High Fidelity Between Saliva Proteomics and the Biologic State of Salivary Glands Defines Biomarker Signatures for Primary Sjogren's Syndrome

ObjectiveDependence on invasive procedures for classification of patients with Sjogren's syndrome (SS) hampers timely diagnosis and suitable patient followup. The aim of this study was to recapitulate the diagnosis of SS through noninvasive means and to define the biologic state of SS patients' salivary glands. MethodsUsing a 187-plex capture antibody-based assay, salivary proteomic biomarker profiles were generated from patients with primary SS, patients with rheumatoid arthritis, and asymptomatic controls. Discriminant function analyses and Gene Ontology-based network analyses allowed data analyses with a reductionist approach and with a focus on systems biology. ResultsCharacterized by significant changes in 61 and 55 proteins, respectively, the salivary proteome of SS patients appeared profoundly altered compared to that of individuals without SS. On this basis, 4-plex and 6-plex biomarker signatures, both including interleukin-4 (IL-4), IL-5, and clusterin, achieved accurate prediction of an individual's group membership for at least 94% of cases. Of note, all misclassified SS patients presented with ectopic germinal center-like structures. Systematic inference of biologic meaning identified SS-related protein patterns delineating B cell-dominated immune responses, macrophage differentiation, and signs of T cell chemotaxis. In addition, proteomic Multi-Analyte Profiles provided insight about proteins related to collagen, cytokine, and growth factor synthesis as well as lipid transport. ConclusionThe SS-related molecular landscape conveyed by saliva showed great congruence with histopathologic features found in SS and advances understanding of this disease at a molecular level. Such salivary biomarker signatures harbor great potential for improving timeliness of SS diagnosis and enabling suitable patient followup.