Background/Purpose: Sjӧgren’s disease (SjD) is characterized by persistent focal infiltration of B- and T lymphocytes in the exocrine gland, mainly salivary gland. Though it is well recognized that the infiltrating lymphocytes is the main cause that leads to gland dysfunction, the mechanisms in how lymphocytes are recruited and persistently activated in salivary gland have not been fully investigated.

Methods: We performed single-cell RNA-sequencing (scRNA-seq) combined with spatial transcriptomics on minor salivary glands (MSGs) from patients with SjD and controls. The crosstalk between stromal cells and immune cells was analyzed. Potential pathogenic cell subsets that may be involved in promoting lymphocytes infiltration were further investigated by ex vivo culture assays and SjD animal model.

Results: The scRNA-seq demonstrated that several cytokines that are important in recruiting and activating lymphocytes such as CXCL12 and BAFF were prominently enriched in fibroblasts, and spatial transcriptomics analysis revealed that fibroblasts were closely associated with lymphocytes. CD74 expression significantly increased in salivary fibroblasts in patients with SjD, and fibroblasts subcluster with high expression of CD74 expanded in patients with SjD, which was enriched in pathways associated with lymphocytes activation and cytokine production. In the in vitro co-culture assay of fibroblasts with B cells, fibroblasts with high expression of CD74 can promote B cell proliferation and survival, while CD74 knockout in fibroblasts diminished this effect. CD74 knockout in mice and anti-CD74 antibody can decrease lymphocytes infiltration in exocrine gland and alleviate the gland dysfunction.

Conclusion: Fibroblasts with high expression of CD74 was pathogenic fibroblasts subsets in SjD, which may be important in promoting lymphocytes infiltration in salivary gland. Targeting CD74 may provided new effective treatment strategy for SjD.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/fibroblasts-with-high-expression-of-cd74-promote-lymphocytes-infiltration-in-salivary-gland-in-sj%d3%a7grens-disease/