Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
A hallmark feature of primary Sjögren’s syndrome (pSS) is B cell hyperactivity, including presence of autoantibodies, aberrant presence of B cells and plasma cells in the salivary glands, elevated serum IgG levels and increased risk of lymphoma development. The mTOR pathway is essential for cell growth, survival and proliferation of B cells and mTOR inhibition has been shown to be effective in immune B cell suppression in transplant patients and in treatment of B cell lymphomas. Interestingly, in a murine pSS model mTOR targeting inhibited lymphocytic infiltration in the lacrimal gland. However, mTOR activation in B cells has not been studied in pSS patients.
Methods: The expression of mTOR pathway related genes (MTOR, RPTOR, RICTOR, DEPTOR, AKT1, IGF1R, IGF1, PTEN) was measured in purified peripheral blood B cells and monocytes from pSS patients (n=12), non-Sjögren’s sicca patients (n=17) and healthy controls (HC, n=9). Gene expression was scrutinized for correlation with clinical parameters (lymphocytic focus scores (LFS), anti-SSA/SSB auto-antibodies, EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), serum IgG levels, ESR), as well as correlation with B cell subset distribution, utilizing Flow Cytometry. Next, culture experiments were performed to study inhibition of the mTORC1 pathway by rapamycin (phosphorylated S6, kinase activity downstream of mTORC1) and its effect on of B cell proliferation and IgG production by mTOR inhibition. Immunofluorescence was performed on pSS salivary gland tissue using colocalizing CD20 and pS6.
Results: RPTOR and IGF1R expression were significantly increased in B cells from pSS patients (p=0.019 and p=0.018, respectively) and correlate with serum IgG levels (r=0.429, p=0.020, and r=0.462, p=0.012). We did not observe a significant difference in monocytes. To better gauge the combined upregulation of mTOR related genes, we calculated a combined index statistic to indicate an mTOR signature. This signature was significantly elevated in pSS (p=0.027), correlating with serum IgG levels (r=0.463, p=0.011). Frequencies of memory and naïve B cells did not differ between pSS and HC in this cohort. Activation of B cells in culture resulted in phosphorylation of S6, B cell proliferation and IgG production in both HC and pSS. In the salivary glands of pSS patients immunofluorescent colocalization showed presence of large percentages of B cells with mTORC1 activity (pS6) at the lymphocytic loci. Inhibition of mTOR by rapamycin reduced B cell proliferation (80.8±9.9 vs 19.1±15.8%, p<0.001), IgG+ B cells (39.5±15.5 vs 11.1±5.7%, p=0.001) and IgG production (800.0±321.8 vs 37.9±70.4 ng/mL, p=0.0014).
The increased mTORC1 signature in peripheral and salivary gland B cells from pSS patients correlates with B cell hyperactivity and IgG levels and can be targeted by rapamycin in vitro, representing a novel potential therapeutic strategy for pSS.
To cite this abstract in AMA style:Blokland SLM, Hillen MR, Kommer-Wichers RGK, Kruize AA, Radstake TRDJ, Broen JCA, van Roon JAG. Elevated mTORC1 Signature in B Cells from Sjögren’s Syndrome Patients: mTOR Inhibition As a Novel Therapeutic Strategy to Halt B Cell Hyperactivity [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/elevated-mtorc1-signature-in-b-cells-from-sjogrens-syndrome-patients-mtor-inhibition-as-a-novel-therapeutic-strategy-to-halt-b-cell-hyperactivity/. Accessed August 10, 2020.
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