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Review
. 2023 Jul 6;24(13):11179.
doi: 10.3390/ijms241311179.

Outline of Salivary Gland Pathogenesis of Sjögren's Syndrome and Current Therapeutic Approaches

Yoshiaki Yura  1 , Masakazu Hamada  1
Affiliations
Review

Outline of Salivary Gland Pathogenesis of Sjögren's Syndrome and Current Therapeutic Approaches

Yoshiaki Yura et al. Int J Mol Sci. .

Abstract

Sjögren's syndrome (SS) is an autoimmune disease characterized by the involvement of exocrine glands such as the salivary and lacrimal glands. The minor salivary glands, from which tissue samples may be obtained, are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of SS. In the onset of SS, autoantigens derived from the salivary glands are recognized by antigen-presenting dendritic cells, leading to the activation of T and B cells, cytokine production, autoantibody production by plasma cells, the formation of ectopic germinal centers, and the destruction of salivary gland epithelial cells. A recent therapeutic approach with immune checkpoint inhibitors for malignant tumors enhances the anti-tumor activity of cytotoxic effector T cells, but also induces SS-like autoimmune disease as an adverse event. In the treatment of xerostomia, muscarinic agonists and salivary gland duct cleansing procedure, as well as sialendoscopy, are expected to ameliorate symptoms. Clinical trials on biological therapy to attenuate the hyperresponsiveness of B cells in SS patients with systemic organ involvement have progressed. The efficacy of treatment with mesenchymal stem cells and chimeric antigen receptor T cells for SS has also been investigated. In this review, we will provide an overview of the pathogenesis of salivary gland lesions and recent trends in therapeutic approaches for SS.

Keywords: Sjögren’s syndrome; biological therapy; immune checkpoint inhibitor; monoclonal antibody; muscarinic agonist; pathogenesis; salivary gland; sialendoscopy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Changes in salivary gland histology with SS. The salivary gland acinus is composed of acinar cells and surrounding myoepithelial cells. Excretory ducts are further divided into intercalated ducts, striated ducts, and terminal excretory ducts (A). In the intercalated ducts, myoepithelial cells surround the ductal cells that form the lumen. The histological changes in the salivary glands in SS are dense periductal cellular infiltration and the loss of acinar cells (B1,B2). eGCs are formed in the salivary glands as a site for autoantibody production (C). Lymphoepithelial lesions consist of the hyperplasia of basal cells of the striated ducts and infiltrating lymphocytes surrounded by B cells (D). SG, salivary gland; eGC, ectopic germinal center.
Figure 2
Figure 2
Proposed model of antigen uptake in salivary glands and autoreactive T cell differentiation in lymph nodes. Damage to salivary gland epithelial cells by viral infection releases autoantigens extracellularly, leading to their exposition to the immune system. Among these autoantigens, anti-viral antibodies react to a soluble autoantigen that has a common epitope with a specific viral antigen. Immune complexes formed by this reaction bind to the FcR of cDC and are taken up intracellularly. cDC may cross-present autoantigens in an MHC I-restricted manner to naive CD8+ T cells, resulting in their differentiation to CD8+ effector T cells (CD8+ CTL). On the other hand, MHC II-restricted antigen presentation from cDC causes naive CD4+ T cells to differentiate into Th1 cells, Th2 cells, Th17 cells, Treg, and Tfh cells. pDC recognizes self-nucleic acids as well as viral RNA and DNA through TRLs and produce type I IFNs. SG, salivary gland, EC, epithelial cell, TLR, Toll-like receptor; cDC, conventional DC; pDC, plasmacytoid DC; LN, lymph node; TCR, T cell receptor.
Figure 3
Figure 3
Epithelial cell damage by CD8+ T cells, CD4+ T cells, and cytokines in salivary glands. CD8+ CTLs recognize autoantigens presented by MHC I on salivary gland epithelial cells and destroy these cells by IFN-γ, TNF-α, and granzyme/perforin. The binding of FasL on CTLs to FAS or the binding of TNF-α to TNF receptors induces cell death. Since salivary gland cells are induced to express MHC II by Th1 cell-derived IFN-γ, they may become the target of CD4+ CTLs. Th1 produces IL-2, IFN-γ, and macrophage colony stimulating factor (M-CSF); Th2 produce IL-4, IL-5, BAFF, and mast cell growth factor (MCGF); Th17 cells produces IL-17 and IL-22; Tfh secretes IL-21 and contributes to B cell maturation. The expression of lytic cycle proteins due to EBV reactivation contributes to B cell immune evasion and proliferation. PD-1 on CTLs binds to PD-L1 on salivary gland cells and acts as a brake against T-cell-induced damage. SG, salivary gland; EC, epithelial cell; TCR, T cell receptor; pDC, plasmacytoid DC; PC, plasma cell; GC, germinal center.
Figure 4
Figure 4
Proposed model of epitope spreading in lymph nodes and salivary glands eGCs. As described in Figure 2, autoantibodies against an autoantigen that shares a common epitope with a specific viral antigen are produced. B cells incorporate autoantigen A through BCR and present the second epitope of autoantigen A to Tfh. If there is a Tfh cell that recognizes this epitope, B cells differentiate into plasma cells and produce an antibody against autoantigen B with the second epitope. This epitope spreading process targeting additional autoepitopes will lead to the development of autoimmune diseases. The autoantigens reported to date in SS patients are shown on the right side of the figure. LN, lymph node; eGC, ectopic germinal center; PC, plasma cell; BCR, B cell receptor; TCR, T cell receptor; AQP5, aquaporin-5; CA6, carbonic anhydrase 6; CENP, centromere protein; NA14, nuclear autoantigen 14 kDa; MDM2, mouse double minute 2; M3R, muscarinic acetylcholine receptor 3; PSP, parotid secretory protein; SP-1, salivary protein-1; SSA/Ro, Sjögren’s syndrome-related antigen A/Ro; SSB/La, Sjögren’s syndrome-related antigen B/La; TRIM38, tripartite motif-containing protein 38.
Figure 5
Figure 5
Biologic therapy for molecular targets in SS. Anti-B-cell agents include rituximab for CD20, epratuzumab for CD22, belimumab for BAFF, and ianalumab for BAFF receptors. Blockers of co-stimulation molecules include abatacept for CD80/86/CTLA4, iscalimab for CD40, and prezalumab for ICOSL. S1P/S1P1 modulators inhibit lymphocyte migration, because the release of lymphocytes from peripheral lymphoid organs into the circulation is mediated by the S1P receptor. MSCs decrease inflammatory responses by Th-17, and Tfh cells, and increase those of Tregs and Th2 cells. CART therapy targeting CD19 in B cells or BCMA in plasma cells. MSC, mesenchymal stem cell; S1P receptor, sphingosine-1-phosphate receptor; BAFFR, BAFF receptor; BCR, B cell receptor; TCR, T cell receptor; CART cell, chimeric antigen receptor T cell.
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References

    1. Jonsson R., Theander E., Sjöström B., Brokstad K., Henriksson G. Autoantibodies present before symptom onset in primary Sjögren syndrome. JAMA. 2013;310:1854–1855. doi: 10.1001/jama.2013.278448. - DOI - PubMed
    1. Risselada A.P., Looije M.F., Kruize A.A., Bijlsma J.W., van Roon J.A. The role of ectopic germinal centers in the immunopathology of primary Sjögren’s syndrome: A systematic review. Semin. Arthritis Rheum. 2013;42:368–376. doi: 10.1016/j.semarthrit.2012.07.003. - DOI - PubMed
    1. Brito-Zerón P., Baldini C., Bootsma H., Bowman S.J., Jonsson R., Mariette X., Sivils K., Theander E., Tzioufas A., Ramos-Casals M. Sjögren syndrome. Nat. Rev. Dis. Primers. 2016;2:16047. doi: 10.1038/nrdp.2016.47. - DOI - PubMed
    1. Shiboski C.H., Shiboski S.C., Seror R., Criswell L.A., Labetoulle M., Lietman T.M., Rasmussen A., Scofield H., Vitali C., Bowman S.J., et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol. 2017;69:35–45. doi: 10.1002/art.39859. - DOI - PMC - PubMed
    1. Mariette X., Criswell L.A. Primary Sjögren’s Syndrome. N. Engl. J. Med. 2018;378:931–939. doi: 10.1056/NEJMcp1702514. - DOI - PubMed

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