Cytotoxic CD8+ T cells may be drivers of tissue destruction in Sjögren’s syndrome

Abstract

Sjögren’s syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren’s syndrome were undertaken, including the quantitation of the frequency of selected cell–cell interactions in the disease milieu. Quantitative analyses of CD4+ T cell subsets and of CD8+ T cells in the labial salivary glands from untreated patients with primary Sjögren’s syndrome revealed that activated CD8+ cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+ T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren’s syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

“…The greater Th1 and Th2 signatures in SGs of Stim1/2 Foxp3 mice compared to their Cre-negative controls are consistent with altered Th1 and Th2 cytokine levels reported in patients with SjD 44,[54][55][56][57][58][64][65][66] .…”

Immune dysregulation in immunoglobulin G4–related disease

“…Increased proportions of HLA-DR + CD8 + T cells were associated with higher disease severity [55] , [56] . Recently, Kaneko et al, reported that infiltrating CD8 + CTLs might induce ductal apoptotic cell death in tissues of patients with Sjogren syndrome [57] . In contrast, we recently reported that infiltrating CD4 + CTLs and CD8 + CTLs might induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin by using scRNA-seq techniques [39] .…”

Single-cell transcriptomics reveals a pivotal role of DOCK2 in Sjögren’s disease

“…Furthermore, it has been observed that transferring Th17 cells in IL-17 deficient mice restores the SjD disease phenotype, highlighting the key role of Th17 cells in the inflammatory cascade and subsequent disease progression 18 . Recent studies have also highlighted the role of CD8 + T cells within the labial salivary gland infiltrates in SjD patients 19,20 .…”

“…These cells tend to localize with salivary duct epithelial cells and acinar cells, and their depletion protects against the disease's pathological manifestations 20 .…”