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OP0010 A MORE MATURE PLASMA CELL AND PLASMABLAST COMPARTMENT IS ASSOCIATED WITH DISEASE MANIFESTATION IN PRIMARY SJÖGREN’S SYNDROME

Sjögren’s syndrome (pSS) is an autoimmune disorder often associated with fatigue, dry eyes and dry mouth symptoms and characterized by chronic inflammation of moisture-producing glands like salivary and lacrimal glands (1). Auto-antibodies, B cell infiltration of affected glands and lymphoma development are signs for B cell hyperactivity in pSS (1-3). The B cell effector branch, namely antibody-secreting cells (ASC) like plasmablasts and plasma cells, can sustain autoimmune pathogenicity over long time periods by secretion of auto-antibodies (4,5).Since B cell hyperactivity is an important pathogenic feature in pSS, antibody-secreting cells as B effector cells are studied to characterize their abundance, maturation stage and inflammatory properties and relate them to pSS manifestations.Peripheral blood mononuclear cells (PBMC) from pSS patients and healthy individuals were subjected to spectral flow cytometry phenotyping. CD27+CD38++ ASCs were analyzed with a comprehensive tSNE approach as well as based on expression of ASC markers. This includes markers described for maturity like CD19, CD138, CD28, Blimp1 and HLA-DR and markers relevant for ASC survival like Mcl1 and BCMA. The pro-inflammatory status of the cells was assessed by CXCR3 and CXCR4 expression and their immune regulatory properties with markers like IL-10 and Lag-3. ASC properties like maturity state were correlated to characteristic pSS disease-associated features.Patients with pSS had higher frequencies and absolute numbers of ASCs then healthy controls. ASCs displayed a higher degree of maturation in pSS. ASC frequencies and their maturity state, for example reflected by CD19 down-regulation or increased CD28 expression (6), correlated with several pSS disease characteristics like ANA titers, focus scores and ocular scores indicating glandular impairment. Additionally, more mature ASCs that express low amounts of CD19 had increased Mcl1 levels indicating prolong survival of these cells. The maturation state of ASCs was associated with CXCR3+ ASC frequencies in pSS patients. Expression levels of anti-inflammatory IL-10 and pathogenic CXCR3 by ASCs in pSS patients was negatively correlated. tSNE related clusters enriched for ASCs from pSS patients were more mature but also had higher expression levels of CXCR3.Circulating ASCs in pSS are more abundant and have a more mature phenotype compared to healthy individuals. Their frequencies and degree of maturation could be linked to pSS disease features. Prolonged survival and pro-inflammatory status might further increase the impact of circulating ASCs on disease manifestations. Together these findings underpin the role of B cell hyperactivity in pSS, that culminates in an altered ASC compartment.Figure 1.(A) Frequencies and absolute numbers of antibody-secreting cells (ASC) are increased in pSS patients and (B) correlate with salivary gland focus scores. (C) More mature CD28+ ASCs are associated with focus scores and (D) higher pro-inflammatory levels of CXCR3.[1]Kroese FG, Abdulahad WH, Haacke E, Bos NA, Vissink A, Bootsma H. B-cell hyperactivity in primary Sjögren’s syndrome. Expert Rev Clin Immunol 2014.[2]Ihrler S, Zietz C, Sendelhofert A, Riederer A, Löhrs U. Lymphoepithelial duct lesions in Sjögren-type sialadenitis. Virchows Arch 1999.[3]Scheinfeld N. Sjögren syndrome and systemic lupus erythematosus are distinct conditions. Dermatol Online J 2006.[4]Schuh W, Mielenz D, Jäck H-M. Unraveling the mysteries of plasma cells. Advances in Immunology.Vol 146. Elsevier; 2020.[5]Hiepe F, Dörner T, Hauser AE, Hoyer BF, Mei H, Radbruch A. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 2011.[6]Mei, H.E., I. Wirries, D. Frölich, M. Brisslert, C. Giesecke, J.R. Grün, T. Alexander, S. Schmidt, K. Luda, A.A. Kühl, et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood 2015.None declared.