Axial spondyloarthritis (axial-SpA) is a multifactorial disease characterized by inflammation in sacroiliac joints and spine, bone reabsorption, and aberrant bone deposition, which may lead to ankylosis. Disease pathogenesis depends on genetic, immunological, mechanical, and bioenvironmental factors. HLA-B27 represents the most important genetic factor, although the disease may also develop in its absence. This MHC class I molecule has been deeply studied from a molecular point of view. Different theories, including the arthritogenic peptide, the unfolded protein response, and HLA-B27 homodimers formation, have been proposed to explain its role. From an immunological point of view, a complex interplay between the innate and adaptive immune system is involved in disease onset. Unlike other systemic autoimmune diseases, the innate immune system in axial-SpA has a crucial role marked by abnormal activity of innate immune cells, including γδ T cells, type 3 innate lymphoid cells, neutrophils, and mucosal-associated invariant T cells, at tissue-specific sites prone to the disease. On the other hand, a T cell adaptive response would seem involved in axial-SpA pathogenesis as emphasized by several studies focusing on TCR low clonal heterogeneity and clonal expansions as well as an interindividual sharing of CD4/8 T cell receptors. As a result of this immune dysregulation, several proinflammatory molecules are produced following the activation of tangled intracellular pathways involved in pathomechanisms of axial-SpA. This review aims to expand the current understanding of axial-SpA pathogenesis, pointing out novel molecular mechanisms leading to disease development and to further investigate potential therapeutic targets.
BackgroundThe Janus kinase (Jak) - signal transducer and activator of transcription (STAT) pathway has 4 Jak proteins and 7 STAT factors that mediate intracellular downstream of cytokine receptors. Targeted small-molecule therapies with different bond affinity to Jak proteins have been demonstrated effective in rheumatoid arthritis (RA) treatment, but the clinical significance of selective inhibition remains unclear.ObjectivesTo explore the effect of selective inhibition of Jak-STAT pathway in peripheral blood mononuclear cells (PBMC) from RA patients compared to healthy donors (HD).MethodsIn vitro Jak inhibition of the subunit 3 of phosphorylated (p) than activated STAT was measured by flow cytometry in peripheral blood mononuclear cells (PBMC) from RA patients with active disease (DAS28>5.1) naïve to any DMARDs (n.5) and HD (n.5), following recombinant human 0.1 ng/ml IL-6 (Peprotech – NJ, USA) stimulation. After blood separation, PBMC were overnight incubated with IC50 concentrations of selective Jak1-, Jak2-, Jak3- and Tyk2-inhibitors (Biovision Inc. – CA, USA) with or without IL-6 stimulation. Mean fold-increase of pSTAT3 was then compared in presence of different compounds stimulation.ResultsMean pSTAT3 activity after overnight incubation was significantly higher in RA patients compared to HD (37%; 95CI 8.2-56.7 vs 17.9%; 95CI 4.6-21 – p=0.01). After IL-6 stimulation, a 2-fold and a 1.4-fold increase in pSTAT3 levels was observed in PBMC from RA patients and HD, respectively. In unstimulated PBMC from HD Jak-inhibitors didn’t significantly reduced pSTAT3 activity. In CD14+ cells from RA patients, pSTAT3 activity was reduced with no differences between all four selective Jak-inhibitors, while in CD4+ cells only Jak1-inhibition was able to reduce by 40% pSTAT3 activity. After IL-6 stimulation, the co-culture with Jak1- or JaK3- selective inhibitors was able to significantly reduce pSTAT3 levels in CD4+ lymphocytes, by an average of 20%. While in CD14+ monocytes Jak1-, Jak2- and Jak3- selective inhibitors were able to reduce pSTAT3 activity by a mean of 30%. Tyk-2 selective inhibitor did not interfere with STAT3 activation by IL-6 stimulation of PBMC from RA patients and HD.ConclusionJak/STAT3 activity of PBMC from RA patients with active disease may be differently modulated by specific inhibitors. Selectivity of Jak-inhibitors seems more relevant in lymphocytes after IL-6 stimulation. These preliminary findings may explain discrepancies in effectiveness of selective Jak-inhibitors and pave the way for different choices in clinical practice.References[1]Tanaka Y, et al. Nat Rev Rheumatol. 2022 Jan 5:1–13.[2]Traves PG, et al. Ann Rheum Dis. 2021 Jul;80(7):865-875.[3]Choy EH. Rheumatology (Oxford). 2019 Jun 1;58(6):953-962.Disclosure of InterestsNone declared
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