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Proteomic Data Analysis for Differential Profiling of the Autoimmune Diseases SLE, RA, SS, and ANCA-Associated Vasculitis.

ABSTRACT: Early and correct diagnosis of inflammatory rheumatic diseases (IRD) poses a clinical challenge due to the multifaceted nature of symptoms, which also may change over time. The aim of this study was to perform protein expression profiling of four systemic IRDs, systemic lupus erythematosus (SLE), ANCA-associated systemic vasculitis (SV), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), and healthy controls to identify candidate biomarker signatures for differential classification. A total of 316 serum samples collected from patients with SLE, RA, SS, or SV and from healthy controls were analyzed using 394-plex recombinant antibody microarrays. Differential protein expression profiling was examined using Wilcoxon signed rank test, and condensed biomarker panels were identified using advanced bioinformatics and state-of-the art classification algorithms to pinpoint signatures reflecting each disease (raw data set available at https://figshare.com/s/3bd3848a28ef6e7ae9a9.). In this study, we were able to classify the included individual IRDs with high accuracy, as demonstrated by the ROC area under the curve (ROC AUC) values ranging between 0.96 and 0.80. In addition, the groups of IRDs could be separated from healthy controls at an ROC AUC value of 0.94. Disease-specific candidate biomarker signatures and general autoimmune signature were identified, including several deregulated analytes. This study supports the rationale of using multiplexed affinity-based technologies to reflect the biological complexity of autoimmune diseases. A multiplexed approach for decoding multifactorial complex diseases, such as autoimmune diseases, will play a significant role for future diagnostic purposes, essential to prevent severe organ- and tissue-related damage.

SUBMITTER: Ohlsson M

PROVIDER: S-EPMC7872503 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Proteomic Data Analysis for Differential Profiling of the Autoimmune Diseases SLE, RA, SS, and ANCA-Associated Vasculitis.

Ohlsson Mattias M Hellmark Thomas T Bengtsson Anders A AA Theander Elke E Turesson Carl C Klint Cecilia C Wingren Christer C Ekstrand Anna Isinger AI

Journal of proteome research 20201223 2

Early and correct diagnosis of inflammatory rheumatic diseases (IRD) poses a clinical challenge due to the multifaceted nature of symptoms, which also may change over time. The aim of this study was to perform protein expression profiling of four systemic IRDs, systemic lupus erythematosus (SLE), ANCA-associated systemic vasculitis (SV), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), and healthy controls to identify candidate biomarker signatures for differential classification. A total ...[more]

PMID: 33356304

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Project description:Methylation variabilities of inflammatory cytokines play important roles in the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS). With heightened focus on personalized and precise medicine, it is necessary to compare and contrast the difference and similarity of cytokine methylation status between the 3 most classic autoimmune diseases (AIDs). In this study, we integrated 5 Cytokine-Chips from genome-wide DNA methylation datasets of the 3 kind of AIDs, delta-beta value was calculated for intergroup difference, and comprehensive bioinformatics analyses of cytokine genes with aberrant methylations were performed. 125 shared differential methylation variabilities (DMVs) were identified. There were 102 shared DMVs with similar methylation status; 3 hypomethylated differential methylation regions (DMRs) across the AIDs were found, and all 3 DMRs were hypomethylated. DMRs (AZU1, LTBR, and RTEL1) were likely to serve as activator in the inflammatory process. Particularly, AZU1 and LTBR with hypomethylated TSS and first exon located in the promoter regions were able to trigger inflammation signaling cascades and play critical roles in autoimmune tautology. Moreover, functional epigenetic module (FEM) algorithm showed that different inflammatory networks are involved in different AIDs; 5 hotspots were identified as biologically plausible pathways in inducing or perpetuating of inflammation which are epigenetically deregulated in AIDs. We concluded methylation variabilities among the same cytokines can greatly impact the perpetuation of inflammatory process or signal pathway of AIDs. Differentiating the cytokine methylation status will serve as valuable resource for researchers alike to gain better understanding of the epigenetic mechanisms of the three AIDs. Even more importantly, better understanding of cytokine methylation variability existing between the three classic AIDs will aid in identification of potential epigenetic biomarkers and therapeutic targets. This trial is registered with ChiCTR-INR-16010290, a clinical trial for the treatment of rheumatoid arthritis with Warming yang and Smoothening Meridians.

Project description:Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.

Dataset Information

Proteomic Data Analysis for Differential Profiling of the Autoimmune Diseases SLE, RA, SS, and ANCA-Associated Vasculitis.

Publications

Proteomic Data Analysis for Differential Profiling of the Autoimmune Diseases SLE, RA, SS, and ANCA-Associated Vasculitis.

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