Characterize and unravel the phenotype of plasma cells in primary Sjögren Syndrome

• Applicant: Dr. Tobit Steinmetz
• Subject Area: Clinical Immunology and Allergology ; Immunology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456067883

Autoimmune disorders are amongst the most common diseases and characterized by a break of tolerance within the immune system leading to its activation against self. Primary Sjögren Syndrome (pSS) typically affects salivary and lacrimal glands, resulting in lymphatic infiltration and tissue destruction. Another main complication of pSS are autoantibodies directed against gland specific antigens. The corresponding plasma cells can be found in the inflamed glands in elevated numbers with shifted isotype frequencies towards IgG. However, little is known about these gland residing plasma cells. As Rituximab treatment does not alter the long term autoantibody pool and CXCL12 and IL-6 producing cells are discovered in close vicinity to glandular plasma cells, the presence of bone marrow-like plasma cell survival niches is likely but remains unexplored in pSS. We hypothesize that besides ectopic germinal centers also plasma cell survival niches are present within secretory glands of pSS patients enabling the long term secretion of autoantibodies and immune regulatory cytokines by phenotypically distinct plasma cells. As a result we expect to find different subsets of plasma cells in pSS than in healthy individuals that are located in bone marrow-like survival niches.This prediction will be addressed by three independent aims. First, the phenotype of plasma cells in diagnostic material of pSS patients and healthy controls will be analyzed via quantification of plasma cell subsets for surface, intracellular and secretory markers and single cell sequencing to unravel their function. Second, putative long-term plasma cell survival niches within exocrine glands of pSS patients will be identified by staining for corresponding receptor/ligand pairs described to be relevant in other plasma cell niches like the bone marrow. Third, the effect of immuno-modulatory treatment during a clinical trial on plasma cells in pSS patients with special focus on pro- and anti-inflammatory functions will be used to investigate a correlation of the clinical outcome with plasma cell functions in pSS. This will be additionally addressed in an in vitro cell culturing system.Research on comparable diseases like SLE has shown important contributions of plasma cells on autoimmune disease progression. This proposed project aims to phenotype the plasma cell subsets in exocrine glands of pSS in detail, to address whether they reside in survival niches and to shed light on their disease contribution. Accordingly, we assume that these findings help to improve disease treatment, following its progression or diagnosis of primary Sjögren Syndrome.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Host: Professor Dr. Frans Kroese