AB0178 TRANSCRIPTION PROFILING OF PERIPHERAL B CELLS IN ANTIBODY-POSITIVE PRIMARY SJOGREN’S SYNDROME REVEALS INTERFERON SIGNATURE AND UPREGULATED EXPRESSION OF GENES WHICH MAY BE PREDICTIVE OF TRANSFORMATION TO LYMPHOMA AND CORRELATED TO CHRONIC PULMONARY NON-TUBERCULOUS MYCOBACTERIAL (NTM) INFECTION
Authors: Mehrnaz Maleki-Fischbach, Fatjon Leti, Brian O’connor, Tasha Fingerlin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Primary Sjögren's syndrome (pSS) is the second most common systemic autoimmune disease (after RA), with a prevalence of about 0.5% in the general population and it occurs primarily in women at a ratio of women to men of 9:1. Key features of the disease include infiltration of salivary and lacrimal glands by lymphocytes, production of inflammatory cytokines, and the production of autoantibodies. Nevertheless, systemic manifestations can arise in a proportion of pSS with pulmonary manifestation and higher incidence of NTM infection. Also, B-cell non-Hodgkin lymphoma (NHL) development represents a severe complication, afflicting approximately 5% of patients. The risk of NHL occurrence in the setting of pSS, has been previously estimated to be 7-19 fold higher than the general population. B activation is one of the proposed hypotheses, that accord with the known biological findings, including hypergammagolubinemia, presence of autoantibodies including SSA/Ro60/TROVE2, SSA/Ro52/TRIM21 and SSB/La48. <h3>Objectives:</h3> B cells play a key role in the pathogenesis of pSS. The aim of this study was to analyze the transcriptome of B cells from patients with pSS and healthy controls to decipher the B cell-specific contribution to pSS. <h3>Methods:</h3> RNA of negatively selected B cells from 5 ANA, SSA (both Ro60 and Ro 52), SSB and rheumatoid factor positive untreated female patients with pSS and 5 healthy controls was subjected to whole transcriptome sequencing. A false discovery rate corrected significance threshold of a &lt; 0.1 was applied to define differential gene expression. <h3>Results:</h3> RNA-sequencing identified 56 and 23 up and down differentially expressed genes, respectively, and hierarchal clustering showed a clear separation between the two groups. Ingenuity Pathway Analysis revealed that these genes may play a role in interferon signaling (IFIT3, IFIT1, OAS1, MX1, STAT2, IFI35, IFITM1, ISG15, IFI27, IFI44L, IFI44, and PARP9), chronic mycobacterial infection (IFI35,IFI44,IFI44L,IFIT1,IFIT3,IFITM1,MX1,OAS1,OAS2,OAS3,STAT2) and transformation to myeloproliferative disorders, especially B cell lymphomas (CD160, CD38, ENAM, FUT4, GADD45B, IFI35, IFI44, IFI44L, IFIT3, IFITM1, ISG15, JCHAIN, MX1, OAS1, OAS2, OASL, RGS16, RNF213, RSAD2, SARS2, SATB1, SMAD7, and STAT2). <h3>Conclusion:</h3> Upregulated expression of type I and type II interferon (IFN)-induced genes was observed, establishing an IFN signature in pSS B cells. There are also genes that may play a role in other concomitant conditions like mycobacterial/NTM infection and higher risk for developing myeloproliferative conditions. This adds insight into the autoimmune process and suggests potential targets for future functional and prognostic studies. <h3>References</h3> [1] Gottenberg, J.-E. Et al. Serum levels of β2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren's syndrome. PLoS ONE2013 [2] Schulte-Pelkum J., Fritzler M., and Mahler M.: Latest update on the Ro/SS-A autoantibody system. Autoimmun Rev2009 [3] Song J.S., Do J.H., and Lee S.W.: The prevalence and the clinical relevance of anti-Ro52 in Korean patients with primary Sjogren's syndrome. Rheumatol Int2011 [4] Salomonsson S, Jonsson MV, Skarstein K, et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum. 2003 [5] Imgenberg-Kreuz J, AC, Nordmark G, et al. Transcription profiling of peripheral B cells in antibody-positive primary Sjögren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature. Scand J Immunol. 2018 <h3>Acknowledgement:</h3> Center for Genes,Environment and Health Ms. Kendra Walton <h3>Disclosure of Interests:</h3> None declared