Abstract
BackgroundAntibodies and upregulated cytokines and chemokines predate the onset of rheumatoid arthritis (RA) symptoms. We aimed to identify the pathways related to the early processes leading to RA development, as well as potential novel biomarkers, using multiple protein analyses.MethodsA case-control study was conducted within the Biobank of northern Sweden. The plasma samples from 118 pre-symptomatic individuals (207 samples; median predating time 4.1 years), 79 early RA patients, and 74 matched controls were analyzed. The levels of 122 unique proteins with an acknowledged relationship to autoimmunity were analyzed using 153 antibodies and a bead-based multiplex system (FlexMap3D; Luminex Corp.). The data were analyzed using multifactorial linear regression model, random forest, and network enrichment analysis (NEA) based on the 10 most significantly differentially expressed proteins for each two-by-two group comparison, using the MSigDB collection of hallmarks.ResultsThere was a high agreement between the different statistical methods to identify the most significant proteins. The adipogenesis and interferon alpha response hallmarks differentiated pre-symptomatic individuals from controls. These two hallmarks included proteins involved in innate immunity. Between pre-symptomatic individuals and RA patients, three hallmarks were identified as follows: apical junction, epithelial mesenchymal transition, and TGF-β signaling, including proteins suggestive of cell interaction, remodulation, and fibrosis. The adipogenesis and heme metabolism hallmarks differentiated RA patients from controls.ConclusionsWe confirm the importance of interferon alpha signaling and lipids in the early phases of RA development. Network enrichment analysis provides a tool for a deeper understanding of molecules involved at different phases of the disease progression.
Highlights
Rheumatoid arthritis (RA) is a common autoimmune disease, characterized by immune cell infiltration of the joints, cartilage and bone degradation, and resulting in joint pain and stiffness
368 samples were included for protein analysis: 209 samples from 118 presymptomatic individuals, 85 samples from these individuals after they were diagnosed with rheumatoid arthritis (RA), and 74 samples from controls matched to the pre-symptomatic individuals (Additional file 1: Table S1)
These adjustments, while introducing potential imbalance to the multifactorial linear model, did not affect our results, except for the comparison between patients vs. presymptomatic individuals where the transforming growth factor-beta 3 (TGFB3) protein was not included in the respective Altered gene set (AGS)
Summary
Rheumatoid arthritis (RA) is a common autoimmune disease, characterized by immune cell infiltration of the joints, cartilage and bone degradation, and resulting in joint pain and stiffness. The etiopathogenic process leading to disease development and progression is not completely understood, there are autoimmune processes ongoing long before any clinical symptoms. In this study, analyzing a larger set of protein markers than previous studies, we aimed to gain further insight into which molecular processes are involved in RA development prior to the onset of symptoms and to identify potential early biomarkers. Antibodies and upregulated cytokines and chemokines predate the onset of rheumatoid arthritis (RA) symptoms. We aimed to identify the pathways related to the early processes leading to RA development, as well as potential novel biomarkers, using multiple protein analyses
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