Tuft cells contribute to the pathogenesis of human primary and experimental murine Sjögren's disease

Tuft cells (TCs) activate type II immunity by interleukin-25 (IL-25) and stimulate proliferation and mucus secretion of goblet cells to defense worms. TCs have been identified in the striated ducts of submandibular glands. Sjögren's disease (SjD) has been linked to type II immunity, with increased IL-25 expression, yet the role of TCs in this context remains and their association with SjD and contribution to IL-25 production are unknown. Labial gland biopsies from SjD patients and patients with labial gland cysts were collected for histological staining. Immunofluorescence was employed to detect the expression and localization of DCLK1, KRT19, and IL-25. C57BL/10 mice and NOD.B10 mice were selected to measure salivary flow rate. RT-qPCR was used to detect the gene expression of POU2F3, DCLK1, and IL-25 in the submandibular glands. DCLK1-positive TCs were detected in labial gland from SjD patients and the submandibular glands of NOD.B10 mice. DCLK1 and IL-25 proteins were strongly expressed in striated ducts adjacent to lymphoid foci in both SjD patient and NOD.B10 mice, showing a positive correlation with the degree of lymphoid infiltration and ductal dilation with colocalization. TC markers, including DCLK1 and POU2F3 were significantly upregulated, concomitant with reduced salivary flow and increased lymphoid infiltration. TCs are closely associated with salivary gland pathology and lymphoid infiltration in SjD. TCs-derived IL-25 implies their involvement in the pathological process of SjD. This work underscores the promise of TCs as a promising target for both understanding and treating SjD pathogenesis.