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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-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.

SUBMITTER: Friedrich M

PROVIDER: S-EPMC8350898 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Intrathecal activation of CD8<sup>+</sup> memory T cells in IgG4-related disease of the brain parenchyma.

Friedrich Mirco M Kehl Niklas N Engelke Niko N Kraus Josephine J Lindner Katharina K Münch Philipp P Mildenberger Iris I Groden Christoph C Gass Achim A Etminan Nima N Fatar Marc M von Deimling Andreas A Reuss David D Platten Michael M Bunse Lukas L

EMBO molecular medicine 20210713 8

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 ...[more]

PMID: 34254741

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Project description:BackgroundCD4+ T cells play critical roles in the pathogenesis of IgG4-related disease (IgG4-RD). The aim of this study was to investigate the TCR repertoire of peripheral blood CD4+ T cells in IgG4-RD.MethodsThe peripheral blood was collected from six healthy controls and eight IgG4-RD patients. TCR β-chain libraries of CD4+ T cells were constructed by 5'-rapid amplification of cDNA ends (5'-RACE) and sequenced by Illumina Miseq platform. The relative similarity of TCR repertoires between samples was evaluated according to the total frequencies of shared clonotypes (metric F), correlation of frequencies of shared clonotypes (metric R), and total number of shared clonotypes (metric D).ResultsThe clonal expansion and diversity of CD4+ T cell repertoire were comparable between healthy controls and IgG4-RD patients, while the proportion of expanded and coding degenerated clones, as an indicator of antigen-driven clonal expansion, was significantly higher in IgG4-RD patients. There was no significant difference in TRBV and TRBJ gene usage between healthy controls and IgG4-RD patients. The complementarity determining region 3 (CDR3) length distribution was skewed towards longer fragments in IgG4-RD. Visualization of relative similarity of TCR repertoires by multi-dimensional scaling analysis showed that TCR repertoires of IgG4-RD patients were separated from that of healthy controls in F and D metrics. We identified 11 IgG4-RD-specific CDR3 amino acid sequences that were expanded in at least 2 IgG4-RD patients, while not detected in healthy controls. According to TCR clonotype networks constructed by connecting all the CDR3 sequences with a Levenshtein distance of 1, 3 IgG4-RD-specific clusters were identified. We annotated the TCR sequences with known antigen specificity according to McPAS-TCR database and found that the frequencies of TCR sequences associated with each disease or immune function were comparable between healthy controls and IgG4-RD patients.ConclusionAccording to our study of CD4+ T cells from eight IgG4-RD patients, TCR repertoires of IgG4-RD patients were different from that of healthy controls in the proportion of expanded and coding degenerated clones and CDR3 length distribution. In addition, IgG4-RD-specific TCR sequences and clusters were identified in our study.

Dataset Information

Intrathecal activation of CD8⁺ memory T cells in IgG4-related disease of the brain parenchyma.

Publications

Intrathecal activation of CD8<sup>+</sup> memory T cells in IgG4-related disease of the brain parenchyma.

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Dataset Information

Intrathecal activation of CD8+ memory T cells in IgG4-related disease of the brain parenchyma.

Publications

Intrathecal activation of CD8<sup>+</sup> memory T cells in IgG4-related disease of the brain parenchyma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Intrathecal activation of CD8⁺ memory T cells in IgG4-related disease of the brain parenchyma.