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Proc Natl Acad Sci U S A. 2026 Mar 31;123(13):e2514753123. doi: 10.1073/pnas.2514753123. Epub 2026 Mar 25.

ABSTRACT

The immunopathogenesis of autoimmune neurological syndromes (AINS) with antibodies against the 65 kDa isoform of glutamic acid decarboxylase (anti-GAD65 AINS) remains poorly understood. To elucidate underlying disease mechanisms and identify relevant cell populations, we performed single-cell RNA and immune repertoire sequencing of cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) of eight anti-GAD65 AINS individuals compared to eight noninflammatory controls. In addition, PBMCs from 19 anti-GAD65 AINS individuals and 20 healthy controls were analyzed by multidimensional flow cytometry, and brain tissue specimens from four anti-GAD65 AINS individuals were examined histologically. We detected higher frequencies of stem cell-like memory T cells (TSCM) within the PBMCs and a marked enrichment and clonal expansion of activated CD4+ TSCM in the CSF of anti-GAD65 AINS individuals. Expanded T cells exhibited increased expression of proinflammatory genes. Histological analyses confirmed intraparenchymal CD8+ TSCM in three of four anti-GAD65 AINS individuals and rare meningeal/intraparenchymal CD4+ TSCM in one person. Although CSF B cell receptors (BCRs) displayed little to no clonal expansion, recombinant expression of 40 CSF BCRs revealed that 25% were GAD65-reactive with increased somatic hypermutations compared to non-GAD65-reactive BCRs. These findings further support the concept of an antigen-specific intrathecal immune response. In summary, we characterize the immune landscape of anti-GAD65 AINS at single-cell resolution and identify clonally expanded TSCM with cytotoxic properties as a hallmark of this disease.

PMID:41880578 | DOI:10.1073/pnas.2514753123


Source: https://pubmed.ncbi.nlm.nih.gov/4188057 ... t6+133c1fe