Biology subjects

Strippel, C.

Publications and source records attributed to Strippel, C..

2 recordsLinked to original sources

bioRxiv2025

CSF single-cell RNA sequencing reveals clonally expanded CD4+ stem cell-like memory T cells in GAD65-antibody associated neurological syndromes

BackgroundGlutamic acid decarboxylase (GAD) antibody-associated autoimmune neurological syndromes (AINS) are a spectrum of autoimmune-mediated CNS disorders. While antibodies targeting the 65 kDa isoform of GAD are of high diagnostic value, T cell mediated cytotoxicity has been identified as a key component of disease pathogenesis. The precise pathophysiological mechanisms by which the disease is triggered and maintained, however, remain incompletely understood. MethodsWe performed single-cell transcriptome and immune repertoire sequencing (sc-seq) in CSF and blood of 8 anti-GAD65 AINS patients compared to 8 non-inflammatory controls. Monoclonal antibodies (mAbs) were synthesized from B cell receptor (BCR) data to evaluate the B cellular immune response. FindingsWe identified an increase and expansion of activated CD4+ stem cell-like memory T cells (TSCM) in the CSF of anti-GAD65 AINS patients. Expanded T cells showed increased expression of proinflammatory genes. The mAb analysis revealed a high frequency of GAD65-reactive BCRs in the CSF of anti-GAD65 AINS patients with increased somatic hypermutations compared to non-GAD-reactive BCRs and BCRs from controls. ConclusionsSc-seq identified clonally expanded CD4+ TSCM in the CSF of anti-GAD65 AINS patients harboring cytotoxic properties likely contributing to disease pathogenesis. GAD-reactive B cells circulate in the CSF of anti-GAD65 AINS patients further supporting the concept of an antigen-specific intrathecal immune response. Future studies need to clarify the actual pathogenicity of these immune cells and the link between T and B cellular immune mechanisms in the pathogenesis of anti-GAD65 AINS. FundingGerman Research Foundation (ERARE18-202 UltraAIE), German Federal Ministry of Education and Research (CONNECT GENERATE (2.0); 01GM1908A and 01GM2208A).

immunology↗

bioRxiv2023

CSF plasma cell expansion in LGI1-/CASPR2-autoimmune encephalitis is associated with loss of regulatory MAIT cells

Anti-Leucine-rich glioma inactivated-1 (LGI1) and anti-contactin-associated-protein-2 (CASPR2) associated autoimmune encephalitis (AIE) variants are characterized by directly pathogenic autoantibodies present in serum and CSF. The dynamics and drivers of intrathecal and systemic autoantibody production are incompletely understood. We aimed to elucidate the immunologic basis of the LGI1-/CASPR2-associated AIE variants by performing multi-omic profiling of CSF/blood in untreated patients. We validated findings by flow cytometry in independent cohorts and confirmed functionality using rodent immunization. We identified clonal IgG2 and IgG4 plasma cell expansion and affinity maturation in the CSF together with clonally restricted, activated, antigen-experienced CD8 and CD4 T cells as a hallmark of these encephalitis variants. Using recombinant cloning, we confirmed that expanded CSF plasma cell clones almost exclusively bound the respective neuronal autoantigen. In addition, we found a loss of regulatory mucosa-associated invariant T (MAIT) cells and gamma delta T cells in the CSF and - to a lesser degree - in blood. We validated the functional role of these invariant T cells using a novel murine active immunization paradigm using both autoantigens: MAIT cells suppressed systemic formation of LGI1 and CASPR2-specific anti-neuronal antibodies. We propose that loss of systemic and intrathecal regulatory mechanisms mediated by innate-like T cells promote plasma cell expansion and autoantibody production as a shared mechanism in AIE. One sentence summaryCerebrospinal fluid (CSF) and peripheral blood (PB) single cell transcriptomics of patients with untreated anti-LGI1 and anti-CASPR2 autoimmune encephalitis demonstrated CSF specific expansion of autoantigen-specific plasma cell clones and systemic loss of invariant mucosa-associated T-cells (MAIT).

neuroscience↗