Article
Multimodal immunophenotyping of interstitial nephritis in sarcoidosis shows a strong Th1 phenotype
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Authors
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Frederic Feindt
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Viona Laas
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Laura-Isabell Ehnold
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Julia Hagenstein
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Pavels Klimicevs
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Georg Herrnstadt
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Zeba Sultana
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Hans-Joachim Paust
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Christian F. Krebs
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Ulf Panzer
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Oliver M. Steinmetz
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
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Simon Melderis
- Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg
| Published: | September 18, 2024 |
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Outline
Text
Introduction: Sarcoidosis (SAR) is a systemic inflammatory disease with unknown immunopathology. Kidney involvement in SAR, usually in the form of interstitial nephritis (IN), causes significant morbidity and mortality. Pathogenic immune responses involved in SAR have mostly been studied in pulmonary manifestations, very little is known about the immunopathology in the kidneys. We thus aimed to close this gap and characterized the immune response in IN-SAR.
Methods: We analysed sorted CD45+ cells from kidney biopsies of active IN-SAR patients by single cell RNA-sequencing (scRNA-seq, n=2) and multi parametric flow cytometry (FC) (n=1). Published cell atlas data from healthy kidneys (HC) were used as controls for transcriptome analyses. We also performed FC of urinary leukocytes from patients with IN-SAR (n=6) to quantify and characterize urinary T-cells. SAR-patients with biopsy proven kidney pathology but without IN (non-IN-SAR; n=7) and HC (n=10) served as controls. Routine clinical data (e.g. serum creatinine, proteinuria) were also collected for all SAR-patients.
Results: scRNA-seq revealed CD4+T helper-cells (Th) as most the abundant leukocyte population in IN-SAR, comprising 32% of all renal leukocytes. Natural killer cells (28%), CD8+ T cells (11%), monocytes (8%), B-cells (5%), macrophages (3%) and other/unclassified leukocytes (13%) made up the other populations. Th of IN-SAR patients expressed significant amounts of TNFα and IFNγ but no Th2 (IL-4, -5, -13) or Th17 (IL-17A) cytokines. Compared to HC, IN-SAR Th expressed significantly more TNFα, IFNγ as well as TBX21 and CXCR3, further indicating a Th1 phenotype. Predominant expression of TNFα and IFNγ by IN-SAR Th was confirmed by flow cytometry.
IN-SAR and non-IN-SAR patients did not show differences in serum-creatinine or proteinuria. Contrary, FC of leukocyturia showed that IN-SAR patients had significantly more Th compared to both HC and non-IN-SAR. Moreover, IN-SAR-Th were significantly more activated (CD69+) and showed skewing towards a Th1 phenotype (CXCR3+).
Conclusion:
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- CD4+Th dominate the inflammatory infiltrate in IN-SAR and show a clear Th1 phenotype.
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- Urinary CD4+Th mirror the renal pathology and are a potential non-invasive biomarker for IN-SAR.
Disclosures: No conflicts of interest.
