JAK/STAT pathway targeting in primary Sjögren syndrome

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease mainly affecting exocrine glands and resulting in disabling symptoms, as dry eye and dry mouth. Mechanisms underlying pSS pathogenesis are intricate, involving multiplanar and, at the same time, interlinked levels, e.g., genetic predisposition, epigenetic modifications and the dysregulation of both immune system and glandular-resident cellular pathways, mainly salivary gland epithelial cells. Unravelling the biological and molecular complexity of pSS is still a great challenge but much progress has been made in recent years in basic and translational research field, allowing the identification of potential novel targets for therapy development. Despite such promising novelties, however, none therapy has been specifically approved for pSS treatment until now. In recent years, growing evidence has supported the modulation of Janus kinases (JAK) - signal transducers and activators of transcription (STAT) pathways as treatment strategy immune mediated diseases. JAK-STAT pathway plays a crucial role in autoimmunity and systemic inflammation, being involved in signal pathways of many cytokines. This review aims to report the state-of-the-art about the role of JAK-STAT pathway in pSS, with particular focus on available research and clinical data regarding the use of JAK inhibitors in pSS.

An Overview of the Dry Eye Disease in Sjögren’s Syndrome Using Our Current Molecular Understanding

“…The pro-inflammatory cytokine IL-6 was shown to be increased in the biological fluids of pSS patients and mediate its pathogenesis through the modulation of B and T cell differentiation and activation. Similarly, IL-21 and IL-23 are involved in the activation of B cells as well as in the generation of IL-17-secreting T cells (Th17 cells) [ 37 ]. IL-23 is also involved in the expansion of innate lymphoid cells (ILC), which mainly produce IL-17, thus enhancing the vicious cycle of inflammation.…”

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren's syndrome

“…[107][108][109][110][111][112][113][114][115] Due to the important role of JAK-STAT pathway in the pathogenesis of pSS and the success of Jakinibs for the treatment of RA and SLE, Jakinibs seem to be promising therapies for pSS patients. [101,116] At the cell level, JAK1/2 inhibitors can suppress JAK-STAT pathway activated by IFNa/g or H 2 O 2 . This suppression subsequently inhibits downstream effects, including the increase in aberrant DNA epigenetic reprograming, [77] high expression of tissue-type plasminogen activator, [97] and CXCL10 expression.…”

“…Though a recent phase-2b clinical trial of ianalumab (VAY736) reported efficacy, clinical trials of other biologic DMARDs (e.g., rituximab, belimumab, and abatacept) had conflicting clinical results in pSS patients [107–115] . Due to the important role of JAK-STAT pathway in the pathogenesis of pSS and the success of Jakinibs for the treatment of RA and SLE, Jakinibs seem to be promising therapies for pSS patients [101,116] . At the cell level, JAK1/2 inhibitors can suppress JAK-STAT pathway activated by IFNα/γ or H 2 O 2 .…”

Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren’s disease

“…Many of the inflammatory cytokines implicated in SjD pathogenesis, in particular type-I and type-II interferons (IFNs), interleukins (IL)-6, IL-7, IL-12 and IL-21, signal through the Janus kinases (JAKs)–signal transducer and activator of transcription (STAT) pathway 12. Previous reports have tried to investigate the role of IFN signalling and involvement of JAK-STAT pathway in SjD using various organoids and mouse models13–16; however, a comprehensive understanding of this pathway in SjD patients’ tissues using multimodal methodologies is still required.…”