Pub Date : 2025-10-02DOI: 10.1016/j.imlet.2025.107098
Bruna Estefânia Diniz Frias , Roberta Oliveira Prado , Mariana Gontijo Ramos , Nathália Werneck Cézar de Oliveira , Fernanda Fortes de Araújo , Liliane Martins dos Santos , Camila Gontijo Ramos , Camila Bechara Kallás , Maria Sílvia Laborne Alves de Sousa , Ismael Artur Costa-Rocha , Joaquim Pedro Brito-de-Sousa , Rachel Basques Caligiorne , Marcelo Antônio Pascoal-Xavier , Vanessa Peruhype-Magalhães , Daniel Gontijo Ramos , Andréa Teixeira-Carvalho , Olindo Assis Martins-Filho
This study aimed to characterize biomarkers of therapeutic response in patients with stable vitiligo undergoing the autologous non-cultured keratinocyte/melanocyte transplantation. The approaches performed were systemic analysis evaluated during pre-transplantation/(D0), seven/(D7), and 28 or more/(D28–45) days after the procedure and compartmentalized analysis in epidermal cell suspension (explant). Increased number of pro-inflammatory monocytes and NK-cells was found during the transplantation follow-up in vitiligo patients compared to the control. There were higher numbers of CD8+T-cells and CD4+HLA-DR+T-cells circulating at D28–45 compared to D0, and increased number of CD8+HLA-DR+T-cells at D28–45 compared to D7. Decreased levels of the most pro-inflammatory chemokines/cytokines during post-transplantation kinetics timeline were observed. Integrative analysis demonstrated that patients with unsatisfactory repigmentation presented higher numbers of connections between the blood/skin components at D0. The data suggest differentiated profiles in the dynamics of the hematological/immunological biomarkers, according to the kinetics timeline and the clinical outcome of repigmentation in vitiligo patients.
{"title":"Immunological features driving distinct repigmentation patterns in patients with stable vitiligo submitted to the autologous keratinocyte/melanocyte transplantation","authors":"Bruna Estefânia Diniz Frias , Roberta Oliveira Prado , Mariana Gontijo Ramos , Nathália Werneck Cézar de Oliveira , Fernanda Fortes de Araújo , Liliane Martins dos Santos , Camila Gontijo Ramos , Camila Bechara Kallás , Maria Sílvia Laborne Alves de Sousa , Ismael Artur Costa-Rocha , Joaquim Pedro Brito-de-Sousa , Rachel Basques Caligiorne , Marcelo Antônio Pascoal-Xavier , Vanessa Peruhype-Magalhães , Daniel Gontijo Ramos , Andréa Teixeira-Carvalho , Olindo Assis Martins-Filho","doi":"10.1016/j.imlet.2025.107098","DOIUrl":"10.1016/j.imlet.2025.107098","url":null,"abstract":"<div><div>This study aimed to characterize biomarkers of therapeutic response in patients with stable vitiligo undergoing the autologous non-cultured keratinocyte/melanocyte transplantation. The approaches performed were systemic analysis evaluated during pre-transplantation/(D0), seven/(D7), and 28 or more/(D28–45) days after the procedure and compartmentalized analysis in epidermal cell suspension (explant). Increased number of pro-inflammatory monocytes and NK-cells was found during the transplantation follow-up in vitiligo patients compared to the control. There were higher numbers of CD8<sup>+</sup> <em>T</em>-cells and CD4<sup>+</sup>HLA-DR<sup>+</sup> <em>T</em>-cells circulating at D28–45 compared to D0, and increased number of CD8<sup>+</sup>HLA-DR<sup>+</sup> <em>T</em>-cells at D28–45 compared to D7. Decreased levels of the most pro-inflammatory chemokines/cytokines during post-transplantation kinetics timeline were observed. Integrative analysis demonstrated that patients with unsatisfactory repigmentation presented higher numbers of connections between the blood/skin components at D0. The data suggest differentiated profiles in the dynamics of the hematological/immunological biomarkers, according to the kinetics timeline and the clinical outcome of repigmentation in vitiligo patients.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107098"},"PeriodicalIF":2.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228437","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 : 2025-10-02DOI: 10.1016/j.imlet.2025.107099
Chibamba Mumba , Nicholas K. Mwale , Victor Mapulanga , Owen Ngalamika
Background
Penile squamous cell carcinoma (PSCC) is the commonest malignancy of the penis, with a higher incidence and poor treatment outcomes in developing countries. T-cell phenotypes have been shown to identify patients who may respond favorably to immune therapy, and also associate with treatment outcomes. This study aimed to determine and compare the tumor and peripheral blood T-cell phenotypes of individuals with PSCC, and whether factors such as smoking and presence of HPV associate with these T-cell phenotypes.
Methods
We conducted a prospective cross-sectional study at the University Teaching Hospital, Lusaka, Zambia. Participants with a histologically-confirmed PSCC were recruited into the study. Socio-demographic information was obtained, and whole blood was collected and subjected to peripheral blood mononuclear cells (PBMCs) isolation. Fresh penile tumors were mechanically and enzymatically digested. CD4 and CD8 cells were sorted from PBMCs and tumor, stained using antibodies against CD3, CD45RO, CCR7, PD-1, CD103 and CD69, and subjected to flow cytometry. Parts of the tumor were subjected to HPV detection, and histological grading and staging.
Results
Twenty-four participants were recruited into the study. The median age was 55.5 years, 45.8 % were smokers, 87.5 % were HIV positive, 62.5 % had high-risk HPV detected in the tumors, and 25 % had advanced-stage disease. There was a significantly higher proportion of naïve cells among CD4 T-cells from PBMCs than tumor (40.2 % vs 3.8 %; p = 0.01). CD4 T cells from the tumor demonstrated a significantly higher proportion of cells expressing CD69 (3.2 % vs 95.9 %; p = 0.0001), CD103 (0.7 % vs 7.3 %; p = 0.0001), and PD-1 (35.5 % vs 92 %; p = 0.0001) than the ones from PBMCs. Tumoral CD8 T-cells had a significantly lower proportion of terminally-differentiated effector cells but higher proportion of central memory cells compared to PBMCs, (7.9 % vs 15.1 %, p = 0.04) and (55 % vs 14.4 %; p = 0.01) respectively. Tumoral CD8 T-cells also had a significantly higher proportion of cells expressing CD69 (96.7 % vs 8.5 %; p = 0.0001), CD103 (22.2 % vs 1.2 %; p = 0.0001), and PD-1 (79.3 % vs 18.8 %; p = 0.0001) when compared to the PBMCs. Early-stage disease was associated with a significantly higher proportion of central memory CD4 T-cells among the PBMCs when compared with advanced stage disease (46.7 % vs 30 %; p = 0.01), while smoking was associated with a significantly higher proportion of tumoral CD8 T-cells expressing the homing marker CD103 (28.2 % vs 17.8 %; p = 0.01).
Conclusion
PSCC tumors demonstrate a higher proportion of primed T-cells with a memory phenotype compared to T-cells in the circulation. T-cells from PSCC tumors also have a higher proportion of cells expressing the immune checkpoint PD-1 and homing markers than those from the circulation.
背景：阴茎鳞状细胞癌（PSCC）是最常见的阴茎恶性肿瘤，在发展中国家发病率较高，治疗效果较差。t细胞表型已被证明可以识别对免疫治疗反应良好的患者，也与治疗结果相关。本研究旨在确定和比较PSCC患者的肿瘤和外周血t细胞表型，以及吸烟和HPV存在等因素是否与这些t细胞表型相关。方法：我们在赞比亚卢萨卡大学教学医院进行了一项前瞻性横断面研究。组织学证实的PSCC参与者被招募到研究中。获得社会人口统计学信息，采集全血并进行外周血单个核细胞（PBMCs）分离。新鲜阴茎肿瘤用机械和酶消化。从pbmc和肿瘤中分离CD4和CD8细胞，用CD3、CD45RO、CCR7、PD-1、CD103和CD69抗体进行染色，并进行流式细胞术检测。部分肿瘤进行HPV检测，并进行组织学分级和分期。结果：24名参与者被纳入研究。中位年龄为55.5岁，45.8%为吸烟者，87.5%为HIV阳性，62.5%为肿瘤中检测到高危HPV， 25%为晚期疾病。外周血淋巴细胞CD4 t细胞中naïve细胞的比例明显高于肿瘤（40.2% vs 3.8%, p=0.01）。来自肿瘤的CD4 T细胞表达CD69 （3.2% vs 95.9%, p=0.0001）、CD103 （0.7% vs 7.3%, p=0.0001）和PD-1 （35.5% vs 92%, p=0.0001）的比例明显高于来自pbmc的细胞。肿瘤CD8 t细胞的终末分化效应细胞比例明显低于PBMCs，而中枢记忆细胞比例明显高于PBMCs，分别为（7.9% vs 15.1%, p=0.04）和（55% vs 14.4%, p=0.01）。与PBMCs相比，肿瘤CD8 t细胞中表达CD69 （96.7% vs 8.5%, p=0.0001）、CD103 （22.2% vs 1.2%, p=0.0001）和PD-1 （79.3% vs 18.8%, p=0.0001）的细胞比例也显著更高。与晚期疾病相比，早期疾病与PBMCs中央性记忆CD4 t细胞比例显著升高相关（46.7% vs 30%, p=0.01），而吸烟与表达归巢标记CD103的肿瘤CD8 t细胞比例显著升高相关（28.2% vs 17.8%, p=0.01）。结论：与循环中的t细胞相比，PSCC肿瘤中具有记忆表型的启动t细胞的比例更高。来自PSCC肿瘤的t细胞也比来自循环的t细胞表达免疫检查点PD-1和归巢标记的细胞比例更高。
{"title":"CD4 and CD8 T-cell lymphocytes from penile squamous cell carcinoma tumors are more differentiated with higher PD-1 expression compared to lymphocytes in peripheral circulation","authors":"Chibamba Mumba , Nicholas K. Mwale , Victor Mapulanga , Owen Ngalamika","doi":"10.1016/j.imlet.2025.107099","DOIUrl":"10.1016/j.imlet.2025.107099","url":null,"abstract":"<div><h3>Background</h3><div>Penile squamous cell carcinoma (PSCC) is the commonest malignancy of the penis, with a higher incidence and poor treatment outcomes in developing countries. T-cell phenotypes have been shown to identify patients who may respond favorably to immune therapy, and also associate with treatment outcomes. This study aimed to determine and compare the tumor and peripheral blood T-cell phenotypes of individuals with PSCC, and whether factors such as smoking and presence of HPV associate with these T-cell phenotypes.</div></div><div><h3>Methods</h3><div>We conducted a prospective cross-sectional study at the University Teaching Hospital, Lusaka, Zambia. Participants with a histologically-confirmed PSCC were recruited into the study. Socio-demographic information was obtained, and whole blood was collected and subjected to peripheral blood mononuclear cells (PBMCs) isolation. Fresh penile tumors were mechanically and enzymatically digested. CD4 and CD8 cells were sorted from PBMCs and tumor, stained using antibodies against CD3, CD45RO, CCR7, PD-1, CD103 and CD69, and subjected to flow cytometry. Parts of the tumor were subjected to HPV detection, and histological grading and staging.</div></div><div><h3>Results</h3><div>Twenty-four participants were recruited into the study. The median age was 55.5 years, 45.8 % were smokers, 87.5 % were HIV positive, 62.5 % had high-risk HPV detected in the tumors, and 25 % had advanced-stage disease. There was a significantly higher proportion of naïve cells among CD4 T-cells from PBMCs than tumor (40.2 % vs 3.8 %; p = 0.01). CD4 T cells from the tumor demonstrated a significantly higher proportion of cells expressing CD69 (3.2 % vs 95.9 %; p = 0.0001), CD103 (0.7 % vs 7.3 %; p = 0.0001), and PD-1 (35.5 % vs 92 %; p = 0.0001) than the ones from PBMCs. Tumoral CD8 T-cells had a significantly lower proportion of terminally-differentiated effector cells but higher proportion of central memory cells compared to PBMCs, (7.9 % vs 15.1 %, p = 0.04) and (55 % vs 14.4 %; p = 0.01) respectively. Tumoral CD8 T-cells also had a significantly higher proportion of cells expressing CD69 (96.7 % vs 8.5 %; p = 0.0001), CD103 (22.2 % vs 1.2 %; p = 0.0001), and PD-1 (79.3 % vs 18.8 %; p = 0.0001) when compared to the PBMCs. Early-stage disease was associated with a significantly higher proportion of central memory CD4 T-cells among the PBMCs when compared with advanced stage disease (46.7 % vs 30 %; p = 0.01), while smoking was associated with a significantly higher proportion of tumoral CD8 T-cells expressing the homing marker CD103 (28.2 % vs 17.8 %; p = 0.01).</div></div><div><h3>Conclusion</h3><div>PSCC tumors demonstrate a higher proportion of primed T-cells with a memory phenotype compared to T-cells in the circulation. T-cells from PSCC tumors also have a higher proportion of cells expressing the immune checkpoint PD-1 and homing markers than those from the circulation.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107099"},"PeriodicalIF":2.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228256","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 : 2025-09-26DOI: 10.1016/j.imlet.2025.107096
Ye You , Jing Li , Jiayi Wang , Xianglan Luo , Jingyuan Liu , Xinmiao Wang , Shichen Yi , Ruizhi He , Yating Shi , Jie Xu , Mengqing Hou , Yanjun Cao , Yang Li , Jing Dong , Jiao He
Taurohyodeoxycholic acid (THDCA), a naturally occurring conjugated bile acid compound formed by the condensation of taurine and deoxycholic acid, possesses various biological activities. Present study attempted to assess whether THDCA can alleviate airway inflammation in allergic asthma through regulating the immune balance among CD4+T cell subgroups. Mice were exposed with ovalbumin (OVA) to build allergic asthma model and THDCA was administrated orally. Pulmonary histopathology analysis was evaluated by H&E and PAS staining. The typical cytokines and transcription factors of CD4+T cell subgroups were determined, and the proportion of CD4+T cell subgroups were analyzed. The oral administration of THDCA attenuated OVA-induced asthma by decreasing inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), reducing tIgE and OVA-sIgE concentration in the serum, and improving histopathological changes in the lung tissue. In addition, THDCA reduced the secretion of IL-4, IL-5, IL-13, IL-6, TNF-α, IL-17A, and TGF-β1, but increased the production of IFN-γ, IL-10, and IL-35 in the BALF and lung tissue. Meanwhile, THDCA inhibited GATA3 and RORγt expression, and STAT3 phosphorylation, but improved T-bet and Foxp3 expression in the lung tissue. Besides, THDCA restored the proportion of CD4+T cell subgroups in the spleen and peripheral blood. These findings indicated that THDCA may have therapeutic potential for treating allergic asthma by regulating the immune balance of CD4+T cell subgroups.
{"title":"Taurohyodeoxycholic acid ameliorates inflammatory response in a murine model of ovalbumin (OVA)-induced allergic asthma","authors":"Ye You , Jing Li , Jiayi Wang , Xianglan Luo , Jingyuan Liu , Xinmiao Wang , Shichen Yi , Ruizhi He , Yating Shi , Jie Xu , Mengqing Hou , Yanjun Cao , Yang Li , Jing Dong , Jiao He","doi":"10.1016/j.imlet.2025.107096","DOIUrl":"10.1016/j.imlet.2025.107096","url":null,"abstract":"<div><div>Taurohyodeoxycholic acid (THDCA), a naturally occurring conjugated bile acid compound formed by the condensation of taurine and deoxycholic acid, possesses various biological activities. Present study attempted to assess whether THDCA can alleviate airway inflammation in allergic asthma through regulating the immune balance among CD4<sup>+</sup> <em>T</em> cell subgroups. Mice were exposed with ovalbumin (OVA) to build allergic asthma model and THDCA was administrated orally. Pulmonary histopathology analysis was evaluated by H&E and PAS staining. The typical cytokines and transcription factors of CD4<sup>+</sup> <em>T</em> cell subgroups were determined, and the proportion of CD4<sup>+</sup> <em>T</em> cell subgroups were analyzed. The oral administration of THDCA attenuated OVA-induced asthma by decreasing inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), reducing tIgE and OVA-sIgE concentration in the serum, and improving histopathological changes in the lung tissue. In addition, THDCA reduced the secretion of IL-4, IL-5, IL-13, IL-6, TNF-α, IL-17A, and TGF-β1, but increased the production of IFN-γ, IL-10, and IL-35 in the BALF and lung tissue. Meanwhile, THDCA inhibited GATA3 and RORγt expression, and STAT3 phosphorylation, but improved T-bet and Foxp3 expression in the lung tissue. Besides, THDCA restored the proportion of CD4<sup>+</sup> <em>T</em> cell subgroups in the spleen and peripheral blood. These findings indicated that THDCA may have therapeutic potential for treating allergic asthma by regulating the immune balance of CD4<sup>+</sup> <em>T</em> cell subgroups.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107096"},"PeriodicalIF":2.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185759","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}
Fli1 is a transcription factor playing a major role in the regulation of normal hematopoiesis and vasculogenesis. Its deficiency has been associated with the development of fibrosis in various diseases, including systemic sclerosis/scleroderma (SSc), a rare autoimmune rheumatic disease. In addition, in Fli1 B cell conditional knockout mice, a striking increase of age-associated B cells (ABCs) has been observed. These cells constitute a CD11c+CD21low/- B cell population that displays an expansion in autoimmunity and drives disease pathogenesis. The exact role and functions of ABCs, though, are not yet fully understood. Taking into consideration all the above, regarding Fli1 deficiency in SSc pathogenesis and ABC expansion, we propose restoration of this specific transcription factor’s expression as a potential therapeutic approach for the aforementioned rheumatic disease. Moreover, we provide some interventions that aim to restore Fli1 expression via modulating the signals of TGF-β pathway, whose activation is considered as crucial for fibrosis development in SSc.
{"title":"Restoration of Fli1 expression as a potential therapeutic approach in Systemic Sclerosis: Effects on age-associated B cells","authors":"Athanasios Sachinidis , Malamatenia Lamprinou , Theodoros Dimitroulas","doi":"10.1016/j.imlet.2025.107094","DOIUrl":"10.1016/j.imlet.2025.107094","url":null,"abstract":"<div><div>Fli1 is a transcription factor playing a major role in the regulation of normal hematopoiesis and vasculogenesis. Its deficiency has been associated with the development of fibrosis in various diseases, including systemic sclerosis/scleroderma (SSc), a rare autoimmune rheumatic disease. In addition, in <em>Fli1</em> B cell conditional knockout mice, a striking increase of age-associated B cells (ABCs) has been observed. These cells constitute a CD11c<sup>+</sup>CD21<sup>low/-</sup> B cell population that displays an expansion in autoimmunity and drives disease pathogenesis. The exact role and functions of ABCs, though, are not yet fully understood. Taking into consideration all the above, regarding Fli1 deficiency in SSc pathogenesis and ABC expansion, we propose restoration of this specific transcription factor’s expression as a potential therapeutic approach for the aforementioned rheumatic disease. Moreover, we provide some interventions that aim to restore Fli1 expression via modulating the signals of TGF-β pathway, whose activation is considered as crucial for fibrosis development in SSc.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107094"},"PeriodicalIF":2.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185729","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}
Tryptophan, an essential amino acid, is primarily metabolized through four key pathways: the kynurenine pathway, serotonin pathways, indole pathways and interleukin 4-induced gene 1 (IL-4I1) pathways. Dysregulation of tryptophan metabolism is implicated in various non-communicable diseases including psychiatric disorders, inflammatory and autoimmune diseases, as well as metabolic diseases. The dogma in the field is that tryptophan is metabolized via the kynurenine pathway in the liver mainly by indoleamine 2,3-dioxygenase 1/2 (IDO 1/2) and Tryptophan dioxygenase 2 (TDO2) enzymes. However, there is growing evidence demonstrating that IL-4I1 and tryptophanase are also crucial tryptophan catabolizing enzymes resulting in metabolites that activate aryl hydrocarbon receptor (AhR) and modulate immune responses. Tryptophan metabolism is crucial in cellular, tissue and organismal function and its disruption is linked to conditions such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and psychiatric disorders like depression, anxiety and metabolic diseases such as obesity and Type 2 diabetes. It is unclear though whether only specific tryptophan pathways are associated with disease or there is a level of redundancy. Some key metabolites from tryptophan catabolism can come from multiple pathways, with opposing or converging effects on cellular functions. This review will explore the critical role of tryptophan metabolism in health and diseases, focusing on its implications in non-communicable diseases. Importantly, this review will focus on recent developments in tryptophan metabolism and strengthen the argument for a revised schematic tryptophan catabolic pathway.
{"title":"Tryptophan metabolism in health and disease- implications for non-communicable diseases","authors":"Andiswa Msizi Gabela, Nontobeko Mthembu, Sabelo Hadebe","doi":"10.1016/j.imlet.2025.107093","DOIUrl":"10.1016/j.imlet.2025.107093","url":null,"abstract":"<div><div>Tryptophan, an essential amino acid, is primarily metabolized through four key pathways: the kynurenine pathway, serotonin pathways, indole pathways and interleukin 4-induced gene 1 (IL-4I1) pathways. Dysregulation of tryptophan metabolism is implicated in various non-communicable diseases including psychiatric disorders, inflammatory and autoimmune diseases, as well as metabolic diseases. The dogma in the field is that tryptophan is metabolized via the kynurenine pathway in the liver mainly by indoleamine 2,3-dioxygenase 1/2 (IDO 1/2) and Tryptophan dioxygenase 2 (TDO2) enzymes. However, there is growing evidence demonstrating that IL-4I1 and tryptophanase are also crucial tryptophan catabolizing enzymes resulting in metabolites that activate aryl hydrocarbon receptor (AhR) and modulate immune responses. Tryptophan metabolism is crucial in cellular, tissue and organismal function and its disruption is linked to conditions such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and psychiatric disorders like depression, anxiety and metabolic diseases such as obesity and Type 2 diabetes. It is unclear though whether only specific tryptophan pathways are associated with disease or there is a level of redundancy. Some key metabolites from tryptophan catabolism can come from multiple pathways, with opposing or converging effects on cellular functions. This review will explore the critical role of tryptophan metabolism in health and diseases, focusing on its implications in non-communicable diseases. Importantly, this review will focus on recent developments in tryptophan metabolism and strengthen the argument for a revised schematic tryptophan catabolic pathway.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107093"},"PeriodicalIF":2.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182024","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 : 2025-09-25DOI: 10.1016/j.imlet.2025.107095
Renato Cerqueira , Elyse Moritz , Josefina A.P. Braga , Akemi K. Chiba , João B. Pesquero , José O. Bordin
Introduction
Autoimmune neutropenia (AIN), a common cause of chronic neutropenia, has been categorized as primary (pAIN) and secondary (sAIN). This study investigates the specificity of anti-HNA autoantibodies in both types.
Materials and Methods
A prospective cohort study of 85 chronic neutropenia patients included those with detectable anti-HNA autoantibodies. Anti-HNA was assessed using granulocyte agglutination (GAT), granulocyte immunofluorescence (GIFT), and LABScreen Multi Kit (LSM). Molecular analysis was performed to assess HNA expression.
Results
Of 85 patients, 7 had pAIN and 8 had sAIN. All pAIN patients exhibited only anti-HNA-1, while anti-HNA-3 was found in 3/8 sAIN patients. All patients with anti-HNA-3 tested positive in LSM; one was positive in both GAT and GIFT.
Discussion
While anti-HNA-3 has been described exclusively as an alloantibody, this is the first report of anti-HNA-3 as an autoantibody in AIN.
Conclusion
Anti-HNA-3 autoantibody is associated only with sAIN, suggesting distinct mechanisms in pAIN and sAIN.
{"title":"Beyond HNA-1: The anti-HNA-3 autoantibody as a protagonist in autoimmune neutropenia","authors":"Renato Cerqueira , Elyse Moritz , Josefina A.P. Braga , Akemi K. Chiba , João B. Pesquero , José O. Bordin","doi":"10.1016/j.imlet.2025.107095","DOIUrl":"10.1016/j.imlet.2025.107095","url":null,"abstract":"<div><h3>Introduction</h3><div>Autoimmune neutropenia (AIN), a common cause of chronic neutropenia, has been categorized as primary (pAIN) and secondary (sAIN). This study investigates the specificity of anti-HNA autoantibodies in both types.</div></div><div><h3>Materials and Methods</h3><div>A prospective cohort study of 85 chronic neutropenia patients included those with detectable anti-HNA autoantibodies. Anti-HNA was assessed using granulocyte agglutination (GAT), granulocyte immunofluorescence (GIFT), and LABScreen Multi Kit (LSM). Molecular analysis was performed to assess HNA expression.</div></div><div><h3>Results</h3><div>Of 85 patients, 7 had pAIN and 8 had sAIN. All pAIN patients exhibited only anti-HNA-1, while anti-HNA-3 was found in 3/8 sAIN patients. All patients with anti-HNA-3 tested positive in LSM; one was positive in both GAT and GIFT.</div></div><div><h3>Discussion</h3><div>While anti-HNA-3 has been described exclusively as an alloantibody, this is the first report of anti-HNA-3 as an autoantibody in AIN.</div></div><div><h3>Conclusion</h3><div>Anti-HNA-3 autoantibody is associated only with sAIN, suggesting distinct mechanisms in pAIN and sAIN.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107095"},"PeriodicalIF":2.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182017","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 : 2025-09-25DOI: 10.1016/j.imlet.2025.107092
Nico Hahn , Serhii Chornyi , Daan Heister , Helga E. de Vries , Martin Giera , Mariëtte R. Boon , Gijs Kooij , Jan Van den Bossche
Inflammatory responses often involve metabolic rewiring within immune cells to support effector functions. Targeting metabolic pathways in immune cells therefore represents a promising strategy to modulate inflammatory diseases and improve therapeutic outcomes. Acyl-CoA synthesis by fatty acid transporter 2 (FATP2/SLC27A2) facilitates the transport of long-chain fatty acids into the cell. It represents a key step in fatty acid metabolism and the subsequent production of bioactive lipid mediators (LMs) with immunoregulatory functions. While the FATP2 inhibitor Lipofermata is currently evaluated for lipid-lowering therapies in metabolic diseases, and to revert the suppressive nature of myeloid cells in cancer, its effect on inflammatory responses in human macrophages remains elusive.
Here, we show that Lipofermata reduced LPS-induced inflammatory responses in whole blood and human monocytes. This anti-inflammatory effect was paralleled by a decreased biosynthesis of arachidonic acid-derived inflammatory LMs, including prostaglandin E2 (PGE2) and thromboxane 2 (TxB2). These findings suggest an anti-inflammatory effect mediated by Lipofermata-mediated redirection of lipid metabolism in monocytes.
Conversely, in mature human monocyte-derived macrophages, Lipofermata treatment enhanced LPS-induced cytokine production and induced cell death, likely through inflammasome activation. Together, these results underscore the cell type-specific effects of FATP2 inhibition and highlight the dual role of Lipofermata in modulating inflammatory immune responses. As such, targeting lipid metabolism with Lipofermata could have therapeutic potential with both anti- and pro-inflammatory applications, depending on the target cell type and context.
{"title":"Fatty acid binding protein 2 (FATP2/SLC27A2) blockade with Lipofermata elicits dual effects on inflammatory responses in human monocytes and macrophages","authors":"Nico Hahn , Serhii Chornyi , Daan Heister , Helga E. de Vries , Martin Giera , Mariëtte R. Boon , Gijs Kooij , Jan Van den Bossche","doi":"10.1016/j.imlet.2025.107092","DOIUrl":"10.1016/j.imlet.2025.107092","url":null,"abstract":"<div><div>Inflammatory responses often involve metabolic rewiring within immune cells to support effector functions. Targeting metabolic pathways in immune cells therefore represents a promising strategy to modulate inflammatory diseases and improve therapeutic outcomes. Acyl-CoA synthesis by fatty acid transporter 2 (FATP2/SLC27A2) facilitates the transport of long-chain fatty acids into the cell. It represents a key step in fatty acid metabolism and the subsequent production of bioactive lipid mediators (LMs) with immunoregulatory functions. While the FATP2 inhibitor Lipofermata is currently evaluated for lipid-lowering therapies in metabolic diseases, and to revert the suppressive nature of myeloid cells in cancer, its effect on inflammatory responses in human macrophages remains elusive.</div><div>Here, we show that Lipofermata reduced LPS-induced inflammatory responses in whole blood and human monocytes. This anti-inflammatory effect was paralleled by a decreased biosynthesis of arachidonic acid-derived inflammatory LMs, including prostaglandin E2 (PGE2) and thromboxane 2 (TxB2). These findings suggest an anti-inflammatory effect mediated by Lipofermata-mediated redirection of lipid metabolism in monocytes.</div><div>Conversely, in mature human monocyte-derived macrophages, Lipofermata treatment enhanced LPS-induced cytokine production and induced cell death, likely through inflammasome activation. Together, these results underscore the cell type-specific effects of FATP2 inhibition and highlight the dual role of Lipofermata in modulating inflammatory immune responses. As such, targeting lipid metabolism with Lipofermata could have therapeutic potential with both anti- and pro-inflammatory applications, depending on the target cell type and context.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107092"},"PeriodicalIF":2.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182068","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 : 2025-09-16DOI: 10.1016/j.imlet.2025.107091
Ivy M. Akehurst, Louisa K. James
Respiratory pathogens pose a significant risk to public health and are responsible for burdening health care by causing worldwide morbidity and mortality. The immune environment in the airway is critical for protection from respiratory pathogens and comprises several specialist subsets of resident lymphocytes and myeloid cells. Tissue resident-memory B cells (BRM) are a subset of memory B cell which reside in mucosal tissues, including the airways. Although, BRM have only recently been characterised, they have a crucial role in generating robust and localised immune responses to respiratory infections, particularly secondary responses, by rapidly differentiating into antibody-secreting cells. A greater understanding of their role in protecting the airways from respiratory pathogens will enable the development of immunisation strategies against respiratory disease. This mini-review aims to summarise the current knowledge of BRM and highlight areas for future research.
呼吸道病原体对公共卫生构成重大风险，并通过在世界范围内造成发病率和死亡率，给卫生保健造成负担。气道内的免疫环境对保护机体免受呼吸道病原体的侵袭至关重要，它由若干专门的淋巴细胞和骨髓细胞亚群组成。组织驻留记忆B细胞（Tissue resident-memory B cells， BRM）是记忆B细胞的一个子集，存在于包括气道在内的粘膜组织中。尽管BRM最近才被描述，但它们通过迅速分化为抗体分泌细胞，在产生针对呼吸道感染的强大和局部免疫反应，特别是继发性反应方面发挥着至关重要的作用。更好地了解它们在保护呼吸道免受呼吸道病原体侵害方面的作用，将有助于制定针对呼吸道疾病的免疫策略。这篇小型综述旨在总结BRM的当前知识，并强调未来研究的领域。
{"title":"Tissue resident memory B cells mediate protective immunity to respiratory pathogens in the airways","authors":"Ivy M. Akehurst, Louisa K. James","doi":"10.1016/j.imlet.2025.107091","DOIUrl":"10.1016/j.imlet.2025.107091","url":null,"abstract":"<div><div>Respiratory pathogens pose a significant risk to public health and are responsible for burdening health care by causing worldwide morbidity and mortality. The immune environment in the airway is critical for protection from respiratory pathogens and comprises several specialist subsets of resident lymphocytes and myeloid cells. Tissue resident-memory B cells (B<sub>RM</sub>) are a subset of memory B cell which reside in mucosal tissues, including the airways. Although, B<sub>RM</sub> have only recently been characterised, they have a crucial role in generating robust and localised immune responses to respiratory infections, particularly secondary responses, by rapidly differentiating into antibody-secreting cells. A greater understanding of their role in protecting the airways from respiratory pathogens will enable the development of immunisation strategies against respiratory disease. This mini-review aims to summarise the current knowledge of B<sub>RM</sub> and highlight areas for future research.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107091"},"PeriodicalIF":2.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086067","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 early cellular and humoral immune responses to SARS-CoV-2 result in a wide range of COVID-19 disease severity. Here we conducted an observational study of these three arms of the immune responses (T, B and NK) to SARS-CoV-2 in 17 patients hospitalized for severe COVID-19 at median of 31 days after first symptoms. We found that the main T cell response was directed against two specific regions of the spike viral protein, called B and E, which are inversely correlated with the expression of the KIR2DL1 inhibitory receptor on NK cells (p = 0.03, and p = 0.0001 respectively). Furthermore, expression of the inhibitory receptor ILT2 on NK cells was only correlated with T cell responses against the specific E region (p = 0.02), suggesting that HLA-G may play a role in the extinction of the NK response to the T cell response. Moreover, the antibody response was mainly directed against the nucleocapsid, whereas the antibody neutralizing response was inversely correlated with the cellular response to spike (p < 0.003). Taken together these data suggest a strong coordination between the innate and adaptive immune responses during the acute phase of infection, which could reflect the further resolution of COVID-19 patients with severe disease.
{"title":"Coordination of cellular responses to SARS-CoV-2 during severe COVID-19 illness","authors":"Assia Samri , Raphael Lhote , Alice Rousseau , Véronique Morin , Nadine Tarantino , Stéphane Marot , Aude Jary , Delphine Sterlin , Anne-Geneviève Marcelin , Zahir Amoura , Guy Gorochov , Vincent Vieillard , Amélie Guihot","doi":"10.1016/j.imlet.2025.107090","DOIUrl":"10.1016/j.imlet.2025.107090","url":null,"abstract":"<div><div>The early cellular and humoral immune responses to SARS-CoV-2 result in a wide range of COVID-19 disease severity. Here we conducted an observational study of these three arms of the immune responses (T, B and NK) to SARS-CoV-2 in 17 patients hospitalized for severe COVID-19 at median of 31 days after first symptoms. We found that the main T cell response was directed against two specific regions of the spike viral protein, called B and E, which are inversely correlated with the expression of the KIR2DL1 inhibitory receptor on NK cells (p = 0.03, and p = 0.0001 respectively). Furthermore, expression of the inhibitory receptor ILT2 on NK cells was only correlated with T cell responses against the specific E region (p = 0.02), suggesting that HLA-G may play a role in the extinction of the NK response to the T cell response. Moreover, the antibody response was mainly directed against the nucleocapsid, whereas the antibody neutralizing response was inversely correlated with the cellular response to spike (p < 0.003). Taken together these data suggest a strong coordination between the innate and adaptive immune responses during the acute phase of infection, which could reflect the further resolution of COVID-19 patients with severe disease.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107090"},"PeriodicalIF":2.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080551","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}
Immune dysregulation plays a key role in the deterioration of COVID-19. This study evaluated immune checkpoint molecules (ICMs) as markers of disease severity. Immunophenotyping of 525 hospitalised patients with moderate (n=464) and severe (n=61) COVID-19 was performed at admission and analysed alongside clinical, laboratory, and imaging data. The strongest correlations with severe outcomes and mortality were found for CD200R+CD3+ T and CD19+ B cells. Significant differences in PD-1+ and PD-L1+ lymphocyte subsets were observed between severity groups. Machine learning (SHAP) confirmed that ICM expression was at least as predictive as conventional risk factors. These findings suggest that markers of immune exhaustion, especially PD-1, PD-L1, and CD200R, may help predict COVID-19 severity. Further research is needed to determine whether targeting immune checkpoints could improve outcomes.
{"title":"Immune checkpoint molecules as predictive markers of COVID-19 severity: A comprehensive univariable and multivariable analysis","authors":"Adam Majchrzak , Paulina Niedźwiedzka-Rystwej , Dominika Bębnowska , Bogusz Aksak-Wąs , Malwina Karasińska-Cieślak , Danuta Cembrowska-Lech , Karolina Skonieczna-Żydecka , Kaja Mielczak , Anna Urbańska , Rafał Hrynkiewicz , Filip Lewandowski , Miłosz Parczewski","doi":"10.1016/j.imlet.2025.107089","DOIUrl":"10.1016/j.imlet.2025.107089","url":null,"abstract":"<div><div>Immune dysregulation plays a key role in the deterioration of COVID-19. This study evaluated immune checkpoint molecules (ICMs) as markers of disease severity. Immunophenotyping of 525 hospitalised patients with moderate (n=464) and severe (n=61) COVID-19 was performed at admission and analysed alongside clinical, laboratory, and imaging data. The strongest correlations with severe outcomes and mortality were found for CD200R+CD3+ T and CD19+ B cells. Significant differences in PD-1+ and PD-L1+ lymphocyte subsets were observed between severity groups. Machine learning (SHAP) confirmed that ICM expression was at least as predictive as conventional risk factors. These findings suggest that markers of immune exhaustion, especially PD-1, PD-L1, and CD200R, may help predict COVID-19 severity. Further research is needed to determine whether targeting immune checkpoints could improve outcomes.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"277 ","pages":"Article 107089"},"PeriodicalIF":2.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080515","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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