical threshold of catch-slip pulses at the pMHC-TcR interface. Costimulation is relegated to a secondary role, becoming crucial only when the frequency of pMHC-TcR catch-slip pulses does not meet the necessary threshold for this quanta-based energy transfer. Therefore, our model posits that it is the quantum nature of energy transfer-not the traditional signal I or signal II-that plays the decisive role in T-cell activation. This paradigm shift highlights the importance of understanding T-cell activation through a quantum lens, offering a potentially transformative perspective on immune response regulation.
我们对免疫反应的了解还远远不够,还缺少分子洞察力所能提供的更详细的解释。为了弥补这一差距,我们引入了 T 细胞活化的量子模型。该模型认为,T 细胞内蛋白质磷酸化过程中的能量转移不是连续流动的,而是以离散的磷酸猝发或 "量子 "形式发生的。这种量子化的能量转移由受体磷酸化和去磷酸化的振荡周期介导,由多肽-主要组织相容性复合体-细胞受体(pMHC-TcR)相互作用中的动态 "捕捉-滑动 "脉冲启动。T 细胞的激活取决于 pMHC-TcR 界面的捕捉-滑动脉冲是否达到临界阈值。成本刺激则处于次要地位,只有当 pMHC-TcR 捕获-滑动脉冲的频率达不到这种基于量子的能量转移的必要阈值时,成本刺激才变得至关重要。因此,我们的模型认为,在 T 细胞活化中起决定性作用的是能量转移的量子性质,而不是传统的信号 I 或信号 II。这一范式的转变凸显了通过量子视角理解 T 细胞活化的重要性,为免疫反应调控提供了一个潜在的变革性视角。
{"title":"The quantum model of T-cell activation: Revisiting immune response theories.","authors":"Masoud H Manjili, Saeed H Manjili","doi":"10.1111/sji.13375","DOIUrl":"10.1111/sji.13375","url":null,"abstract":"<p><p>Our understanding of the immune response is far from complete, missing out on more detailed explanations that could be provided by molecular insights. To bridge this gap, we introduce the quantum model of T-cell activation. This model suggests that the transfer of energy during protein phosphorylation within T cells is not a continuous flow but occurs in discrete bursts, or 'quanta', of phosphates. This quantized energy transfer is mediated by oscillating cycles of receptor phosphorylation and dephosphorylation, initiated by dynamic 'catch-slip' pulses in the peptide-major histocompatibility complex-T-cell receptor (pMHC-TcR) interactions. T-cell activation is predicated upon achieving a critical threshold of catch-slip pulses at the pMHC-TcR interface. Costimulation is relegated to a secondary role, becoming crucial only when the frequency of pMHC-TcR catch-slip pulses does not meet the necessary threshold for this quanta-based energy transfer. Therefore, our model posits that it is the quantum nature of energy transfer-not the traditional signal I or signal II-that plays the decisive role in T-cell activation. This paradigm shift highlights the importance of understanding T-cell activation through a quantum lens, offering a potentially transformative perspective on immune response regulation.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-24DOI: 10.1111/sji.13394
Rikke Svensson, Michelle Malon, Lone G Stensballe, Steffen U Thorsen, Jannet Svensson
Stress has been associated with less effective vaccine responses in adults. This review aims to investigate the evidence for a similar association in children. A systematic review search was conducted in January 2021 in three databases: Medline, Embase and PsycInfo. An updated search of the Medline database was systematically conducted until the most recent update on September 25th, 2023, to ensure the inclusion of the most current research available. Keywords related to stress, vaccines and children were used, and a total of 7263 (+1528) studies were screened by two independent investigators. Six studies met the inclusion criteria for data extraction and analysis. For quality assessment of the studies, the risk of bias in non-randomized studies-of interventions (ROBINS-I) tool was applied. Most of the studies suggest a negative role of stress on vaccine responses. However, the scarcity of studies, lack of confirmatory studies, risk of bias and heterogeneity according to age, type of vaccine, measures of stress and vaccine responses prevent a clear conclusion. Future studies should emphasize the use of as strict study designs as possible, including well-defined stress metrics and thorough examination of both pre- and post-vaccination responses. Systematic review registration: Prospero CRD42021230490.
{"title":"The effect of stress on the antibody response after vaccination in children aged 0-18 years: A systematic review.","authors":"Rikke Svensson, Michelle Malon, Lone G Stensballe, Steffen U Thorsen, Jannet Svensson","doi":"10.1111/sji.13394","DOIUrl":"10.1111/sji.13394","url":null,"abstract":"<p><p>Stress has been associated with less effective vaccine responses in adults. This review aims to investigate the evidence for a similar association in children. A systematic review search was conducted in January 2021 in three databases: Medline, Embase and PsycInfo. An updated search of the Medline database was systematically conducted until the most recent update on September 25th, 2023, to ensure the inclusion of the most current research available. Keywords related to stress, vaccines and children were used, and a total of 7263 (+1528) studies were screened by two independent investigators. Six studies met the inclusion criteria for data extraction and analysis. For quality assessment of the studies, the risk of bias in non-randomized studies-of interventions (ROBINS-I) tool was applied. Most of the studies suggest a negative role of stress on vaccine responses. However, the scarcity of studies, lack of confirmatory studies, risk of bias and heterogeneity according to age, type of vaccine, measures of stress and vaccine responses prevent a clear conclusion. Future studies should emphasize the use of as strict study designs as possible, including well-defined stress metrics and thorough examination of both pre- and post-vaccination responses. Systematic review registration: Prospero CRD42021230490.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-16DOI: 10.1111/sji.13373
Rania Najm, Lemis Yavuz, Ruchi Jain, Maha El Naofal, Sathishkumar Ramaswamy, Walid Abuhammour, Tom Loney, Norbert Nowotny, Alawi Alsheikh-Ali, Ahmad Abou Tayoun, Richard K Kandasamy
The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole-exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2-related disorders.
{"title":"IFIH1 loss of function predisposes to inflammatory and SARS-CoV-2-related infectious diseases.","authors":"Rania Najm, Lemis Yavuz, Ruchi Jain, Maha El Naofal, Sathishkumar Ramaswamy, Walid Abuhammour, Tom Loney, Norbert Nowotny, Alawi Alsheikh-Ali, Ahmad Abou Tayoun, Richard K Kandasamy","doi":"10.1111/sji.13373","DOIUrl":"10.1111/sji.13373","url":null,"abstract":"<p><p>The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole-exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2-related disorders.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959048","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}