Background/Purpose: Neuroinflammation is a severe manifestation of the systemic inflammatory disorders. Sarcoidosis, which leads to neurologic disease in 5-10 % of cases, has traditionally been thought to be driven by CD4 T cells. However, this model has been inferred by studies in pulmonary disease and has not been directly evaluated in the central nervous system (CNS). Here, we evaluated T and B cell clonal expansion in neurosarcoidosis to identify putative antigen-driven T or B cell responses.

Methods: We performed single-cell RNA-sequencing to obtain an unbiased gene expression survey of cerebral spinal fluid (CSF) and blood immune cells in participants with neurosarcoidosis and controls. This analysis allowed quantification, cell type identification, and transcriptional profiling of individual lymphocytes within the inflamed CNS as compared to cells in circulation, along with T cell receptor and B cell receptor sequencing to determine clonotype distribution.

Results: The plurality of CSF cells were CD4 T cells followed by CD8 T cells, with smaller and variable contributions of B cells, NK cells, and myeloid cells. Unexpectedly, B and T cell receptor sequencing revealed robust CD8 T cell clonal expansion specific to the CSF in neurosarcoidosis participants, with minimal CD4 T and B cell clonality. These CSF-specific CD8 T cells expressed higher levels of CD27 and granzyme K and lower levels of CX3CR1, granzyme B, and granulysin, consistent with reduced cytotoxicity and similar to CD8 T cells seen in uveitis and rheumatoid arthritis. Finally, a core transcriptional signature of CSF-specific CD8 T cells was predominantly composed of interferon-stimulated genes, suggestive of a potential therapeutic target.

Conclusion: These data suggest that neurosarcoidosis may be driven by clonally expanded CD8 T cells that mediate inflammation not via direct cytotoxicity but rather through pro-inflammatory cytokines. As inhibition of interferon signaling with JAK inhibitors has been efficacious in published cases of cutaneous and pulmonary sarcoidosis, this strategy may also be effective in patients with neurologic disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/csf-specific-cd8-t-cell-clonal-expansion-in-neurosarcoidosis/