Journal of Translational Autoimmunity最新文献

The AhR pathway is dysregulated in alopecia areata

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-03-07 DOI: 10.1016/j.jtauto.2025.100282

Arno Belpaire , Annelies Demeyer , Elise Van Caelenberg , Nanja van Geel , Reinhart Speeckaert

Despite significant progress in the treatment of alopecia areata (AA), many aspects of its immune-based pathogenesis remain unexplored. IFN-γ, primarily produced by CD8⁺ T cells and NK cells, is considered central to AA pathogenesis. However, the complex immune signaling network contributes to therapeutic resistance and frequent disease flares after treatment discontinuation. The aryl hydrocarbon receptor (AhR) pathway, upregulated by IFN-γ, modulates Th17 responses, but its inhibitory effects on IFN-γ remain unclear. Although IL-17 levels are elevated in AA, clinical trials indicate that IL-17A inhibitors are ineffective. AhR expression is known to induce immune checkpoints (ICPs) such as PD-1, suggesting a potential role as a negative feedback mechanism. This study investigated AhR expression in lymphocytes from AA patients and its association with clinical and laboratory markers of disease activity. AhR expression was significantly reduced in CD4, CD8, Th1, and Th17 lymphocytes in AA patients compared to healthy controls (p < 0.005), and it correlated inversely with SALTII scores (p < 0.05). ROC analysis showed that AhR levels in CD8 cells could differentiate mild AA from healthy controls with a sensitivity of 82.35 % and specificity of 86.84 %, suggesting potential diagnostic utility. Lower AhR levels were associated with increased IFN-γ+ lymphocytes and decreased IL-17+ immune cells. Interestingly, immune profiles differed between atopic and non-atopic patients: in severe AA, higher AhR expression was linked to increased sPD-1 concentrations, whereas in limited AA, AhR failed to upregulate any investigated ICP. These findings highlight the significant downregulation of the AhR pathway in AA and suggest its potential as a therapeutic target. Future research should explore the development of AhR agonists or antagonists to modulate immune responses in AA.

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引用次数: 0

Pediatric autoimmune diseases in the light of COVID-19 pandemic, A retrospective observational big data study

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-03-06 DOI: 10.1016/j.jtauto.2025.100281

Rim Kasem Ali Sliman , Hilla Cohen , Shereen Shehadeh , Reut Batcir , Yigal Elenberg Alter , Keren Cohen , Ilana Koren , Inbal Halabi , Hussein Sliman , Mohamad Hamad Saied

Background

The COVID-19 pandemic has raised concerns about potential links between SARS-CoV-2 infection and autoimmune diseases. This study investigated changes in the incidence rate (IR) of autoimmune diseases among children following the pandemic's onset.

Methods

A retrospective cross-sectional study analyzed data from Clalit Health Services, Israel's largest healthcare provider, examining the IR of different autoimmune diseases in children aged 0–18. The study compared pre-pandemic (2019) with pandemic/post-pandemic periods (2020–2023), encompassing a cohort of over 1.5 million children.

Results

Significant IR increases were observed across multiple autoimmune diseases. Rheumatic diseases (Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Henoch Schoenlein Purpura (HSP)) showed consistent increases, with HSP demonstrating the most pronounced trend. Endocrine disorders exhibited diverse patterns, with autoimmune thyroid diseases and Type 1 diabetes showing overall increases, while diabetic ketoacidosis exhibited an initial spike followed by a decline. Gastrointestinal diseases displayed heterogeneous patterns; Celiac disease and Ulcerative colitis showed general increases, Crohn's disease showed a downward trend, and autoimmune hepatitis exhibited an initial significant decrease followed by a significant increase. Dermatological conditions, including Psoriasis and Vitiligo, demonstrated consistent elevations throughout 2020–2023. Immune Thrombocytopenia Purpura showed initial decreases followed by significant increases in 2022–2023.

Conclusions

This comprehensive analysis reveals significant changes in pediatric autoimmune disease incidence following the COVID-19 pandemic, suggesting potential associations between SARS-CoV-2 infection and autoimmune dysregulation. The diverse patterns observed across different conditions highlight the complex interplay between viral infection and autoimmunity, emphasizing the need for continued surveillance and investigation of long-term immunological consequences of COVID-19 in pediatric populations.

{"title":"Pediatric autoimmune diseases in the light of COVID-19 pandemic, A retrospective observational big data study","authors":"Rim Kasem Ali Sliman , Hilla Cohen , Shereen Shehadeh , Reut Batcir , Yigal Elenberg Alter , Keren Cohen , Ilana Koren , Inbal Halabi , Hussein Sliman , Mohamad Hamad Saied","doi":"10.1016/j.jtauto.2025.100281","DOIUrl":"10.1016/j.jtauto.2025.100281","url":null,"abstract":"<div><h3>Background</h3><div>The COVID-19 pandemic has raised concerns about potential links between SARS-CoV-2 infection and autoimmune diseases. This study investigated changes in the incidence rate (IR) of autoimmune diseases among children following the pandemic's onset.</div></div><div><h3>Methods</h3><div>A retrospective cross-sectional study analyzed data from Clalit Health Services, Israel's largest healthcare provider, examining the IR of different autoimmune diseases in children aged 0–18. The study compared pre-pandemic (2019) with pandemic/post-pandemic periods (2020–2023), encompassing a cohort of over 1.5 million children.</div></div><div><h3>Results</h3><div>Significant IR increases were observed across multiple autoimmune diseases. Rheumatic diseases (Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Henoch Schoenlein Purpura (HSP)) showed consistent increases, with HSP demonstrating the most pronounced trend. Endocrine disorders exhibited diverse patterns, with autoimmune thyroid diseases and Type 1 diabetes showing overall increases, while diabetic ketoacidosis exhibited an initial spike followed by a decline. Gastrointestinal diseases displayed heterogeneous patterns; Celiac disease and Ulcerative colitis showed general increases, Crohn's disease showed a downward trend, and autoimmune hepatitis exhibited an initial significant decrease followed by a significant increase. Dermatological conditions, including Psoriasis and Vitiligo, demonstrated consistent elevations throughout 2020–2023. Immune Thrombocytopenia Purpura showed initial decreases followed by significant increases in 2022–2023.</div></div><div><h3>Conclusions</h3><div>This comprehensive analysis reveals significant changes in pediatric autoimmune disease incidence following the COVID-19 pandemic, suggesting potential associations between SARS-CoV-2 infection and autoimmune dysregulation. The diverse patterns observed across different conditions highlight the complex interplay between viral infection and autoimmunity, emphasizing the need for continued surveillance and investigation of long-term immunological consequences of COVID-19 in pediatric populations.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100281"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NETosis: A key player in autoimmunity, COVID-19, and long COVID

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-02-21 DOI: 10.1016/j.jtauto.2025.100280

Diana M. Monsalve , Yeny Acosta-Ampudia , Nicolás Guerrero Acosta , Mariana Celis-Andrade , Ali Şahin , Ahsen Morva Yilmaz , Yehuda Shoenfeld , Carolina Ramírez-Santana

NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.

{"title":"NETosis: A key player in autoimmunity, COVID-19, and long COVID","authors":"Diana M. Monsalve , Yeny Acosta-Ampudia , Nicolás Guerrero Acosta , Mariana Celis-Andrade , Ali Şahin , Ahsen Morva Yilmaz , Yehuda Shoenfeld , Carolina Ramírez-Santana","doi":"10.1016/j.jtauto.2025.100280","DOIUrl":"10.1016/j.jtauto.2025.100280","url":null,"abstract":"<div><div>NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100280"},"PeriodicalIF":4.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Understanding the role of immune-mediated inflammatory disease related cytokines interleukin 17 and 23 in pregnancy: A systematic review

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-02-07 DOI: 10.1016/j.jtauto.2025.100279

Aniek Plug , Liana Barenbrug , Bart G.J. Moerings , Elke M.G. de Jong , Renate G. van der Molen

Background

Pregnancy requires a careful immune balance between tolerance for the semi-allogenic fetus and protection against pathogens. Women with immune-mediated inflammatory diseases (IMIDs), where the interleukin (IL)-23/IL-17 axis plays an important role, often experience changes in disease severity during pregnancy. These changes and the association between disease flares and pregnancy complications, suggests a role for IL-17 and IL-23 in pregnancy.

Methods

We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related in vitro assays, animal or human studies.

Results

Eighty articles (8 in vitro, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. In vitro trophoblast proliferation, migration and invasion was increased in the presence of IL-17, but impaired with IL-23. IL-17 levels were increased in animal models for pregnancy complications. In humans, IL-17 levels seemed to be increased in pregnant women versus non-pregnant women. Additionally, elevated IL-17 levels were associated with pregnancy complications. Although similar trends were found for IL-23, data were limited.

Conclusions

We identified a large, but heterogenic, body of evidence for a significant role of IL-17 in all stages of pregnancy: while an excessive increase seemed to be associated with complications. The limited number of studies prevents firm conclusions on the role of IL-23. Future research is needed to find biomarkers for patients with IMIDs to predict the effect of possible disease flares on pregnancy, and the effect of therapeutic inhibition of IL-17 or IL-23.

{"title":"Understanding the role of immune-mediated inflammatory disease related cytokines interleukin 17 and 23 in pregnancy: A systematic review","authors":"Aniek Plug , Liana Barenbrug , Bart G.J. Moerings , Elke M.G. de Jong , Renate G. van der Molen","doi":"10.1016/j.jtauto.2025.100279","DOIUrl":"10.1016/j.jtauto.2025.100279","url":null,"abstract":"<div><h3>Background</h3><div>Pregnancy requires a careful immune balance between tolerance for the semi-allogenic fetus and protection against pathogens. Women with immune-mediated inflammatory diseases (IMIDs), where the interleukin (IL)-23/IL-17 axis plays an important role, often experience changes in disease severity during pregnancy. These changes and the association between disease flares and pregnancy complications, suggests a role for IL-17 and IL-23 in pregnancy.</div></div><div><h3>Methods</h3><div>We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related <em>in vitro</em> assays, animal or human studies.</div></div><div><h3>Results</h3><div>Eighty articles (8 <em>in vitro</em>, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. <em>In vitro</em> trophoblast proliferation, migration and invasion was increased in the presence of IL-17, but impaired with IL-23. IL-17 levels were increased in animal models for pregnancy complications. In humans, IL-17 levels seemed to be increased in pregnant women versus non-pregnant women. Additionally, elevated IL-17 levels were associated with pregnancy complications. Although similar trends were found for IL-23, data were limited.</div></div><div><h3>Conclusions</h3><div>We identified a large, but heterogenic, body of evidence for a significant role of IL-17 in all stages of pregnancy: while an excessive increase seemed to be associated with complications. The limited number of studies prevents firm conclusions on the role of IL-23. Future research is needed to find biomarkers for patients with IMIDs to predict the effect of possible disease flares on pregnancy, and the effect of therapeutic inhibition of IL-17 or IL-23.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100279"},"PeriodicalIF":4.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancement of CD8+T cell cytotoxicity activity by IFN-α implies alternative pathologic role in systemic lupus erythematosus

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-02-04 DOI: 10.1016/j.jtauto.2025.100276

Chen-xing Zhang , You-ying Mao , Yu-pin Tan , Mei-yu Zhang , Kang Shao , Shu-jun Wang , Ping Ji , Jia-yuan Wang , Lei Yin , Ying Wang

Objective

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which is affected by the environmental, genetic factors as well as the immune system. Previous reports have implicated IFN-α in the pathogenesis of SLE. Up to date, however, no research has ever investigated the effect of IFN-α on CD8⁺T cells, which might be implicated in the pathogenesis of SLE. In the present study, we aimed to explore the pathologic role of IFN-α in regard to dysfunction of CD8⁺T cells in SLE.

Methods

Serum level of IFN-α was detected in SLE and healthy controls (HC). Surface expression of lysosome-associated membrane protein 1 (LAMP-1; CD107a) and secretion of granzyme B of CD8⁺T cells was measured in SLE and HC with or without IFN-α co-stimulation/PI3K inhibitor.

Results

Our results demonstrated that there was increased surface expression of CD107a of CD8⁺T cells in SLE patients compared with healthy controls (HC), indicating enhanced cytotoxicity of CD8⁺T cells in SLE patients. Meanwhile, increased secretion of granzyme B was also detected in CD8⁺T cells of SLE compared with HC, which correlated with the disease activity (SLEDAI). Furthermore, elevated serum level of IFN-α in SLE was confirmed in our study. In vitro study, granzyme B secretion by CD8⁺T cells was upregulated upon IFN-α costimulation, which was consistent with enhanced cytotoxicity of CD8⁺T cells upon IFN-α costimulation, as reflected by elevated surface expression of CD107a. PI3K inhibitor reversed increased granzyme B synthesis upon IFN-α costimulation in a dose-dependent manner.

Conclusion

In summary, elevated serum level of IFN-α was responsible for increased secretion of granzyme B and enhanced cytotoxicity of CD8⁺T cells in SLE and this process may be related to PI3K pathway. Relevant molecules and mechanism remains to be explored in the future.

{"title":"Enhancement of CD8+T cell cytotoxicity activity by IFN-α implies alternative pathologic role in systemic lupus erythematosus","authors":"Chen-xing Zhang , You-ying Mao , Yu-pin Tan , Mei-yu Zhang , Kang Shao , Shu-jun Wang , Ping Ji , Jia-yuan Wang , Lei Yin , Ying Wang","doi":"10.1016/j.jtauto.2025.100276","DOIUrl":"10.1016/j.jtauto.2025.100276","url":null,"abstract":"<div><h3>Objective</h3><div>Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which is affected by the environmental, genetic factors as well as the immune system. Previous reports have implicated IFN-α in the pathogenesis of SLE. Up to date, however, no research has ever investigated the effect of IFN-α on CD8<sup>+</sup>T cells, which might be implicated in the pathogenesis of SLE. In the present study, we aimed to explore the pathologic role of IFN-α in regard to dysfunction of CD8<sup>+</sup>T cells in SLE.</div></div><div><h3>Methods</h3><div>Serum level of IFN-α was detected in SLE and healthy controls (HC). Surface expression of lysosome-associated membrane protein 1 (LAMP-1; CD107a) and secretion of granzyme B of CD8<sup>+</sup>T cells was measured in SLE and HC with or without IFN-α co-stimulation/PI3K inhibitor.</div></div><div><h3>Results</h3><div>Our results demonstrated that there was increased surface expression of CD107a of CD8<sup>+</sup>T cells in SLE patients compared with healthy controls (HC), indicating enhanced cytotoxicity of CD8<sup>+</sup>T cells in SLE patients. Meanwhile, increased secretion of granzyme B was also detected in CD8<sup>+</sup>T cells of SLE compared with HC, which correlated with the disease activity (SLEDAI). Furthermore, elevated serum level of IFN-α in SLE was confirmed in our study. In vitro study, granzyme B secretion by CD8<sup>+</sup>T cells was upregulated upon IFN-α costimulation, which was consistent with enhanced cytotoxicity of CD8<sup>+</sup>T cells upon IFN-α costimulation, as reflected by elevated surface expression of CD107a. PI3K inhibitor reversed increased granzyme B synthesis upon IFN-α costimulation in a dose-dependent manner.</div></div><div><h3>Conclusion</h3><div>In summary, elevated serum level of IFN-α was responsible for increased secretion of granzyme B and enhanced cytotoxicity of CD8<sup>+</sup>T cells in SLE and this process may be related to PI3K pathway. Relevant molecules and mechanism remains to be explored in the future.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100276"},"PeriodicalIF":4.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The follow-up of patients with celiac disease

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-01-30 DOI: 10.1016/j.jtauto.2025.100278

Marco Di Tola , Hetty J. Bontkes , Juan Irure-Ventura , Marcos López-Hoyos , Nicola Bizzaro

Celiac disease (CD) is a very common immune-mediated enteropathy resulting from the interaction between dietary gluten and the immune system in genetically predisposed individuals. The immune response leads to intestinal damage, malabsorption and, ultimately, to a broad spectrum of both intestinal and extra-intestinal symptoms. According to current criteria, a proper diagnosis of CD requires an initial phase consisting of clinical case identification and serological screening that, over time, has increased in importance. In most adults and in selected children, the diagnosis is subsequently defined by histological evidence of intestinal damage as a confirmatory test, which usually returns to normal after a suitable period of a gluten-free diet (GFD). The clinical remission and disappearance of circulating antibodies after a GFD further confirm the diagnosis and represent a goal to be achieved to improve the quality of life and reduce the risk of long-term complications. However, although the diagnostic criteria for CD are well defined and described in specific guidelines, the monitoring of CD patients undergoing GFD has been less studied and, consequently, specific guidelines for this phase are still lacking. The aim of this report was to evaluate the classical tools used to monitor the adherence and response to GFD, other non-invasive biomarkers that have been proposed for CD monitoring, and the histological follow-up of CD patients in order to provide a starting point for future discussions on this specific topic.

{"title":"The follow-up of patients with celiac disease","authors":"Marco Di Tola , Hetty J. Bontkes , Juan Irure-Ventura , Marcos López-Hoyos , Nicola Bizzaro","doi":"10.1016/j.jtauto.2025.100278","DOIUrl":"10.1016/j.jtauto.2025.100278","url":null,"abstract":"<div><div>Celiac disease (CD) is a very common immune-mediated enteropathy resulting from the interaction between dietary gluten and the immune system in genetically predisposed individuals. The immune response leads to intestinal damage, malabsorption and, ultimately, to a broad spectrum of both intestinal and extra-intestinal symptoms. According to current criteria, a proper diagnosis of CD requires an initial phase consisting of clinical case identification and serological screening that, over time, has increased in importance. In most adults and in selected children, the diagnosis is subsequently defined by histological evidence of intestinal damage as a confirmatory test, which usually returns to normal after a suitable period of a gluten-free diet (GFD). The clinical remission and disappearance of circulating antibodies after a GFD further confirm the diagnosis and represent a goal to be achieved to improve the quality of life and reduce the risk of long-term complications. However, although the diagnostic criteria for CD are well defined and described in specific guidelines, the monitoring of CD patients undergoing GFD has been less studied and, consequently, specific guidelines for this phase are still lacking. The aim of this report was to evaluate the classical tools used to monitor the adherence and response to GFD, other non-invasive biomarkers that have been proposed for CD monitoring, and the histological follow-up of CD patients in order to provide a starting point for future discussions on this specific topic.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100278"},"PeriodicalIF":4.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143174021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The antibody repertoire of autoimmune sensory neuronopathies targets pathways of the innate and adaptive immune system. An autoantigenomic approach

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-01-30 DOI: 10.1016/j.jtauto.2025.100277

Christian P. Moritz , Yannick Tholance , Nadia Boutahar , Coralie Borowczyk , Anne-Emmanuelle Berger , Stéphane Paul , Jean-Christophe Antoine , Jean-Philippe Camdessanché

Sensory neuronopathies (SNN) encompass diverse etiologies, with autoimmunity playing a major role through both cellular and humoral responses. To investigate the humoral autoantibody repertoire in autoimmune SNN, we conducted a retrospective cohort study using large Human Proteome-wide protein microarrays (HuProt 3.1, HuProt 4.0, ProtoArrays). We specifically analyzed immune system pathways targeted within the autoantigen repertoire (the autoantigenome). We included 131 participants: 44 patients with non-paraneoplastic autoimmune SNN (12 with anti-FGFR3 and/or anti-AGO antibodies), 8 with paraneoplastic SNN, and 79 controls. Findings were validated in an independent cohort of 16 SNN patients. Overrepresentation of immune-system-related proteins was assessed using the Reactome database, and serum levels of IFN-γ and IL-6 were measured with the Bio-Plex Pro™ Reagent Kit. Autoimmune SNN sera interact with significantly more immune system proteins than healthy controls (ProtoArrays: 271/863 vs. 14/863, HuProt: 112/1694 vs. 39/1694, both p < 0.0001). Overrepresentation was observed across all major immune sub-pathways, including innate and adaptive immune responses as well as cytokine signaling. Anti-FGFR3-positive SNN patients showed more frequent reactivity to immune system proteins than anti-FGFR3-negative ones. The independent SNN cohort validated the overrepresentation of targeted immune system pathways. Validation with dot blot and ELISA confirmed reactivity to TRIM21 and IL-6 and identified anti-IFN-γ-positive SNN patients. IFN-γ levels correlated weakly with levels of anti-IFN-γ antibodies (Pearson's r = 0.22, p = 0.03). We conclude that the antibody repertoire of autoimmune SNN targets pathways of the innate and adaptive immune system, potentially reflecting key disease-related immune pathways and highlighting the systemic role of immune dysregulation in SNN.

{"title":"The antibody repertoire of autoimmune sensory neuronopathies targets pathways of the innate and adaptive immune system. An autoantigenomic approach","authors":"Christian P. Moritz , Yannick Tholance , Nadia Boutahar , Coralie Borowczyk , Anne-Emmanuelle Berger , Stéphane Paul , Jean-Christophe Antoine , Jean-Philippe Camdessanché","doi":"10.1016/j.jtauto.2025.100277","DOIUrl":"10.1016/j.jtauto.2025.100277","url":null,"abstract":"<div><div>Sensory neuronopathies (SNN) encompass diverse etiologies, with autoimmunity playing a major role through both cellular and humoral responses. To investigate the humoral autoantibody repertoire in autoimmune SNN, we conducted a retrospective cohort study using large Human Proteome-wide protein microarrays (HuProt 3.1, HuProt 4.0, ProtoArrays). We specifically analyzed immune system pathways targeted within the autoantigen repertoire (the autoantigenome). We included 131 participants: 44 patients with non-paraneoplastic autoimmune SNN (12 with anti-FGFR3 and/or anti-AGO antibodies), 8 with paraneoplastic SNN, and 79 controls. Findings were validated in an independent cohort of 16 SNN patients. Overrepresentation of immune-system-related proteins was assessed using the Reactome database, and serum levels of IFN-γ and IL-6 were measured with the Bio-Plex Pro™ Reagent Kit. Autoimmune SNN sera interact with significantly more immune system proteins than healthy controls (ProtoArrays: 271/863 vs. 14/863, HuProt: 112/1694 vs. 39/1694, both p < 0.0001). Overrepresentation was observed across all major immune sub-pathways, including innate and adaptive immune responses as well as cytokine signaling. Anti-FGFR3-positive SNN patients showed more frequent reactivity to immune system proteins than anti-FGFR3-negative ones. The independent SNN cohort validated the overrepresentation of targeted immune system pathways. Validation with dot blot and ELISA confirmed reactivity to TRIM21 and IL-6 and identified anti-IFN-γ-positive SNN patients. IFN-γ levels correlated weakly with levels of anti-IFN-γ antibodies (Pearson's <em>r</em> = 0.22, p = 0.03). We conclude that the antibody repertoire of autoimmune SNN targets pathways of the innate and adaptive immune system, potentially reflecting key disease-related immune pathways and highlighting the systemic role of immune dysregulation in SNN.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100277"},"PeriodicalIF":4.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Helicobacter mastomyrinus infection induces autoimmune hepatitis in mice

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-01-24 DOI: 10.1016/j.jtauto.2025.100275

Liqi Zhu , Yuanyuan Liang , Linghan Yang , Qihui Yang , Jun Yin , Tao Wang , Xiangming Xu , Quan Zhang

Background

Autoimmune hepatitis (AIH) is a chronic progressive liver disease caused by the immune system mistakenly attacking its own hepatocytes. The role of the gut microbiome in the pathogenesis and progression of AIH is of considerable significance. However, the dearth of suitable animal models has significantly constrained advancements in the pathogenesis and the development of therapeutic strategies for AIH. Helicobacter mastomyrinus (H. mastomyrinus, Hm) is a potentially zoonotic pathogenic microorganism capable of causing diseases of the enterohepatic system in rodent laboratory animals. Nevertheless, research on its role and mechanisms in causing liver disease is severely limited.

Methods

In this study, male BALB/c mice were infected with Hm isolate Hm-17, and were sacrificed at 4 w, 8 w, 14 w and 22 w after infection, respectively. The serum was collected for detecting a number of AIH indicators, including the aminotransferases level, IgG content and autoantibody level. Additionally, the liver tissue was examined for pathological analysis, fibrosis, bacterial content, and the distribution of immune cells.

Results

It was observed that the infection initially caused focal necrotizing hepatitis and subsequently progressed to interface hepatitis with lymphocyte/plasma cell infiltration, as well as hypergammaglobulinemia and autoantibody reactions, predominantly to Anti-nuclear and anti-smooth muscle antibodies. Furthermore, as the infection persisted, the mice exhibited a progressive increase in liver fibrosis and mild steatosis. Despite the maintenance of a low level of Hm colonization in the liver, there was a notable infiltrate of macrophages, T and B lymphocytes. In particular, the inflammatory foci in the Hm-infected liver were highly enriched for IL17⁺ cells.

Conclusion

The present study provides an animal model of immunological liver injury induced by Hm infection that exhibits main characteristics similar to those observed in AIH-1 patients. This model may serve as a novel animal model for the study of the pathogenesis and potential therapeutic strategies for human AIH.

{"title":"Helicobacter mastomyrinus infection induces autoimmune hepatitis in mice","authors":"Liqi Zhu , Yuanyuan Liang , Linghan Yang , Qihui Yang , Jun Yin , Tao Wang , Xiangming Xu , Quan Zhang","doi":"10.1016/j.jtauto.2025.100275","DOIUrl":"10.1016/j.jtauto.2025.100275","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune hepatitis (AIH) is a chronic progressive liver disease caused by the immune system mistakenly attacking its own hepatocytes. The role of the gut microbiome in the pathogenesis and progression of AIH is of considerable significance. However, the dearth of suitable animal models has significantly constrained advancements in the pathogenesis and the development of therapeutic strategies for AIH. <em>Helicobacter mastomyrinus</em> (<em>H. mastomyrinus,</em> Hm) is a potentially zoonotic pathogenic microorganism capable of causing diseases of the enterohepatic system in rodent laboratory animals. Nevertheless, research on its role and mechanisms in causing liver disease is severely limited.</div></div><div><h3>Methods</h3><div>In this study, male BALB/c mice were infected with Hm isolate Hm-17, and were sacrificed at 4 w, 8 w, 14 w and 22 w after infection, respectively. The serum was collected for detecting a number of AIH indicators, including the aminotransferases level, IgG content and autoantibody level. Additionally, the liver tissue was examined for pathological analysis, fibrosis, bacterial content, and the distribution of immune cells.</div></div><div><h3>Results</h3><div>It was observed that the infection initially caused focal necrotizing hepatitis and subsequently progressed to interface hepatitis with lymphocyte/plasma cell infiltration, as well as hypergammaglobulinemia and autoantibody reactions, predominantly to Anti-nuclear and anti-smooth muscle antibodies. Furthermore, as the infection persisted, the mice exhibited a progressive increase in liver fibrosis and mild steatosis. Despite the maintenance of a low level of Hm colonization in the liver, there was a notable infiltrate of macrophages, T and B lymphocytes. In particular, the inflammatory foci in the Hm-infected liver were highly enriched for IL17<sup>+</sup> cells.</div></div><div><h3>Conclusion</h3><div>The present study provides an animal model of immunological liver injury induced by Hm infection that exhibits main characteristics similar to those observed in AIH-1 patients. This model may serve as a novel animal model for the study of the pathogenesis and potential therapeutic strategies for human AIH.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100275"},"PeriodicalIF":4.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143174953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aberrant B cell receptor signaling responses in circulating double-negative 2 B cells from radiographic axial spondyloarthritis patients

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-01-23 DOI: 10.1016/j.jtauto.2025.100270

Rick Wilbrink , Stefan F.H. Neys , Rudi W. Hendriks , Anneke Spoorenberg , Frans G.M. Kroese , Odilia B.J. Corneth , Gwenny M.P.J. Verstappen

Objective

Radiographic axial spondyloarthritis (r-axSpA) is a chronic rheumatic disease in which innate immune cells and T cells are thought to play a major role. However, recent studies also hint at B cell involvement. Here, we performed an in-depth analysis on alterations within the B-cell compartment from r-axSpA patients.

Methods

We performed immune gene expression profiling on total peripheral blood B cells from 8 r-axSpA patients and 8 healthy controls (HCs). Next, we explored B cell subset distribution and B-cell receptor (BCR) signaling responses in circulating B cells from 28 r-axSpA patients and 15 HCs, by measuring spleen tyrosine kinase, phosphoinositide 3-kinase and extracellular signal regulated kinase 1/2 phosphorylation upon α-Ig stimulation using phosphoflow cytometry.

Results

Immune gene expression profiling indicated an elevated pathway score for BCR signaling in total B cells from r-axSpA patients compared with HCs. Flow cytometric analysis revealed an increase in frequency of both total and double-negative 2 (DN2) B cells in r-axSpA patients compared with HCs. In r-axSpA patients, DN2 B cells displayed an isotype shift towards IgA. Remarkably, where DN2 B cells from HCs were hyporesponsive, these cells displayed significant proximal BCR signaling responses in r-axSpA patients. Enhanced BCR signaling responses were also observed in the transitional and naïve B cell population from r-axSpA patients compared with HCs. The enhanced BCR signaling responses in DN2 B cells correlated with clinical disease parameters.

Conclusion

In r-axSpA patients, circulating DN2 B cells are expanded and, together with transitional and naïve B cells, display significantly enhanced BCR signaling responses upon stimulation. Together, our data suggest B cell involvement in the pathogenesis of r-axSpA.

{"title":"Aberrant B cell receptor signaling responses in circulating double-negative 2 B cells from radiographic axial spondyloarthritis patients","authors":"Rick Wilbrink , Stefan F.H. Neys , Rudi W. Hendriks , Anneke Spoorenberg , Frans G.M. Kroese , Odilia B.J. Corneth , Gwenny M.P.J. Verstappen","doi":"10.1016/j.jtauto.2025.100270","DOIUrl":"10.1016/j.jtauto.2025.100270","url":null,"abstract":"<div><h3>Objective</h3><div>Radiographic axial spondyloarthritis (r-axSpA) is a chronic rheumatic disease in which innate immune cells and T cells are thought to play a major role. However, recent studies also hint at B cell involvement. Here, we performed an in-depth analysis on alterations within the B-cell compartment from r-axSpA patients.</div></div><div><h3>Methods</h3><div>We performed immune gene expression profiling on total peripheral blood B cells from 8 r-axSpA patients and 8 healthy controls (HCs). Next, we explored B cell subset distribution and B-cell receptor (BCR) signaling responses in circulating B cells from 28 r-axSpA patients and 15 HCs, by measuring spleen tyrosine kinase, phosphoinositide 3-kinase and extracellular signal regulated kinase 1/2 phosphorylation upon α-Ig stimulation using phosphoflow cytometry.</div></div><div><h3>Results</h3><div>Immune gene expression profiling indicated an elevated pathway score for BCR signaling in total B cells from r-axSpA patients compared with HCs. Flow cytometric analysis revealed an increase in frequency of both total and double-negative 2 (DN2) B cells in r-axSpA patients compared with HCs. In r-axSpA patients, DN2 B cells displayed an isotype shift towards IgA. Remarkably, where DN2 B cells from HCs were hyporesponsive, these cells displayed significant proximal BCR signaling responses in r-axSpA patients. Enhanced BCR signaling responses were also observed in the transitional and naïve B cell population from r-axSpA patients compared with HCs. The enhanced BCR signaling responses in DN2 B cells correlated with clinical disease parameters.</div></div><div><h3>Conclusion</h3><div>In r-axSpA patients, circulating DN2 B cells are expanded and, together with transitional and naïve B cells, display significantly enhanced BCR signaling responses upon stimulation. Together, our data suggest B cell involvement in the pathogenesis of r-axSpA.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100270"},"PeriodicalIF":4.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143175347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-01-22 DOI: 10.1016/j.jtauto.2025.100271

Elisa Arribas-Rodríguez , Ángel De Prado , Beatriz de Andrés , Benito Velayos , Jesús Barrio , Alejandro Romero , Francisco Javier García-Alonso , Álvaro Martín-Muñoz , José A. Garrote , Eduardo Arranz , Luis Fernández-Salazar , David Bernardo

Background

Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC.

Methods

Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were ex-vivo cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells.

Results

Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following ex-vivo culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC.

Conclussion

Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells.

{"title":"Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function","authors":"Elisa Arribas-Rodríguez , Ángel De Prado , Beatriz de Andrés , Benito Velayos , Jesús Barrio , Alejandro Romero , Francisco Javier García-Alonso , Álvaro Martín-Muñoz , José A. Garrote , Eduardo Arranz , Luis Fernández-Salazar , David Bernardo","doi":"10.1016/j.jtauto.2025.100271","DOIUrl":"10.1016/j.jtauto.2025.100271","url":null,"abstract":"<div><h3>Background</h3><div>Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC.</div></div><div><h3>Methods</h3><div>Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were <em>ex-vivo</em> cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells.</div></div><div><h3>Results</h3><div>Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following <em>ex-vivo</em> culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC.</div></div><div><h3>Conclussion</h3><div>Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100271"},"PeriodicalIF":4.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143176736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0