HERV-K Envelope Protein Induces Long-Lasting Production of Autoantibodies in T1DM Patients at Onset in Comparison to ZNT8 Autoantibodies

Abstract

Human endogenous retroviruses (HERVs) have been thought of as silent passengers within our genomes, but their reactivation has been linked with several autoimmune diseases, including type 1 diabetes (T1DM). In order to evaluate the potential role of HERVs, in addition to the recognized role of HERV-W, we focused on the debated role of the HERV-K family in T1DM. Therefore, we performed a serological evaluation of IgG antibodies against HERV-K Env epitope (HERV-K Env19–37) in comparison to an important β-cellular autoimmunity biomarker, ZnT8, from plasma samples of Sardinian children at the onset of T1DM, different T1DM groups (1–5 and 6–12 years since diagnosis), and healthy controls (HCs), by an indirect enzyme-linked immunosorbent assay (ELISA). A significant antibody response was observed against HERV-K Env19–37 (p < 0.0001) in T1DM patients compared to HCs, and significantly higher IgG responses were detected in the group at the onset compared to the other T1DM groups and HCs. Unlike the trend of the β-cellular autoimmunity autoantibodies, for HERV-K Env antibodies we observed positive values that persist over time up to 5 years since the onset of T1DM. Our results add new evidence about the presence of antibodies against HERV-K in T1DM, but further investigations are necessary to relate these results with the established role of HERVs, considering the contrasting results for HERV-K.

Antibody Response to HERV-K and HERV-W Envelope Epitopes in Patients with Myasthenia Gravis

“…Notably, AAbs targeting the epitope HERV-K-env-su (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) were detected in 30% of MG patients compared to 8% of HCs, as corroborated by Fisher's exact test (p = 0.0137) (Figure 1A). Regarding HERV-K-env-su (109-126) , the assay allowed us to differentiate between patient and control populations with a specificity of 100%.…”

“…In the following analysis, the HCs population was compared with the MG pa subgroups. We observed a heightened humoral response in the MG AchR Ab+ subg compared to the controls for the peptides HERV-K-env-su (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37), with a p-value of (Figure 3A), and HERV-K-env-su(109-126), which showed 100% specificity, identif 70.59% of the patients as positive for AAbs (Figure 3B). Additionally, for HERV-K In the following analysis, the HCs population was compared with the MG patient subgroups.…”

“…In Type 1 Diabetes Mellitus (T1D), a notable antibody response to HERV-K-env (19−37) was significantly increased in patients when compared to HCs [ 34 ].…”

Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

“…An emerging source of potentially valuable biomarkers in T1D stems from the immunological impact of exogenous viral and bacterial antigens, and post-translational modifications (PTMs) of native proteins that may escape immune tolerance [8][9][10]. Mycobacterium avium subspecies paratuberculosis (MAP) is associated with a variety of autoimmune Diagnostics 2023, 13, 2859 2 of 12 diseases, including T1D, possibly via molecular mimicry of MAP peptides that cross-react to sequences in proinsulin, GAD-65, and ZnT8 [9,10]. Enteroviruses have long been proposed to induce T1D by various mechanisms (including molecular mimicry) [11], and human endogenous retroviral (HERV) proteins have been shown to act as antigens for humoral immunity.…”

“…A correlation between the presence of anti-HERV-W envelope protein antibodies and IAAs has been reported among T1D individuals. Additionally, a higher prevalence of anti-HERV-K envelope antibodies has been reported in the sera of T1D patients compared to healthy controls [10]. A number of PTMs have been reported to induce T cell immunoreactivity in T1D, including oxidation, deamidation, transglutamination, citrullination, and aberrant secondary structure [8,12,13], all of which may increase binding affinity to disease-associated HLA binding grooves.…”