Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma
Abstract IgG4‐related disease (IgG4‐RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4‐restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4‐RD remain elusive. There are very few cases of IgG4‐R...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-07-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202113953 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761881580896256 |
|---|---|
| author | Mirco Friedrich Niklas Kehl Niko Engelke Josephine Kraus Katharina Lindner Philipp Münch Iris Mildenberger Christoph Groden Achim Gass Nima Etminan Marc Fatar Andreas von Deimling David Reuss Michael Platten Lukas Bunse |
| author_facet | Mirco Friedrich Niklas Kehl Niko Engelke Josephine Kraus Katharina Lindner Philipp Münch Iris Mildenberger Christoph Groden Achim Gass Nima Etminan Marc Fatar Andreas von Deimling David Reuss Michael Platten Lukas Bunse |
| author_sort | Mirco Friedrich |
| collection | DOAJ |
| description | Abstract IgG4‐related disease (IgG4‐RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4‐restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4‐RD remain elusive. There are very few cases of IgG4‐RD with isolated central nervous system manifestation. By leveraging single‐cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4‐RD. Our data illustrate an IgG4‐RD‐associated polyclonal T‐cell response in the CSF and an oligoclonal T‐cell response in the parenchymal lesions, the latter being the result of a multifaceted cell–cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8+ T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)‐CD74 signaling to immature B cells and CC‐chemokine ligand 5 (CCL5)‐mediated recruitment of cytotoxic CD4+ T cells. These findings highlight the central role of T cells in sustaining IgG4‐RD and open novel avenues for targeted therapies. |
| format | Article |
| id | doaj-art-2092b8d7df0b40dfac224be28ccddb6d |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2092b8d7df0b40dfac224be28ccddb6d2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-07-0113811010.15252/emmm.202113953Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchymaMirco Friedrich0Niklas Kehl1Niko Engelke2Josephine Kraus3Katharina Lindner4Philipp Münch5Iris Mildenberger6Christoph Groden7Achim Gass8Nima Etminan9Marc Fatar10Andreas von Deimling11David Reuss12Michael Platten13Lukas Bunse14DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg UniversityDKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Department of Neuroradiology, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Neurosurgery, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Neuropathology, Heidelberg University HospitalDepartment of Neuropathology, Heidelberg University HospitalDKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Abstract IgG4‐related disease (IgG4‐RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4‐restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4‐RD remain elusive. There are very few cases of IgG4‐RD with isolated central nervous system manifestation. By leveraging single‐cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4‐RD. Our data illustrate an IgG4‐RD‐associated polyclonal T‐cell response in the CSF and an oligoclonal T‐cell response in the parenchymal lesions, the latter being the result of a multifaceted cell–cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8+ T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)‐CD74 signaling to immature B cells and CC‐chemokine ligand 5 (CCL5)‐mediated recruitment of cytotoxic CD4+ T cells. These findings highlight the central role of T cells in sustaining IgG4‐RD and open novel avenues for targeted therapies.https://doi.org/10.15252/emmm.202113953CSF single‐cell sequencingcytotoxic T helper cellIgG4‐related diseaseinflammatory pseudotumorpathogenic B‐cell |
| spellingShingle | Mirco Friedrich Niklas Kehl Niko Engelke Josephine Kraus Katharina Lindner Philipp Münch Iris Mildenberger Christoph Groden Achim Gass Nima Etminan Marc Fatar Andreas von Deimling David Reuss Michael Platten Lukas Bunse Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma EMBO Molecular Medicine CSF single‐cell sequencing cytotoxic T helper cell IgG4‐related disease inflammatory pseudotumor pathogenic B‐cell |
| title | Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma |
| title_full | Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma |
| title_fullStr | Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma |
| title_full_unstemmed | Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma |
| title_short | Intrathecal activation of CD8+ memory T cells in IgG4‐related disease of the brain parenchyma |
| title_sort | intrathecal activation of cd8 memory t cells in igg4 related disease of the brain parenchyma |
| topic | CSF single‐cell sequencing cytotoxic T helper cell IgG4‐related disease inflammatory pseudotumor pathogenic B‐cell |
| url | https://doi.org/10.15252/emmm.202113953 |
| work_keys_str_mv | AT mircofriedrich intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT niklaskehl intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT nikoengelke intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT josephinekraus intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT katharinalindner intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT philippmunch intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT irismildenberger intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT christophgroden intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT achimgass intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT nimaetminan intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT marcfatar intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT andreasvondeimling intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT davidreuss intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT michaelplatten intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma AT lukasbunse intrathecalactivationofcd8memorytcellsinigg4relateddiseaseofthebrainparenchyma |