Michael Mingueneau1, Saida Boudaoud2, Scott Haskett3, Taylor L Reynolds3, Gaetane Nocturne4, Elizabeth Norton3, Xueli Zhang3, Myrtha Constant3, Daniel Park3, Wenting Wang3, Thierry Lazure4, Christine Le Pajolec5, Ayla Ergun3, Xavier Mariette4. 1. Immunology Research, Biogen, Cambridge, Mass. Electronic address: michael.mingueneau@biogen.com. 2. Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, France; INSERM, U1184, Center for immunology of viral infections and autoimmune diseases, Le Kremlin-Bicêtre, France. 3. Immunology Research, Biogen, Cambridge, Mass. 4. Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, France; INSERM, U1184, Center for immunology of viral infections and autoimmune diseases, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. 5. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France.
Abstract
BACKGROUND: Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjögren's syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist. OBJECTIVE: This observational case-control study was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS. METHODS: Forty-nine patients with pSS and 45 control subjects were enrolled for clinical evaluation and mass cytometry quantification of 34 protein markers in blood. For a third of these subjects, matched labial salivary gland biopsy specimens were also analyzed by mass cytometry and immunohistochemistry. RESULTS: In salivary gland biopsy specimens from patients with pSS, we identified a high number of activated CD8(+) T cells, terminally differentiated plasma cells, and activated epithelial cells, pointing to new pathogenic mechanisms for future clinical intervention. In blood, we identified a 6-cell disease signature defined by decreased numbers of CD4 and memory B lymphocytes, decreased plasmacytoid dendritic cell numbers, and increased representation of activated CD4 and CD8 T cells and plasmablasts. These blood cellular components correlated with clinical parameters and, when taken together, clustered patients into subsets with distinct disease activity and glandular inflammation. CONCLUSION: This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.
BACKGROUND: Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjögren's syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist. OBJECTIVE: This observational case-control study was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS. METHODS: Forty-nine patients with pSS and 45 control subjects were enrolled for clinical evaluation and mass cytometry quantification of 34 protein markers in blood. For a third of these subjects, matched labial salivary gland biopsy specimens were also analyzed by mass cytometry and immunohistochemistry. RESULTS: In salivary gland biopsy specimens from patients with pSS, we identified a high number of activated CD8(+) T cells, terminally differentiated plasma cells, and activated epithelial cells, pointing to new pathogenic mechanisms for future clinical intervention. In blood, we identified a 6-cell disease signature defined by decreased numbers of CD4 and memory B lymphocytes, decreased plasmacytoid dendritic cell numbers, and increased representation of activated CD4 and CD8 T cells and plasmablasts. These blood cellular components correlated with clinical parameters and, when taken together, clustered patients into subsets with distinct disease activity and glandular inflammation. CONCLUSION: This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.
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