Advertisement
Clinical MedicineIn-Press PreviewAutoimmunityInfectious disease
Open Access | 10.1172/JCI179391
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Dirks, J. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Fischer, J. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Klaussner, J. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Hofmann, C. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Holl-Wieden, A. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Buck, V. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Klemann, C. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Girschick, H. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by
Caruana, I.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by
Erhard, F.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology, University Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Immunology, Rheumatology, & Infectiology, Leipzig University, Leipzig, Germany
4Department of Pediatrics, Vivantes Hospital, Berlin, Germany
5Department of Paediatric Haematology, Oncology and Stem Cell Transplantatio, University Hospital Würzburg, Würzburg, Germany
6Institute for Virology and Immunobiology, University Hospital Würzburg, Würzburg, Germany
Find articles by Morbach, H. in: JCI | PubMed | Google Scholar
Published July 4, 2024 - More info
Background: Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens succeeding towards autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells. Methods: Using flow cytometry, high-throughput T cell receptor (TCR) sequencing and scRNA-seq of CD4+ Th cells isolated from the joints of European ARLA patients, we aimed at inferring antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs and connecting TCR specificity to transcriptional patterns. Results: PD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCRβ motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in North American ARLA patients, were unexpectedly prevalent in our European cohort. The identified TCRβ motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-seq dataset, the TCRβ motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ. Conclusion: By inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of ARLA patients that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response. Funding: Supported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).