Primary Sjogren's syndrome (pSS) is a systemic chronic inflammatory autoimmune disease characterized by dry eyes and dry mouth. Essential histopathologic features of pSS include focal infiltrations of T and B cells in the salivary and lacrimal glands that lead to tissue injury and chronic inflammation. In some cases, the histopathologic changes develop into tertiary lymphoid tissues or organs (TLs) via a process called lymphoid neogenesis. TLOs resemble spleen and lymph nodes in their cellular composition and organization. TLOs may serve as a place where recruitment of T cells with lymphoid homing capacity (naive and central memory cells) as well as their activation, proliferation and differentiation occur. CD4+ T cells that orchestrate immune responses can be divided into T-helper (Th)1, Th2 and Th17 cells as well as CD4+ T cells with regulatory function including forkhead box P3 (FOXP3)-positive regulatory T cells (Treg). Although T cells and their cytokines are found in the salivary tissues of pSS, it is unknown which type of T cells has a leading role in the pathogenesis. This project investigates the hypothesis that patients with pSS have an altered balance of Th17 and Treg immune responses that is caused by chronic inflammation with lymphoid neogenesis and defect(s) in differentiating and functioning of Th17 cells and Treg based on the facts that Th17 cells potently induce inflammation while Treg suppress it. Plus, the both cell types are linked with autoimmunity and have a reciprocal relationship in cellular differentiation under inflammatory milieu. The hypothesis will be addressed with: 1) Aim 1. Determine if the TLOs in pSS could serve as sites of antigen presentation for induction of autoantibodies, tolerance or activation, focusing on Treg and Th17 cells;2) Aim 2. Determine if patients with pSS have an altered balance of Th17 and Treg immune responses in the peripheral blood secondary to a defect(s) in Th17 cells and Treg differentiation and function;and 3) Aim 3. Determine if the altered balance of Th17 and Treg immune responses in peripheral blood correlates with TLOs in the fresh minor salivary tissues in patients with pSS. These studies will shed new light on the pathogenesis and treatment of autoimmune diseases including pSS.
Primary Sjogren's syndrome (pSS) is a chronic inflammatory autoimmune disease characterized by dry eyes and dry mouth. This proposal investigates roles for T cells (type of immune cells) and specialized tissues called tertiary lymphoid organs (TLOs) developed in the presence of chronic inflammation in pSS. These studies will shed new light on the pathogenesis and treatment of pSS and other autoimmune diseases.
|Gies, Vincent; Schickel, Jean-Nicolas; Jung, Sophie et al. (2018) Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus. JCI Insight 3:|
|Glauzy, Salomé; Boccitto, Marco; Bannock, Jason M et al. (2018) Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21-/low B Cells From Patients With Sjögren's Syndrome. Arthritis Rheumatol 70:298-307|
|Schickel, Jean-Nicolas; Glauzy, Salomé; Ng, Yen-Shing et al. (2017) Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria. J Exp Med 214:1991-2003|
|Glauzy, Salomé; Sng, Joel; Bannock, Jason M et al. (2017) Defective Early B Cell Tolerance Checkpoints in Sjögren's Syndrome Patients. Arthritis Rheumatol 69:2203-2208|
|Cantaert, Tineke; Schickel, Jean-Nicolas; Bannock, Jason M et al. (2016) Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint. J Clin Invest 126:4289-4302|
|Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler et al. (2016) Rituximab does not reset defective early B cell tolerance checkpoints. J Clin Invest 126:282-7|
|Morbach, Henner; Schickel, Jean-Nicolas; Cunningham-Rundles, Charlotte et al. (2016) CD19 controls Toll-like receptor 9 responses in human B cells. J Allergy Clin Immunol 137:889-98.e6|
|Tooley, James E; Vudattu, Nalini; Choi, Jinmyung et al. (2016) Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol 46:230-41|
|Cantaert, Tineke; Schickel, Jean-Nicolas; Bannock, Jason M et al. (2015) Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance. Immunity 43:884-95|
|McHugh, Michael D; Park, Jason; Uhrich, Ross et al. (2015) Paracrine co-delivery of TGF-? and IL-2 using CD4-targeted nanoparticles for induction and maintenance of regulatory T cells. Biomaterials 59:172-81|
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