Targeted Therapy for Severe Sjogren's Syndrome: A Focus on Mesenchymal Stem Cells

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by the infiltration of lymphocytes on salivary and lacrimal glands, resulting in their dysfunction. Patients suffering from severe pSS have an increased risk of developing multi-organ dysfunction syndrome due to the development of systemic inflammatory response, which results in immune cell-driven injury of the lungs, kidneys, liver, and brain. Therapeutic agents that are used for the treatment of severe pSS encounter various limitations and challenges that can impact their effectiveness. Accordingly, there is a need for targeted, personalized therapy that could address the underlying detrimental immune response while minimizing side effects. Results obtained in a large number of recently published studies have demonstrated the therapeutic efficacy of mesenchymal stem cells (MSCs) in the treatment of severe pSS. MSCs, in a juxtacrine and paracrine manner, suppressed the generation of inflammatory Th1 and Th17 lymphocytes, induced the expansion of immunosuppressive cells, impaired the cross-talk between auto-reactive T and B cells, and prevented the synthesis and secretion of auto-antibodies. Additionally, MSC-derived growth and trophic factors promoted survival and prevented apoptosis of injured cells in inflamed lacrimal and salivary glands, thereby enhancing their repair and regeneration. In this review article, we summarized current knowledge about the molecular mechanisms that are responsible for the beneficial effects of MSCs in the suppression of immune cell-driven injury of exocrine glands and vital organs, paving the way for a better understanding of their therapeutic potential in the targeted therapy of severe pSS.

Keywords: autoimmune response; immunosuppression; mesenchymal stem cells; primary Sjögren’s syndrome; targeted therapy.

Figure 1

The effects of MSC-derived immunomodulatory and growth factors on survival, migration, phenotype and function of immune cells and parenchymal cells in inflamed and injured lacrimal and salivary glands. MSC-derived HGF, TGF-β, IGF and bGFGF bind to their receptors on injured cells of the ocular surface, salivary and lacrimal glands, activate PI3K kinase which produces PIP3 that induces activation of Akt kinase. Akt then phosphorylates and inhibits pro-apoptotic factors Bad, FOXO, and ASK1, thereby preventing apoptosis of injured cells in the corneas, salivary and lacrimal glands. When MSC-derived IL-1Ra binds to IL-1R on endothelial cells of lacrimal and salivary glands, it blocks the interaction of IL-1β with IL-1R. Similarly, MSC-sourced sTNFR prevents TNF-α from binding to its receptor on endothelial cells. In this way, MSC-derived IL-1Ra and sTNFR reduce influx of circulating leucocytes in inflamed lacrimal and salivary glands of pSS patients. MSC-derived TGF-β prevents proliferation and expansion of inflammatory, IFN-γ-producing Th1 and IL-17-producing Th17 cells by inhibiting Jak-Stat signaling pathway, causing cell cycle arrest in these inflammatory cells. MSC-derived IL-10 promotes the development of tolerogenic DCs which support differentiation of naïve CD4+ T cells into immunosuppressive FoxP3+ Tregs. MSC-sourced IDO prevents transdifferentiation of Tregs in Th17 cells and increases Tregs/Th17 cell ratio in inflamed and injured lacrimal and salivary glands, crucially contributing to the creation of immunosuppressive environment. MSC-sourced pro-angiogenic factors (VEGF, angiopoietin, HGF, bFGF, PDGF) promote survival and proliferation of endothelial cells, increase blood flow and provide nutrients for enhanced regeneration of injured cells in the corneas, salivary and lacrimal glands.

Figure 2

Molecular mechanisms responsible for the suppression of T:B cell cross-talk in inflamed glandular tissues. MSCs induce programmed cell death of rapidly proliferating lymphocytes in PD-L1 and Fas-dependent manner, reduce production of IFN-γ in activated Th1 cells, prevent IFN-γ-dependent synthesis of auto-reactive IgG in B cells and favored expression of FoxP3 in naïve T cells, enabling generation and expansion of immunosuppressive Tregs. MSCs, in PD-L1-dependent manner, prevent differentiation of naïve CD4+T cells in follicular T cells. By delivering IL-6, MSCs activate the Jak2/Stat3 pathway in MDSCs which led to the enhanced production of Arginase-1, NO and ROS. These mediators induce oxidative stress of inflammatory T cells and reduce their number in lachrymal and salivary glands. MSC-sourced miR-125b inhibits expansion of CD19+CD20-CD27+CD38+ plasma cells and reduces production of autoantibodies, attenuating antibody-dependent pathological changes in the inflamed salivary and lacrimal glands.