Antibody response to homologous epitopes of Epstein-Barr virus, Mycobacterium avium subsp. paratuberculosis and IRF5 in patients with different connective tissue diseases and in mouse model of antigen-induced arthritis

Abstract

Background Improved knowledge of different biomarkers is crucial for early diagnosis of rheumatic diseases and to provide important insights for clinical management. In this study, we evaluated the seroreactivity of patients with different connective tissue diseases (CTDs) (rheumatoid arthritis, RA; systemic lupus erythematosus, SLE; systemic sclerosis, SSc; and Sjogren’s syndrome, SSj) to interferon regulatory factor 5 (IRF5) peptide and homologs derived from Epstein-Barr virus (EBV) and Mycobacterium avium subsp. paratuberculosis (MAP). Antigen-induced arthritis (AIA) experiments have been performed in control and IRF5 conditional knockout mice to reinforce the hypothesis that antibodies generated against the three homologous peptides are cross-reactive. Methods Reactivity against wild-type (wt) and citrullinated (cit) IRF5 (IRF5 424-434 ), MAP (MAP_4027 18-32 ) and EBV (BOLF1 305-320 ) peptides were tested by indirect ELISA in sera from 100 RA patients, 54 patients with other CTDs (14 SLE, 28 SSc and 12 SSj) and 100 healthy subjects (HCs). Antibody responses to the same wt peptides have been tested in AIA mouse sera after immunization with complete Freud’s adjuvant (CFA) and methylated bovine serum albumin (mBSA) to induce arthritis in the knee joint. Results BOLF1, MAP_4027 and IRF5 peptides triggered different antibody responses in CTD diseases with a stronger reactivity in RA ( p =0.0001). Similar trends were observed in AIA mice with significantly higher reactivity after 7 days from induction of arthritis. We also found statistically significant differences in antibody responses between SSc and HCs for BOLF1 ( p =0.003), MAP_4027 ( p =0.0076) and IRF5 ( p =0.0042). Peripheral reactivity to cit peptides was lower compared to their wt counterparts, except for cit-MAP_4027 18-32 , which induced stronger responses in RA than wt-MAP_4027 18-32 (46% vs. 26%, p =0.0170). Conclusion(s) : Our results show differential antibody responses to BOLF1, MAP_4027 and IRF5 peptides among CTDs, highlighting their potential as diagnostic biomarkers in these diseases. Experiments performed in IRF5 conditional knockout mice support the hypothesis of cross-reactivity between the investigated homologous antigens.

Patterns of T and B cell responses to Mycobacterium tuberculosis membrane-associated antigens and their relationship with disease activity in rheumatoid arthritis patients with latent tuberculosis infection

“…This discordance was also flagged in a recent study [ 28 ] wherein a group of household contacts who were negative for TST and IGRA had shown antibodies to MtM-associated antigens. In related studies [ 42 , 43 ], RA patients had also shown antibodies to mycobacterial proteins PknG, PtpA and MAP_4027. Though the authors had sourced these proteins from Mycobacterium avium subsp.…”

“…RA patients harbour antibodies to a peptide epitope of MAP_4027 (this antigen is also present in Mtb) which cross-reacts with interferon regulatory factor 5 (IRF5). This structural mimicry could contribute to the pathogenesis of IMIDs by dysregulating the signalling by IRF5 which is a central regulator of inflammatory responses [ 43 , 54 ]. The regions of low TB prevalence (e.g., USA, Canada and Europe) show a high prevalence of MAP which could substitute for Mtb as an environmental trigger for IMIDs [ 55 ].…”

Detection of latent forms of Mycobacterium avium subsp. paratuberculosis infection using host biomarker-based ELISAs greatly improves paratuberculosis diagnostic sensitivity

“…That is especially relevant since PTB is a disease that affects not only cattle but also other domestic (sheep, goats) [59] and wild ruminants (deer, fallow-deer) [60,61], and other species like camelids [62], that have similar digestive characteristics although they are not true ruminants [63]. Improvement of the identification of MAP-infected animals through sensitive biomarker-based ELISAs could also help to study and confirm the potential role of MAP-infection as a common pathogenetic contributor to various autoimmune diseases [10].…”

“…Furthermore, MAP has a clear zoonotic potential since it has been postulated as a possible trigger factor in several autoimmune diseases in humans such as Crohn's disease (CD) [3,4], type I diabetes (T1D) [5], multiple sclerosis (MS) [6,7] or rheumatoid arthritis (RA) [8,9]. One mechanism that has been suggested to cause the onset and/or exacerbation of autoimmune disease is molecular mimicry, whereby MAP antigens share sequences or structural similarities with self-antigens [10], so the immune response against MAP antigens could also induced undesirable immune responses against host proteins in genetically predisposed individuals [11].…”

Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria

“…This discovery supports the hypothesis that IRF5 is a potential auto-immune target of RA. However, further studies in a larger group of patients are needed to further confirm these findings [ 60 ].…”