Influence of the shared epitope on the elicitation of experimental autoimmune arthritis biomarkers

Abstract

Our previous studies have shown that inoculation of the oral cavity of “humanized” B6.DR1/4 mice with the periodontal pathogen Porphyromonas gingivalis results in an increase in the percentage of circulating Th17 cells, loss of bone and an exacerbation of experimental autoimmune arthritis. The aim of this study was to assess the role played by the human HLA-DRβ molecule containing the shared epitope supplied as a transgene to I-A˚ (murine class II null) C57BL/6 (B6) mice in driving these findings. We compared various immune response parameters as well as alveolar and peri-articular bone loss between humanized B6.DR1 (or B6.DR4) mice and their WT (B6) counterparts. We found that the presence of the shared epitope in the context of inoculation with P. gingivalis enhanced the percentage of Th17 cells generated, dramatically enhanced bone loss and importantly allowed for the generation of CCP2⁺ ACPAs that are not found in C57BL/6 or DBA/1 arthritic mouse serum. Due to the exceedingly complex nature of environmental factors impacting on genetic elements, it has been difficult to unravel mechanisms that drive autoimmune arthritis in susceptible individuals. The findings in this study may provide one small piece of this puzzle that can help us to better understand part of this complexity.

Higher odds of periodontitis in systemic lupus erythematosus compared to controls and rheumatoid arthritis: a systematic review, meta-analysis and network meta-analysis

“…This epitope facilitates the presentation of arthritogenic peptides to CD4 + T cells, particularly those containing citrulline, thereby promoting the development of anti-CCP antibodies ( 31 ). The interaction between the shared epitope and smoking has been extensively studied and its interplay with Porphyromonas gingivalis in arthritis-prone B6.DR1 mice leading to increased anti-CCP production makes periodontitis an even more compelling risk factor for RA ( 95 ). RA is considered a continuum that begins with a high-risk or susceptibility state influenced by genetic factors and progresses through preclinical, early, and established disease, where environmental factors contribute to the inflammatory and destructive synovial response ( 15 ).…”

Role of Citrullinated Collagen in Autoimmune Arthritis

“…In animal models, PAD enzyme inhibition has been shown to ameliorate collagen-induced arthritis [ 24 ] and four single nucleotide polymorphisms (SNPs) have been identified in the exons of the PADI type 4 (PADI-4) gene associated with the severity of RA. In addition, the presence of the human RA susceptibility allele expressed as a transgene in our B6.DR1 mice rendered them capable of producing anti-citrullinated peptide antobodies during CIA development [ 18 , 25 ]. Similarly, patients with multiple sclerosis (MS), have increased levels of citrullinated myelin basic protein, which leads to demyelination of the myelin sheath reducing nerve signal transduction [ 26 ].…”

Another Look at the Contribution of Oral Microbiota to the Pathogenesis of Rheumatoid Arthritis: A Narrative Review

“…Inoculation of the oral cavity of "humanized" B6.DR1/4 mice with Pg results in an increase in the percentage of circulating Th17 cells, loss of bone, and an exacerbation of experimental autoimmune arthritis. The presence of the SE in the context of inoculation with Pg enhanced the percentage of Th17 cells, dramatically enhanced bone loss, and allowed for the generation of ACPAs not found in C57BL/6 or DBA/1 arthritic mouse serum [88]. In humans, separate analyses for patients with RA with or without SE could also tell whether oral bacteria, including Pg, are pathogenic and/or foster ACPAs only in patients with the HLA DR1/4 background.…”