Plasma proteomic profiles from disease-discordant monozygotic twins suggest that molecular pathways are shared in multiple systemic autoimmune diseases*

Terrance P O'Hanlon,Lisa G Rider,Mark F Gourley,Lu Gan,Zhuoyan Li,Frederick W Miller

doi:10.1186/ar3506

Abstract

IntroductionAlthough systemic autoimmune diseases (SAID) share many clinical and laboratory features, whether they also share some common features of pathogenesis remains unclear. We assessed plasma proteomic profiles among different SAID for evidence of common molecular pathways that could provide insights into pathogenic mechanisms shared by these diseases.MethodsDifferential quantitative proteomic analyses (one-dimensional reverse-phase liquid chromatography-mass spectrometry) were performed to assess patterns of plasma protein expression. Monozygotic twins (four pairs discordant for systemic lupus erythematosus, four pairs discordant for juvenile idiopathic arthritis and two pairs discordant for juvenile dermatomyositis) were studied to minimize polymorphic gene effects. Comparisons were also made to 10 unrelated, matched controls.ResultsMultiple plasma proteins, including acute phase reactants, structural proteins, immune response proteins, coagulation and transcriptional factors, were differentially expressed similarly among the different SAID studied. Multivariate Random Forest modeling identified seven proteins whose combined altered expression levels effectively segregated affected vs. unaffected twins. Among these seven proteins, four were also identified in univariate analyses of proteomic data (syntaxin 17, α-glucosidase, paraoxonase 1, and the sixth component of complement). Molecular pathway modeling indicated that these factors may be integrated through interactions with a candidate plasma biomarker, PON1 and the pro-inflammatory cytokine IL-6.ConclusionsTogether, these data suggest that different SAID may share common alterations of plasma protein expression and molecular pathways. An understanding of the mechanisms leading to the altered plasma proteomes common among these SAID may provide useful insights into their pathogeneses.

Highlights

Systemic autoimmune diseases (SAID) share many clinical and laboratory features, whether they share some common features of pathogenesis remains unclear
Patients were defined as those meeting American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), or juvenile dermatomyositis (JDM) and required the exclusion of inherited, metabolic, infectious diseases or other mimics of systemic autoimmune diseases (SAID); patients were within four years of diagnosis
Study subjects comprised three groups: (1) 10 SAID probands (4 SLE, 4 JIA, and 2 JDM); (2) probands’ 10 autoimmune disease unaffected MZ twins; and (3) 10 unrelated, matched controls who were free of SAID

Summary

Introduction

Systemic autoimmune diseases (SAID) share many clinical and laboratory features, whether they share some common features of pathogenesis remains unclear. Studies utilizing bio-fluid proteomics have identified multiple, pathologic markers and molecular pathways associated with different disease phenotypes, severities, and therapeutic responses [3,4]. Despite these in-roads, considerable variability in the published SAID literature exists and likely results from multiple factors including different proteomic methodologies (for example, 2-D electrophoresis, mass spectrometry, antibody array), choice of bio-fluids or tissues analyzed, and the inherent heterogeneity of SAID phenotypes, patient histories, and human genetic variations. These common findings in multiple rheumatic diseases to date include Type I interferon inducible proteins, autoantibodies, numerous inflammatory cytokines/chemokines, and markers of molecular pathways associated with chronic immune activation (for example, NF-kB, TNFa, and complement fixation), oxidative stress, coagulation, protein degradation and lipid metabolism [3,4,5,6,7,8]

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