Fatimah Mohammad Budair, Takashi Nomura, Masahiro Hirata, Kenji Kabashima
T-cell recruitment to skin tissues is essential for inflammation in different cutaneous diseases; however, the mechanisms by which these T cells access the skin remain unclear. High endothelial venules expressing peripheral node address in (PNAd), an L-selectin ligand, are located in secondary lymphoid organs and are responsible for increasing T-cell influx into the lymphoid tissues. They are also found in non-lymphoid tissues during inflammation. However, their presence in different common inflammatory cutaneous diseases and their correlation with T-cell infiltration remain unclear. Herein, we explored the mechanisms underlying the access of T cells to the skin by investigating the presence of PNAd-expressing vessels in different cutaneous diseases, and its correlation with T cells' presence. Skin sections of 43 patients with different diseases were subjected to immunohistochemical and immunofluorescence staining to examine the presence of PNAd-expressing vessels in the dermis. The correlation of the percentage of these vessels in the dermis of these patients with the severity/grade of CD3+ T-cell infiltration was assessed. PNAd-expressing vessels were commonly found in the skin of patients with different inflammatory diseases. A high percentage of these vessels in the dermis was associated with increased severity of CD3+ T-cell infiltration (P < 0.05). Additionally, CD3+ T cells were found both around the PNAd-expressing vessels and within the vessel lumen. PNAd-expressing vessels in cutaneous inflammatory diseases, characterized by CD3+ T-cell infiltration, could be a crucial entry point for T cells into the skin. Thus, selective targeting of these vessels could be beneficial in cutaneous inflammatory disease treatment.
T 细胞被招募到皮肤组织对不同皮肤病的炎症至关重要;然而,这些 T 细胞进入皮肤的机制仍不清楚。表达外周结节地址(PNAd)(一种 L 选择素配体)的高内皮静脉位于次级淋巴器官,负责增加 T 细胞流入淋巴组织。在炎症期间,它们也会出现在非淋巴组织中。然而,它们在不同常见皮肤炎症疾病中的存在及其与 T 细胞浸润的相关性仍不清楚。在此,我们通过研究 PNAd 表达血管在不同皮肤病中的存在及其与 T 细胞存在的相关性,探索了 T 细胞进入皮肤的机制。对 43 例不同疾病患者的皮肤切片进行免疫组化和免疫荧光染色,以检测真皮层中是否存在表达 PNAd 的血管。评估了这些患者真皮层中这些血管的百分比与 CD3+ T 细胞浸润的严重程度/等级的相关性。在不同炎症性疾病患者的皮肤中普遍发现了表达 PNAd 的血管。这些血管在真皮中的高比例与 CD3+ T 细胞浸润的严重程度有关(P < 0.05)。此外,在表达 PNAd 的血管周围和血管腔内都发现了 CD3+ T 细胞。皮肤炎症性疾病中以 CD3+ T 细胞浸润为特征的 PNAd 表达血管可能是 T 细胞进入皮肤的关键入口。因此,选择性靶向这些血管可能有益于皮肤炎症性疾病的治疗。
{"title":"PNAd-expressing vessels characterize the dermis of CD3+ T-cell-mediated cutaneous diseases.","authors":"Fatimah Mohammad Budair, Takashi Nomura, Masahiro Hirata, Kenji Kabashima","doi":"10.1093/cei/uxae003","DOIUrl":"10.1093/cei/uxae003","url":null,"abstract":"<p><p>T-cell recruitment to skin tissues is essential for inflammation in different cutaneous diseases; however, the mechanisms by which these T cells access the skin remain unclear. High endothelial venules expressing peripheral node address in (PNAd), an L-selectin ligand, are located in secondary lymphoid organs and are responsible for increasing T-cell influx into the lymphoid tissues. They are also found in non-lymphoid tissues during inflammation. However, their presence in different common inflammatory cutaneous diseases and their correlation with T-cell infiltration remain unclear. Herein, we explored the mechanisms underlying the access of T cells to the skin by investigating the presence of PNAd-expressing vessels in different cutaneous diseases, and its correlation with T cells' presence. Skin sections of 43 patients with different diseases were subjected to immunohistochemical and immunofluorescence staining to examine the presence of PNAd-expressing vessels in the dermis. The correlation of the percentage of these vessels in the dermis of these patients with the severity/grade of CD3+ T-cell infiltration was assessed. PNAd-expressing vessels were commonly found in the skin of patients with different inflammatory diseases. A high percentage of these vessels in the dermis was associated with increased severity of CD3+ T-cell infiltration (P < 0.05). Additionally, CD3+ T cells were found both around the PNAd-expressing vessels and within the vessel lumen. PNAd-expressing vessels in cutaneous inflammatory diseases, characterized by CD3+ T-cell infiltration, could be a crucial entry point for T cells into the skin. Thus, selective targeting of these vessels could be beneficial in cutaneous inflammatory disease treatment.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The precise pathogenesis of Kawasaki disease remains unknown. In an attempt to elucidate the pathogenesis of KD through the analysis of acquired immunity, we comprehensively examined the immunophenotypic changes in immune cells such as lymphocytes and monocytes along with various cytokines, focusing on differences between pre- and post- treatment samples. We found high levels of CXCL9 and CXCL10 chemokines that decreased with treatment, which coincided with a post-treatment expansion of Th1 cells expressing CXCR3. Our results show that the CXCL10-CXCR3 axis plays an important role in the pathogenesis of KD.
{"title":"The CXCL10-CXCR3 axis plays an important role in Kawasaki disease.","authors":"Sho Hosaka, Kazuo Imagawa, Yusuke Yano, Lisheng Lin, Junko Shiono, Miho Takahashi-Igari, Hideki Hara, Daisuke Hayashi, Hironori Imai, Atsushi Morita, Hiroko Fukushima, Hidetoshi Takada","doi":"10.1093/cei/uxad125","DOIUrl":"10.1093/cei/uxad125","url":null,"abstract":"<p><p>The precise pathogenesis of Kawasaki disease remains unknown. In an attempt to elucidate the pathogenesis of KD through the analysis of acquired immunity, we comprehensively examined the immunophenotypic changes in immune cells such as lymphocytes and monocytes along with various cytokines, focusing on differences between pre- and post- treatment samples. We found high levels of CXCL9 and CXCL10 chemokines that decreased with treatment, which coincided with a post-treatment expansion of Th1 cells expressing CXCR3. Our results show that the CXCL10-CXCR3 axis plays an important role in the pathogenesis of KD.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89717155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rami Karkout, Véronique Gaudreault, Lydia Labrie, Haya Aldossary, Noelia Azalde Garcia, Jichuan Shan, Elizabeth D Fixman
A sex disparity in asthma prevalence and severity exists in humans. Multiple studies have highlighted the role of innate cells in shaping the adaptive immune system in chronic asthma. To explore the sex bias in the eosinophilic response, we delivered IL-33 to the lungs of mice and delineated the kinetics by which the inflammatory response was induced. Our data demonstrate that females recruited more eosinophils capable of responding to IL-33. Eosinophil activation occurred selectively in the lung tissue and was enhanced in females at all time points. This increase was associated with increased ex vivo type 2 cytokine and chemokine production and female-specific expansion of group 2 innate lymphoid cells lacking expression of the killer-cell lectin-like receptor G1. Our findings suggest that the enhanced eosinophilic response in females is due, firstly, to a greater proportion of eosinophils recruited to the lungs in females that can respond to IL-33; and secondly, to an enhanced production of type 2 cytokines in females. Our data provide insight into the mechanisms that guide the female-specific enhancement of eosinophil activation in the mouse and form the basis to characterize these responses in human asthmatics.
{"title":"Female-specific enhancement of eosinophil recruitment and activation in a type 2 innate inflammation model in the lung.","authors":"Rami Karkout, Véronique Gaudreault, Lydia Labrie, Haya Aldossary, Noelia Azalde Garcia, Jichuan Shan, Elizabeth D Fixman","doi":"10.1093/cei/uxad100","DOIUrl":"10.1093/cei/uxad100","url":null,"abstract":"<p><p>A sex disparity in asthma prevalence and severity exists in humans. Multiple studies have highlighted the role of innate cells in shaping the adaptive immune system in chronic asthma. To explore the sex bias in the eosinophilic response, we delivered IL-33 to the lungs of mice and delineated the kinetics by which the inflammatory response was induced. Our data demonstrate that females recruited more eosinophils capable of responding to IL-33. Eosinophil activation occurred selectively in the lung tissue and was enhanced in females at all time points. This increase was associated with increased ex vivo type 2 cytokine and chemokine production and female-specific expansion of group 2 innate lymphoid cells lacking expression of the killer-cell lectin-like receptor G1. Our findings suggest that the enhanced eosinophilic response in females is due, firstly, to a greater proportion of eosinophils recruited to the lungs in females that can respond to IL-33; and secondly, to an enhanced production of type 2 cytokines in females. Our data provide insight into the mechanisms that guide the female-specific enhancement of eosinophil activation in the mouse and form the basis to characterize these responses in human asthmatics.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10107586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuchen Zhang, Kunpeng Zhang, Haoyu Wen, Di Ge, Jie Gu, Chunyi Zhang
Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy.
{"title":"FGL1 in plasma extracellular vesicles is correlated with clinical stage of lung adenocarcinoma and anti-PD-L1 response.","authors":"Yuchen Zhang, Kunpeng Zhang, Haoyu Wen, Di Ge, Jie Gu, Chunyi Zhang","doi":"10.1093/cei/uxad137","DOIUrl":"10.1093/cei/uxad137","url":null,"abstract":"<p><p>Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139037406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Based on the efficacy of intravenous immunoglobulin (IVIg) for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we developed a recombinant single-chain-fragment variable clone, VasSF, therapeutic against AAV in a mouse model (SCG/Kj mice). VasSF is thought to bind to vasculitis-associated apolipoprotein A-II (APOA2) as a target molecule. VasSF is a promising new drug against AAV, but difficulties in the yield and purification of VasSF remain unresolved. We produced monomers of new VasSF molecules by modifying the plasmid structure for VasSF expression and simplifying the purification method using high-performance liquid chromatography. We compared the therapeutic effects between 5-day continuous administration of the monomers, as in IVIg treatment, and single shots of 5-day-equivalent doses. We also evaluated the life-prolonging effect of the single-shot treatment. Two-dimensional western blots were used to examine the binding of VasSF to APOA2. Our improved manufacturing method resulted in a 100-fold higher yield of VasSF than in our previous study. Monomerization of VasSF stabilized its efficacy. Single shots of a small amount (1/80 000 of IVIg) produced sufficient therapeutic effects, including decreased glomerular crescent formation, a decreasing trend of serum ANCA against myeloperoxidase (MPO-ANCA), decreases in multiple proinflammatory cytokines, and a trend toward prolonged survival. Two-dimensional western blots confirmed the binding of VasSF to APOA2. The newly produced pure VasSF monomers are stable and therapeutic for AAV with a single low-dose injection, possibly by removing vasculitis-associated APOA2. Thus, the new VasSF described herein is a promising drug against AAV.
{"title":"Enhanced efficacy of the novel recombinant clone VasSF in a mouse model of antineutrophil cytoplasmic antibody-associated vasculitis.","authors":"Minako Koura, Yosuke Kameoka, Fukuko Kishi, Yoshio Yamakawa, Fuyu Ito, Ryuichi Sugamata, Yuko Doi, Kazuko Uno, Toshinori Nakayama, Takashi Miki, Hiroshi Nakajima, Kazuo Suzuki, Osamu Suzuki","doi":"10.1093/cei/uxad140","DOIUrl":"10.1093/cei/uxad140","url":null,"abstract":"<p><p>Based on the efficacy of intravenous immunoglobulin (IVIg) for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we developed a recombinant single-chain-fragment variable clone, VasSF, therapeutic against AAV in a mouse model (SCG/Kj mice). VasSF is thought to bind to vasculitis-associated apolipoprotein A-II (APOA2) as a target molecule. VasSF is a promising new drug against AAV, but difficulties in the yield and purification of VasSF remain unresolved. We produced monomers of new VasSF molecules by modifying the plasmid structure for VasSF expression and simplifying the purification method using high-performance liquid chromatography. We compared the therapeutic effects between 5-day continuous administration of the monomers, as in IVIg treatment, and single shots of 5-day-equivalent doses. We also evaluated the life-prolonging effect of the single-shot treatment. Two-dimensional western blots were used to examine the binding of VasSF to APOA2. Our improved manufacturing method resulted in a 100-fold higher yield of VasSF than in our previous study. Monomerization of VasSF stabilized its efficacy. Single shots of a small amount (1/80 000 of IVIg) produced sufficient therapeutic effects, including decreased glomerular crescent formation, a decreasing trend of serum ANCA against myeloperoxidase (MPO-ANCA), decreases in multiple proinflammatory cytokines, and a trend toward prolonged survival. Two-dimensional western blots confirmed the binding of VasSF to APOA2. The newly produced pure VasSF monomers are stable and therapeutic for AAV with a single low-dose injection, possibly by removing vasculitis-associated APOA2. Thus, the new VasSF described herein is a promising drug against AAV.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139073496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mattia Emanuela Ligotti, Giulia Accardi, Anna Aiello, Anna Calabrò, Calogero Caruso, Anna Maria Corsale, Francesco Dieli, Marta Di Simone, Serena Meraviglia, Giuseppina Candore
The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e. oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1, and Vδ2, and their functional subsets using the markers defining Tαβ cells, i.e. CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (from >90 years old to<105 years old), and eight oldest centenarians (≥105 years old), all of them were previously analysed for Tαβ and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in the oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαβ cell values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity.
半(从≥105 岁到 90 岁到
{"title":"Sicilian semi- and supercentenarians: age-related Tγδ cell immunophenotype contributes to longevity trait definition.","authors":"Mattia Emanuela Ligotti, Giulia Accardi, Anna Aiello, Anna Calabrò, Calogero Caruso, Anna Maria Corsale, Francesco Dieli, Marta Di Simone, Serena Meraviglia, Giuseppina Candore","doi":"10.1093/cei/uxad132","DOIUrl":"10.1093/cei/uxad132","url":null,"abstract":"<p><p>The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e. oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1, and Vδ2, and their functional subsets using the markers defining Tαβ cells, i.e. CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (from >90 years old to<105 years old), and eight oldest centenarians (≥105 years old), all of them were previously analysed for Tαβ and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in the oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαβ cell values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138799481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Our purpose was to characterize the pattern of B cell subsets in children with a combined diagnosis of type 1 diabetes (T1D) and celiac disease (C) since children with single or double diagnosis of these autoimmune diseases may differ in peripheral B cell subset phenotype patterns. B cells were analyzed with flow cytometry for the expression of differentiation/maturation markers to identify transitional, naive, and memory B cells. Transitional (CD24hiCD38hiCD19+) and memory Bregs (mBregs; CD24hiCD27+CD19+, CD1d+CD27+CD19+, and CD5+CD1d+CD19+) were classified as B cells with regulatory capacity. Children with a combined diagnosis of T1D and C showed a pattern of diminished peripheral B cell subsets. The B cells compartment in children with combined diagnosis had higher percentages of memory B subsets and Bregs, including activated subsets, compared to children with either T1D or C. Children with combined diagnosis had a lower percentage of naive B cells (CD27-CD19+; IgD+CD19+) and an increased percentage of memory B cells (CD27+CD19+; IgD-CD19+). A similar alteration was seen among the CD39+ expressing naive and memory B cells. Memory Bregs (CD1d+CD27+CD19+) were more frequent, contrary to the lower percentage of CD5+ transitional Bregs in children with a combined diagnosis. In children with either T1D or C, the peripheral B cell compartment was dominated by naive cells. Differences in the pattern of heterogeneous peripheral B cell repertoire subsets reflect a shifting in the B cell compartment between children with T1D and/or C. This is an immunological challenge of impact on the pathophysiology of these autoimmune diseases.
我们的目的是描述合并诊断为1型糖尿病(T1D)和乳糜泻(C)的儿童的B细胞亚群模式,因为单一或双重诊断为这些自身免疫性疾病的儿童的外周B细胞亚群表型模式可能有所不同。用流式细胞术分析 B 细胞的分化/成熟标记表达,以确定过渡型、幼稚型和记忆型 B 细胞。过渡性 B 细胞(CD24hiCD38hiCD19+)和记忆性 B 细胞(CD24hiCD27+CD19+、CD1d+CD27+CD19+、CD5+CD1d+CD19+)被归类为具有调节能力的 B 细胞。合并诊断为 T1D 和 C 的儿童表现出外周 B 细胞亚群减少的模式。与 T1D 或 C 合并诊断的儿童相比,合并诊断的儿童的 B 细胞分区中记忆 B 亚群和 Bregs(包括活化亚群)的比例更高。在表达 CD39+ 的幼稚 B 细胞和记忆 B 细胞中也出现了类似的变化。记忆B细胞(CD1d+CD27+CD19+)更常见,而在合并诊断的儿童中,CD5+过渡B细胞的比例较低。在患有 T1D 或 C 的儿童中,外周 B 细胞区系以幼稚细胞为主。外周B细胞异源汇集亚群模式的差异反映了T1D和/或C患儿B细胞区系的变化。
{"title":"Shift in the B cell subsets between children with type 1 diabetes and/or celiac disease.","authors":"Andrea Tompa, Maria Faresjö","doi":"10.1093/cei/uxad136","DOIUrl":"10.1093/cei/uxad136","url":null,"abstract":"<p><p>Our purpose was to characterize the pattern of B cell subsets in children with a combined diagnosis of type 1 diabetes (T1D) and celiac disease (C) since children with single or double diagnosis of these autoimmune diseases may differ in peripheral B cell subset phenotype patterns. B cells were analyzed with flow cytometry for the expression of differentiation/maturation markers to identify transitional, naive, and memory B cells. Transitional (CD24hiCD38hiCD19+) and memory Bregs (mBregs; CD24hiCD27+CD19+, CD1d+CD27+CD19+, and CD5+CD1d+CD19+) were classified as B cells with regulatory capacity. Children with a combined diagnosis of T1D and C showed a pattern of diminished peripheral B cell subsets. The B cells compartment in children with combined diagnosis had higher percentages of memory B subsets and Bregs, including activated subsets, compared to children with either T1D or C. Children with combined diagnosis had a lower percentage of naive B cells (CD27-CD19+; IgD+CD19+) and an increased percentage of memory B cells (CD27+CD19+; IgD-CD19+). A similar alteration was seen among the CD39+ expressing naive and memory B cells. Memory Bregs (CD1d+CD27+CD19+) were more frequent, contrary to the lower percentage of CD5+ transitional Bregs in children with a combined diagnosis. In children with either T1D or C, the peripheral B cell compartment was dominated by naive cells. Differences in the pattern of heterogeneous peripheral B cell repertoire subsets reflect a shifting in the B cell compartment between children with T1D and/or C. This is an immunological challenge of impact on the pathophysiology of these autoimmune diseases.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138884612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Agnieszka Małecka, Ingunn Østlie, Gunhild Trøen, Jędrzej Małecki, Jan Delabie, Anne Tierens, Ludvig A Munthe, Sigbjørn Berentsen, Geir E Tjønnfjord
Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.
冷凝集素病(Cold Agglutinin Disease,CAD)是一种罕见的骨髓 B 细胞淋巴细胞增生性疾病,表现为单克隆 IgM 自身抗体与 I 抗原结合引起的自身免疫性溶血性贫血。此前已有相关基因变化的报道,但其对基因表达谱的影响尚不清楚。在这里,我们确定了 CAD B 细胞中表达不同的基因。为了揭示细胞通路的下游变化,我们通过 RNA 测序进行了基因表达分析。我们分析了 12 例 CAD 患者的克隆 B 细胞样本和 4 例健康人的 IgM 表达记忆 B 细胞。通过差异表达分析和筛选,得出了 93 个具有显著差异表达的基因。上调最多的基因包括 SLC4A1、SPTA1、YBX3、TESC、HBD、AHSP、TRAF1、HBA2、RHAG、CA1、SPTB、IL10、UBASH3B、ALAS2、HBA1、CRYM、RGCC、KANK2 和 IGHV4-34。与对照组 B 细胞相比,它们在克隆 CAD B 细胞中上调了至少 8 倍,而补体受体 1(CR1/CD35)则下调了 11 倍。流式细胞术分析进一步证实,与对照组的 IgM+ 记忆 B 细胞相比,克隆 CAD IgM+ B 细胞的 CR1(CD35)蛋白表达减少。CR1 (CD35) 是 B 细胞活化和分化的重要负调控因子。因此,CR1(CD35)表达的减少可能会增加 CAD 相关克隆 B 细胞的活化、增殖和抗体产生。
{"title":"Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease.","authors":"Agnieszka Małecka, Ingunn Østlie, Gunhild Trøen, Jędrzej Małecki, Jan Delabie, Anne Tierens, Ludvig A Munthe, Sigbjørn Berentsen, Geir E Tjønnfjord","doi":"10.1093/cei/uxad135","DOIUrl":"10.1093/cei/uxad135","url":null,"abstract":"<p><p>Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138828441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Orlee Marini-Rapoport, Monica L Fernández-Quintero, Tarun Keswani, Guangning Zong, Jane Shim, Lars C Pedersen, Geoffrey A Mueller, Sarita U Patil
In peanut allergy, Arachis hypogaea 2 (Ara h 2) and Arachis hypogaea 6 (Ara h 6) are two clinically relevant peanut allergens with known structural and sequence homology and demonstrated cross-reactivity. We have previously utilized X-ray crystallography and epitope binning to define the epitopes on Ara h 2. We aimed to quantitatively characterize the cross-reactivity between Ara h 2 and Ara h 6 on a molecular level using human monoclonal antibodies (mAbs) and structural characterization of allergenic epitopes. We utilized mAbs cloned from Ara h 2 positive single B cells isolated from peanut-allergic, oral immunotherapy-treated patients to quantitatively analyze cross-reactivity between recombinant Ara h 2 (rAra h 2) and Ara h 6 (rAra h 6) proteins using biolayer interferometry and indirect inhibitory ELISA. Molecular dynamics simulations assessed time-dependent motions and interactions in the antibody-antigen complexes. Three epitopes-conformational epitopes 1.1 and 3, and the sequential epitope KRELRNL/KRELMNL-are conserved between Ara h 2 and Ara h 6, while two more conformational and three sequential epitopes are not. Overall, mAb affinity was significantly lower to rAra h 6 than it was to rAra h 2. This difference in affinity was primarily due to increased dissociation of the antibodies from rAra h 6, a phenomenon explained by the higher conformational flexibility of the Ara h 6-antibody complexes in comparison to Ara h 2-antibody complexes. Our results further elucidate the cross-reactivity of peanut 2S albumins on a molecular level and support the clinical immunodominance of Ara h 2.
在花生过敏中,Arachis hypogaea 2(Ara h 2)和Arachis hypogaea 6(Ara h 6)是两种与临床相关的花生过敏原,它们在结构上和序列上具有已知的同源性,并显示出交叉反应性。我们以前曾利用 X 射线晶体学和表位分选来确定 Ara h 2 上的表位。我们的目标是利用人类单克隆抗体(mAbs)和过敏原表位的结构特征,在分子水平上定量描述 Ara h 2 和 Ara h 6 之间的交叉反应。我们利用从花生过敏、口服免疫疗法患者体内分离出的 Ara h 2 阳性单 B 细胞克隆出的 mAbs,使用生物层干涉测量法和间接抑制性 ELISA 定量分析了重组 Ara h 2(rAra h 2)和 Ara h 6(rAra h 6)蛋白之间的交叉反应。分子动力学模拟评估了抗体-抗原复合物中随时间变化的运动和相互作用。三个表位--构象表位 1.1 和 3 以及序列表位 KRELRNL/KRELMNL 在 Ara h 2 和 Ara h 6 之间是保守的,而另外两个构象表位和三个序列表位则不保守。总体而言,mAb 与 rAra h 6 的亲和力明显低于与 rAra h 2 的亲和力。这种亲和力上的差异主要是由于抗体与 rAra h 6 的解离度增加所致,与 Ara h 2-抗体复合物相比,Ara h 6-抗体复合物具有更高的构象灵活性。我们的研究结果进一步阐明了花生 2S 蛋白在分子水平上的交叉反应性,并支持 Ara h 2 的临床免疫优势。
{"title":"Defining the cross-reactivity between peanut allergens Ara h 2 and Ara h 6 using monoclonal antibodies.","authors":"Orlee Marini-Rapoport, Monica L Fernández-Quintero, Tarun Keswani, Guangning Zong, Jane Shim, Lars C Pedersen, Geoffrey A Mueller, Sarita U Patil","doi":"10.1093/cei/uxae005","DOIUrl":"10.1093/cei/uxae005","url":null,"abstract":"<p><p>In peanut allergy, Arachis hypogaea 2 (Ara h 2) and Arachis hypogaea 6 (Ara h 6) are two clinically relevant peanut allergens with known structural and sequence homology and demonstrated cross-reactivity. We have previously utilized X-ray crystallography and epitope binning to define the epitopes on Ara h 2. We aimed to quantitatively characterize the cross-reactivity between Ara h 2 and Ara h 6 on a molecular level using human monoclonal antibodies (mAbs) and structural characterization of allergenic epitopes. We utilized mAbs cloned from Ara h 2 positive single B cells isolated from peanut-allergic, oral immunotherapy-treated patients to quantitatively analyze cross-reactivity between recombinant Ara h 2 (rAra h 2) and Ara h 6 (rAra h 6) proteins using biolayer interferometry and indirect inhibitory ELISA. Molecular dynamics simulations assessed time-dependent motions and interactions in the antibody-antigen complexes. Three epitopes-conformational epitopes 1.1 and 3, and the sequential epitope KRELRNL/KRELMNL-are conserved between Ara h 2 and Ara h 6, while two more conformational and three sequential epitopes are not. Overall, mAb affinity was significantly lower to rAra h 6 than it was to rAra h 2. This difference in affinity was primarily due to increased dissociation of the antibodies from rAra h 6, a phenomenon explained by the higher conformational flexibility of the Ara h 6-antibody complexes in comparison to Ara h 2-antibody complexes. Our results further elucidate the cross-reactivity of peanut 2S albumins on a molecular level and support the clinical immunodominance of Ara h 2.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical & Experimental Immunology: Highlights of 2023.","authors":"Leonie S Taams, Sevda Dogan","doi":"10.1093/cei/uxae017","DOIUrl":"https://doi.org/10.1093/cei/uxae017","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}