Rheumatoid arthritis patient antibodies highly recognize IL-2 in the immune response pathway involving IRF5 and EBV antigens

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive joint damage due to largely unknown environmental factors acting in concert with risk alleles conferring genetic susceptibility. A major role has been attributed to viral infections that include past contacts with Epstein-Barr virus (EBV) and, more recently, to non-protein coding sequences of human endogenous retrovirus K (HERV-K) integrated in the human genome. Molecular mimicry between viral and self proteins is supposed to cause the loss of immune tolerance in predisposed hosts. There are evidences that anti-IL-2 antibodies (Abs) are present in subjects affected by autoimmune diseases and may be responsible for alterations in regulatory T cell responses. In this study, we evaluated the levels of Abs against IL-2, viral epitopes and interferon regulatory factor 5 (IRF5) in 140 RA patients and 137 healthy controls (HCs). Ab reactivity reached the highest levels for IRF5, EBV and IL-2 (56%, 44% and 39%, respectively) in RA with significantly lower values among HCs (7–9%, p < 0.0001), which suggests a possible cross-reaction between IRF5/EBV homologous antigens and shifts in T cell balance disrupted by anti-IL-2 Abs.

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

“…MAP and EBV infections can lead to the deregulation of the Interferon regulatory factor 5 (IRF5) pathway. The frequency of Abs reactivity against IRF5 was increased in RA patients compared to healthy controls (56% vs. 9%, p < 0.0001) [ 59 ]. A similar trend was found for Abs against the EBV tegument protein called BOLF1, where the frequency of reactivity was 44% vs. 9% ( p < 0.0001), in RA patients and healthy controls, respectively [ 59 ].…”

“…The frequency of Abs reactivity against IRF5 was increased in RA patients compared to healthy controls (56% vs. 9%, p < 0.0001) [ 59 ]. A similar trend was found for Abs against the EBV tegument protein called BOLF1, where the frequency of reactivity was 44% vs. 9% ( p < 0.0001), in RA patients and healthy controls, respectively [ 59 ]. Finally, it was found that Abs against MAP_4027 have a higher reactivity in RA patients compared to the control group (21% vs. 9%, p < 0.0076) [ 59 ].…”

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

“…paratuberculosis (MAP), that is responsible for important economic losses due to reduced milk production, premature culling, reduced slaughter value and continued spread of infection [1,2]. 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].…”

Progress in interleukin‐2 therapy for rheumatic immune diseases by regulating the immune balance of T cells

“…The low level of IL‐2 and the absence of IL‐2 signal in RA patients lead to the development and dysfunction of regulatory T cells, the weakening of immunosuppressive function of autoreactive T cells, the breakdown of immune tolerance and homeostasis of internal environment and the occurrence of autoimmune inflammation . The latest study found that anti‐IL‐2 antibodies exist in RA patients, which can destroy T cell immune balance . Low dose of IL‐2 can promote the proliferation of regulatory T cells, inhibit the role and function of Thl7 cells and help control inflammation‐mediated joint damage .…”

“…63 The latest study found that anti-IL-2 antibodies exist in RA patients, which can destroy T cell immune balance. 75 Low dose of IL-2 can promote the proliferation of regulatory T cells, inhibit the role and function of Thl7 cells and help control inflammation-mediated joint damage. 46 Kosmaczewska et al separated PBMCs from RA patients and stimulated them with recombinant IL-2 in vitro.…”