Fig. 1

Multifactorial pathogenesis of primary Sjögren’s syndrome: interferons as culprits in the self-amplifying pathogenic loop. A damage trigger such as stress or infection leads to accumulating apoptotic debris, inducing rapid interferon (IFN) type I production by plasmacytoid dendritic cells (pDCs). IFN type I then binds to IFNα,β receptor (IFNAR) on adjacent target cells, which induces an IFN signature and IFN-primed mature effector cells, amongst others, by perpetuating the TLR7 pathway in autoreactive plasma cells as well as self-amplification in the pDCs. TLR7 upregulation in autoreactive plasma cells increases RNA-associated autoantibody production (SSA/Ro52, SSA/Ro60 and SSB/La). These RNA-associated autoantibodies form immune complexes together with self-apoptotic debris, further triggering the TLR7 pathway. Prolonged inflammation can lead to exhaustion of the complement system with decreased complement-mediated solubilisation and further accumulation of immune complexes. Neutrophils can cause further tissue damage by forming neutrophil extracellular traps, these netting neutrophils also being potent inducers of IFN type I production. Autoantibodies induce netting of IFN-primed neutrophils, further amplifying the loop. IFN-primed dendritic cells (DCs) activate T cells, as well as natural killer and natural killer T cells (data not shown), to produce vast amounts of IFN type II (IFNγ). Although TLRs are widely considered the usual suspects in autoimmune pathophysiology, recently the cytoplasmic RIG-I-like family of helicases (RLHs), RIG-I (DDX58) and MDA5 (IFIH1) have been gaining the spotlight as co-conspirators. Evidence points towards a collaborative effort between TLRs and RLHs, together enhancing inappropriate self-recognition and sustained IFN overactivation. IFIH1 upregulation has been identified in IFN-positive pDCs of primary Sjögren’s syndrome patients (unpublished data), as previously in glands of Sjögren’s syndrome-like (C57BL/6.NOD-Aec1Aec2) mice [61]. This IFN-driven pathogenic loop in primary Sjögren’s syndrome, in part driven by aberrant sensing of nucleic acids, can potentially lead to functional decline or even loss of function in target tissues. APRIL, a proliferation inducing ligand; BAFF, B-cell activating factor; IL, interleukin; MDA5, melanoma differentiation-associated protein 5; MHC, major histocompatibility complex; RIG-I, retinoic acid-inducible gene 1; Th17, T-helper type 17; TLR, Toll-like receptor; Treg, regulatory T cells