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.

Figure 1

ELISA-based analysis of Abs reactivity against human, viral and MAP-derived peptides in RA, NMOSD and HCs. The sera were tested against plate-coated IL-2_6–20KK (B), IL-2_56–70 (A), IRF5_424–434 (C), BOLF1_305–320 (D), Herv-Kenv_19–37 (E) and MAP_4027_18–32 (F) peptides. Bars represent the median ± interquartile range. Thresholds for Abs positivity are indicated by dashed lines. Percentages of Abs prevalence respective to each group, AUC and P-values are indicated above the distributions.

Figure 2

Abs reactivity against the antigenic peptide derived from H. pylori in RA patients and HCs. Bars represent mean value ± interquartile range, while dashed lines indicate the positivity threshold. Despite sequence homology to human ZnT8 protein fragment, no significant differences in Abs levels were detected.

Figure 3

Scatter plots showing correlations between Abs titers in RA patients. Pairwise distributions are classified for homologous peptides (A), IL-2_6–20KK (B) and IL-2_56–70 (C). Each dot correspond to OD values obtained for a single patient.