[Pathophysiological aspects of primary Sjögren's disease : From epithelial activation to systemic autoimmunity]

Primary Sjögren's disease (SjD) is a chronic autoimmune disease that predominantly affects exocrine glands but can also show numerous systemic organ manifestations.

Presentation of the current understanding of the pathogenesis of the disease, focusing on genetic predisposition, epithelial activation, interferon signature and the resulting B‑T cell interaction, which form the basis for innovative treatment approaches.

Selective literature review of current original articles, reviews and clinical studies.

Current research postulates that SjD triggers epithelial dysregulation through a combination of genetic and epigenetic predispositions, hormonal influences and possible viral triggers. This leads to the release of dsDNA, dsRNA or ssRNA, which in turn activate the innate immune system. Salivary gland epithelial cells (SGECs), plasmacytoid dendritic cells (pDCs), and monocytes produce proinflammatory cytokines and additional immune cells are recruited. The pDCs produce massive amounts of type I interferon. This results in the formation of an inflammatory microenvironment, which causes SGECs to undergo apoptosis, the release of further antigens and the recruitment of T cells. In this context, myeloid cells and SGECs produce large amounts of the cytokine B‑cell activating factor (BAFF). This promotes the further recruitment of B cells. Through Th1 cells and Tfh cells a T-B cell interaction is formed, leading to the development of ectopic germinal centers, including the induction of autoreactive B cells.

The pathophysiology of SjD is a multistage process in which the early activation of the salivary epithelium and subsequent activation of the innate immune system with IFN play a crucial role in its initiation. This is followed by activation of the adaptive immune system with a focus on T‑B cell interaction and pathological B cell activation. The chronic inflammation in SjD can be understood as positive feedback from the activation of the innate and adaptive immune systems, which innovative therapeutic approaches aim to interrupt. These comprise TLR and IFN blockade, inhibition of T‑B cell interaction via CD154/CD40 blockade (e.g., dazodalibep, iscalimab) or B cell depletion strategies including. anti-BAFF‑R and anti-CD19 CAR-T cells.