Identification of Key Biomarkers in RF-negative Polyarticular and Oligoarticular Juvenile Idiopathic Arthritis by Bioinformatic Analysis

Overview

Journal Pediatr Rheumatol Online J

Publisher Biomed Central

Specialty Pediatrics

Date 2023 Nov 24

PMID 38001449

Authors

Yun Liu

Xuemei Tang

Affiliations

Soon will be listed here.

Abstract

Objective: Juvenile idiopathic arthritis (JIA) is a broad term used to describe arthritis of unknown origin. JIA commonly persists into adulthood, often causing substantial morbidity such as restricted joint function, which can lead to challenges in employment and independence. This study aims to identify diagnostic biomarkers and investigate the role of immune cells in the pathogenesis of rheumatoid factor-negative polyarticular juvenile idiopathic arthritis (RF-negative pJIA) and oligoarticular juvenile idiopathic arthritis (oJIA).

Methods: We retrieved a JIA dataset from the GEO database and conducted an analysis of differentially expressed genes (DEGs). Subsequently, functional enrichment analysis was performed on the DEGs. Weighted gene co-expression network analysis (WGCNA) was utilized to identify key modules. Additionally, we constructed a protein‒protein interaction network to identify hub genes that serve as signature genes. Furthermore, we employed CIBERSORT to classify immune cell infiltration.

Results: From the GSE20307 dataset, we identified a total of 1438 DEGs in RF-negative pJIA and 688 DEGs in oJIA. WGCNA clustered the data into 6 modules in pJIA and 4 modules in oJIA. Notably, the ME5 and ME2 modules exhibited significant associations with pJIA and oJIA, respectively. In both pJIA and oJIA, we identified six hub genes, four of which demonstrated high diagnostic sensitivity and specificity in pJIA, while five showed high diagnostic sensitivity and specificity in oJIA. CIBERSORT analysis suggested the potential involvement of these signature genes in immune cell infiltration.

Conclusion: In this study, we identified JUN, CXCL8, SOCS3, and KRAS as biomarkers for RF-negative pJIA and JUN, CXCL8, SOCS3, PTGS2, and NFKBIA as biomarkers for oJIA. Furthermore, our findings suggest that Tfh cells may play a role in the early onset of both RF-negative pJIA and oJIA.

References

Petty R, Southwood T, Manners P, Baum J, Glass D, Goldenberg J . International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31(2):390-2. View

Walz A, Peveri P, Aschauer H, Baggiolini M . Purification and amino acid sequencing of NAF, a novel neutrophil-activating factor produced by monocytes. Biochem Biophys Res Commun. 1987; 149(2):755-61. DOI: 10.1016/0006-291x(87)90432-3. View

McHenry J, Leon A, Matthaei K, Cohen D . Overexpression of fra-2 in transgenic mice perturbs normal eye development. Oncogene. 1998; 17(9):1131-40. DOI: 10.1038/sj.onc.1202044. View

Ravelli A, Martini A . Juvenile idiopathic arthritis. Lancet. 2007; 369(9563):767-778. DOI: 10.1016/S0140-6736(07)60363-8. View

Strieter R, Polverini P, Kunkel S, Arenberg D, Burdick M, Kasper J . The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 1995; 270(45):27348-57. DOI: 10.1074/jbc.270.45.27348. View

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

Casanova J, Holland S, Notarangelo L . Inborn errors of human JAKs and STATs. Immunity. 2012; 36(4):515-28. PMC: 3334867. DOI: 10.1016/j.immuni.2012.03.016. View

Choi Y, Kageyama R, Eto D, Escobar T, Johnston R, Monticelli L . ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity. 2011; 34(6):932-46. PMC: 3124577. DOI: 10.1016/j.immuni.2011.03.023. View

Bombardieri M, Lewis M, Pitzalis C . Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol. 2017; 13(3):141-154. DOI: 10.1038/nrrheum.2016.217. View

10.

Manzo A, Vitolo B, Humby F, Caporali R, Jarrossay D, DellAccio F . Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum. 2008; 58(11):3377-87. DOI: 10.1002/art.23966. View

11.

Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H . Negative Regulation of Cytokine Signaling in Immunity. Cold Spring Harb Perspect Biol. 2017; 10(7). PMC: 6028070. DOI: 10.1101/cshperspect.a028571. View

12.

Maki Y, Bos T, Davis C, Starbuck M, Vogt P . Avian sarcoma virus 17 carries the jun oncogene. Proc Natl Acad Sci U S A. 1987; 84(9):2848-52. PMC: 304757. DOI: 10.1073/pnas.84.9.2848. View

13.

Liongue C, Taznin T, Ward A . Signaling via the CytoR/JAK/STAT/SOCS pathway: Emergence during evolution. Mol Immunol. 2016; 71:166-175. DOI: 10.1016/j.molimm.2016.02.002. View

14.

Petty R, Southwood T, Baum J, Bhettay E, Glass D, Manners P . Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol. 1998; 25(10):1991-4. View

15.

Steelman L, Pohnert S, Shelton J, Franklin R, Bertrand F, McCubrey J . JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004; 18(2):189-218. DOI: 10.1038/sj.leu.2403241. View

16.

Schroder J, Mrowietz U, Christophers E . Purification and partial biologic characterization of a human lymphocyte-derived peptide with potent neutrophil-stimulating activity. J Immunol. 1988; 140(10):3534-40. View

17.

Gregory H, Young J, Schroder J, Mrowietz U, Christophers E . Structure determination of a human lymphocyte derived neutrophil activating peptide (LYNAP). Biochem Biophys Res Commun. 1988; 151(2):883-90. DOI: 10.1016/s0006-291x(88)80364-4. View

18.

Havenar-Daughton C, Lindqvist M, Heit A, Wu J, Reiss S, Kendric K . CXCL13 is a plasma biomarker of germinal center activity. Proc Natl Acad Sci U S A. 2016; 113(10):2702-7. PMC: 4790995. DOI: 10.1073/pnas.1520112113. View

19.

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

20.

Ritchie M, Phipson B, Wu D, Hu Y, Law C, Shi W . limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43(7):e47. PMC: 4402510. DOI: 10.1093/nar/gkv007. View