Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Autoimmunity

  • 253 Articles
  • 0 Posts
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 25
  • 26
  • Next →
Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA-vasculitis
Gang Xi, … , J. Charles Jennette, Ronald J. Falk
Gang Xi, … , J. Charles Jennette, Ronald J. Falk
Published February 28, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI178813.
View: Text | PDF

Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA-vasculitis

  • Text
  • PDF
Abstract

Drug-induced autoimmune diseases are increasingly recognized although mechanistic insight into disease causation is lacking. Hydralazine exposure has been linked to autoimmune diseases, including anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. We in vitro observed formation of carbonyl derivatives on amine groups in the presence of acrolein. This facilitated the subsequent binding of hydralazine to heme-containing proteins, including MPO, via a Michael addition. Our studies demonstrated that carbonyl derivatives and hydrazone adducts induce conformational changes in the MPO heavy chain, potentially changing its immunogenicity. We identified hydrazone adducts on circulating MPO in patients with hydralazine-associated ANCA vasculitis. These patients exhibited elevated anti-MPO IgM levels, while anti-MPO IgG levels were comparable between hydralazine-associated and non-hydralazine-associated vasculitis patients. IgM isolated from hydralazine-associated MPO ANCA patients demonstrated a heightened affinity to hydralazine-modified MPO and activated neutrophil-like HL-60 cells. Hydralazine-modified MPO was pathogenic, as demonstrated by splenocyte transfer in a mouse model of ANCA vasculitis. Our findings unveil a mechanism of drug-induced autoimmunity wherein stepwise chemical modifications of MPO lead to conformational changes and hydrazone adduct formation producing a neoantigen to which pathogenic autoantibodies are generated.

Authors

Gang Xi, Elizabeth A. Mclnnis, Olivier Lardinois, Peiqi Hu, John S. Poulton, Meghan E. Free, Dhruti P. Chen, Evan M. Zeitler, Eveline Y. Wu, Nicole M. Orzechowski, Vimal K. Derebail, J. Charles Jennette, Ronald J. Falk

×

Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis
Michael Kramer, … , Benedetta Terziroli Beretta-Piccoli, Federica Sallusto
Michael Kramer, … , Benedetta Terziroli Beretta-Piccoli, Federica Sallusto
Published January 16, 2025
Citation Information: J Clin Invest. 2025;135(2):e183776. https://doi.org/10.1172/JCI183776.
View: Text | PDF

Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis

  • Text
  • PDF
Abstract

Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease characterized by the presence of autoantibodies, including those targeting O-phosphoseryl-tRNA:selenocysteine-tRNA synthase (SepSecS), also known as soluble liver antigen (SLA). Anti-SepSecS antibodies have been associated with a more severe phenotype, suggesting a key role for the SepSecS autoantigen in AIH. To analyze the immune response to SepSecS in patients with AIH at the clonal level, we combined sensitive high-throughput screening assays with the isolation of monoclonal antibodies (mAbs) and T cell clones. The anti-SepSecS mAbs isolated were primarily IgG1, affinity-matured compared with their germline versions, and recognized at least 3 nonoverlapping epitopes. SepSecS-specific CD4+ T cell clones were found in patients with AIH who were anti-SLA-positive and anti-SLA-negative,and, to a lesser extent, in patients with non-AIH liver diseases and in healthy individuals. SepSecS-specific T cell clones from patients with AIH produced IFN-γ, IL-4, and IL-10, targeted multiple SepSecS epitopes, and, in one patient, were clonally expanded in both blood and liver biopsy. Finally, SepSecS-specific B cell clones, but not those of unrelated specificities, were able to present soluble SepSecS to specific T cells. Collectively, our study provides the first detailed analysis of B and T cell repertoires targeting SepSecS in patients with AIH, offering a rationale for improved targeted therapies.

Authors

Michael Kramer, Federico Mele, Sandra Jovic, Blanca Maria Fernandez, David Jarrossay, Jun Siong Low, Christiane Sokollik, Magdalena Filipowicz Sinnreich, Sylvie Ferrari-Lacraz, Giorgina Mieli-Vergani, Diego Vergani, Antonio Lanzavecchia, Antonino Cassotta, Benedetta Terziroli Beretta-Piccoli, Federica Sallusto

×

Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions
Felicitas E. Hengel, … , Tobias B. Huber, Nicola M. Tomas
Felicitas E. Hengel, … , Tobias B. Huber, Nicola M. Tomas
Published January 16, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186769.
View: Text | PDF

Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions

  • Text
  • PDF
Abstract

Authors

Felicitas E. Hengel, Silke Dehde, Oliver Kretz, Jonas Engesser, Tom Zimmermann, Tobias B. Huber, Nicola M. Tomas

×

Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model
Jing Zhou, … , Michael R. Wilson, Samuel J. Pleasure
Jing Zhou, … , Michael R. Wilson, Samuel J. Pleasure
Published December 31, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI173493.
View: Text | PDF

Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model

  • Text
  • PDF
Abstract

NMDA receptor mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long- term effects of exposure to a patient-derived GluN1-specific monoclonal antibody (mAb) during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced inter-hemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions.

Authors

Jing Zhou, Ariele L. Greenfield, Rita P. Loudermilk, Christopher M. Bartley, Chun Chen, Xiumin Chen, Morgane A.H. Leroux, Yujun Lu, Deanna Necula, Thomas T. Ngo, Baouyen T. Tran, Patrick S. Honma, Kelli Lauderdale, Chao Zhao, Xiaoyuan Zhou, Hong Wang, Roger A. Nicoll, Cong Wang, Jeanne T. Paz, Jorge J. Palop, Michael R. Wilson, Samuel J. Pleasure

×

Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models
Xiang Xiao, … , Zhiqiang Zhang, Xian C. Li
Xiang Xiao, … , Zhiqiang Zhang, Xian C. Li
Published December 31, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI183671.
View: Text | PDF

Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models

  • Text
  • PDF
Abstract

T cells have a remarkable capacity to clonally expand, a process that is intricately linked to their effector activities. As vigorously proliferating T cell also incur substantial DNA lesions, how the dividing T cells safeguard their genomic integrity to allow the generation of T effector cells remains largely unknown. Here we report the identification of the apurinic/apyrimidinic endonuclease-1 (Apex1) as an indispensable molecule for the induction of cytopathic T effectors in mouse models. We demonstrate that conditional deletion of Apex1 in T cells results in a remarkable accumulation of baseless DNA sites in the genome of proliferating T cells, which further leads to genomic instability and apoptotic cell death. Consequently, Apex1-deleted T cells fail to acquire any effector features after activation and fail to mediate autoimmune diseases and allergic tissue damages. Detailed mutational analyses pinpoint the importance of its endonuclease domain in the generation of T effector cells. We provide further evidence that inhibiting the base repair activities of Apex1 with chemical inhibitors similarly abrogates the induction of autoimmune diseases. Collectively, our study suggests that Apex1 serves as a gatekeeper for the generation of cytopathic T cells and that therapeutically targeting Apex1 may have important clinical implications in the treatment of autoimmune diseases.

Authors

Xiang Xiao, Yong Du, Si Sun, Xiaojun Su, Junji Xing, Guangchuan Wang, Steven M. Elzein, Dawei Zou, Laurie J. Minze, Zhuyun Mao, Rafik M. Ghobrial, Ashton A. Connor, Wenhao Chen, Zhiqiang Zhang, Xian C. Li

×

PINK1 is a target of T cell responses in Parkinson's disease
Gregory P. Williams, … , Alessandro Sette, Cecilia S. Lindestam Arlehamn
Gregory P. Williams, … , Alessandro Sette, Cecilia S. Lindestam Arlehamn
Published December 17, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI180478.
View: Text | PDF

PINK1 is a target of T cell responses in Parkinson's disease

  • Text
  • PDF
Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. While there is no curative treatment, the immune system's involvement with autoimmune T cells that recognize the protein alpha-synuclein (α-syn) in a subset of individuals suggests new areas for therapeutic strategies. As not all patients with PD have T cells specific for α-syn, we explored additional autoantigenic targets of T cells in PD. We generated 15-mer peptides spanning several PD-related proteins implicated in PD pathology, including Glucosylceramidase Beta 1 (GBA), Superoxide dismutase 1 (SOD1), PTEN Induced Kinase 1 (PINK1), Parkin RBR E3 Ubiquitin Protein Ligase (parkin), Oxoglutarate Dehydrogenase (OGDH), and Leucine Rich Repeat Kinase 2 (LRRK2). Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. We identified PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells, as well as its unique epitopes, and their HLA restriction. The PINK1-specific T cell reactivity revealed sex-based differences as it was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

Authors

Gregory P. Williams, Antoine Freuchet, Tanner Michaelis, April Frazier, Ngan K. Tran, João Rodrigues Lima-Junior, Elizabeth J. Phillips, Simon A. Mallal, Irene Litvan, Jennifer G. Goldman, Roy N. Alcalay, John Sidney, David Sulzer, Alessandro Sette, Cecilia S. Lindestam Arlehamn

×

Estimation of prevalence of autoimmune diseases in the United States using electronic health record data
Aaron H. Abend, … , George C. Tsokos, DeLisa Fairweather
Aaron H. Abend, … , George C. Tsokos, DeLisa Fairweather
Published December 12, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI178722.
View: Text | PDF

Estimation of prevalence of autoimmune diseases in the United States using electronic health record data

  • Text
  • PDF
Abstract

BACKGROUND. Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease. METHODS. To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time. RESULTS. Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least one autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than one autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age. CONCLUSION. Thus, we provide, for the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age. FUNDING. Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.

Authors

Aaron H. Abend, Ingrid He, Neil Bahroos, Stratos Christianakis, Ashley B. Crew, Leanna M. Wise, Gloria P. Lipori, Xing He, Shawn N. Murphy, Christopher D. Herrick, Jagannadha Avasarala, Mark G. Weiner, Jacob S. Zelko, Erica Matute-Arcos, Mark Abajian, Philip R.O. Payne, Albert M. Lai, Heath A. Davis, Asher A. Hoberg, Chris E. Ortman, Amit D. Gode, Bradley W. Taylor, Kristen I. Osinski, Damian N. Di Florio, Noel R. Rose, Frederick W. Miller, George C. Tsokos, DeLisa Fairweather

×

Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation
Subash Chand Verma, … , Roland Liblau, Julien Diana
Subash Chand Verma, … , Roland Liblau, Julien Diana
Published December 10, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI184502.
View: Text | PDF

Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation

  • Text
  • PDF
Abstract

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that was required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1–39 at the peak of EAE promoted disease remission. In vitro, CRAMP1–39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR)2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors (FFAR)2/3, and prevented EAE. This study shows that CRAMP produced by different cell types have opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.

Authors

Subash Chand Verma, Emmanuelle Enée, Kanchanadevi Manasse, Feriel Rebhi, Axelle Penc, David Romeo-Guitart, Cuc Bui Thi, Matthias Titeux, Franck Oury, Simon Fillatreau, Roland Liblau, Julien Diana

×

Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice
Alexis N. Cattin-Roy, … , Adam G. Schrum, Habib Zaghouani
Alexis N. Cattin-Roy, … , Adam G. Schrum, Habib Zaghouani
Published December 2, 2024
Citation Information: J Clin Invest. 2024;134(23):e163417. https://doi.org/10.1172/JCI163417.
View: Text | PDF

Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice

  • Text
  • PDF
Abstract

Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.

Authors

Alexis N. Cattin-Roy, Kimberly G. Laffey, Luan B. Le, Adam G. Schrum, Habib Zaghouani

×

Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model
Elizabeth E. McCarthy, … , Arthur Weiss, Judith F. Ashouri
Elizabeth E. McCarthy, … , Arthur Weiss, Judith F. Ashouri
Published November 26, 2024
Citation Information: J Clin Invest. 2024. https://doi.org/10.1172/JCI174647.
View: Text | PDF

Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model

  • Text
  • PDF
Abstract

The development of pathogenic autoreactive CD4+ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We profiled a highly arthritogenic subset of naïve CD4+ T cells using bulk and single-cell RNA and TCR sequencing from SKG mice, which develop CD4+ T cell mediated autoimmune arthritis driven by a hypomorphic mutation in Zap70—a key TCR signaling kinase. Despite impaired signaling, these cells exhibit heightened expression of T cell activation and cytokine signaling genes, but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared to wild-type cells. The arthritogenic cells show an enrichment for TCR variable beta (Vβ) chains targeting superantigens from the endogenous mouse mammary tumor virus (MMTV) but exhibit diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of negative regulators seen in wild-type cells. In arthritic joints, cells expressing superantigen-reactive Vβs expand alongside detectable MMTV proviruses. Antiretroviral treatment and superantigen-reactive T cell depletion curtail SKG arthritis, suggesting that endogenous retroviruses disrupt peripheral tolerance and promote the activation and differentiation of self-reactive CD4+ T cells into pathogenic effector cells.

Authors

Elizabeth E. McCarthy, Steven Yu, Noah Perlmutter, Yuka Nakao, Ryota Naito, Charles Lin, Vivienne Riekher, Joe DeRisi, Chun Jimmie Ye, Arthur Weiss, Judith F. Ashouri

×
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 25
  • 26
  • Next →

No posts were found with this tag.

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts