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

Noli, Marta; Meloni, T; Ruberto, Stefano; Jasemi, Seyedesomaye; Simula, Elena Rita; Cossu, Davide; Bo, Marco; Palermo, Mario; Sechi, Leonardo Antonio

doi:10.3390/pathogens11101188

Cited by 5 publications

(12 citation statements)

References 35 publications

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“…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%.…”

Section: Resultsmentioning

confidence: 59%

“…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.…”

Section: Resultsmentioning

confidence: 96%

“…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 ].…”

Section: Discussionmentioning

confidence: 99%

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

Simula,

Zarbo,

Arru

et al. 2023

IJMS

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Myasthenia gravis is an antibody-mediated autoimmune neurological disorder characterized by impaired neuromuscular junction transmission, resulting in muscle weakness. Recently, the involvement of Human Endogenous Retroviruses (HERVs) in the pathophysiology of different immune-mediated and neurodegenerative diseases, such as multiple sclerosis, has been demonstrated. We aimed to investigate potential immune system involvement related to humoral responses targeting specific epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis. Myasthenia gravis patients were recruited in the Neurology Unit, while healthy controls were selected from the Blood Transfusion Center, both affiliated with AOU Sassari. Highly immunogenic antigens of HERV-K and HERV-W envelope proteins were identified using the Immune Epitope Database (IEDB) online tool. These epitopes were utilized in enzyme-linked immunosorbent assays (ELISA) to detect autoantibodies in serum directed against these sequences. The study involved 39 Healthy Donors and 47 MG patients, further categorized into subgroups based on the presence of autoantibodies: MG-AchR Ab+ (n = 17), MG-MuSK Ab+ (n = 7), double seronegative patients (MG-DSN, n = 18), MG-LRP4 Ab + (n = 4), and one patient with no antibodies data (n = 1). Our findings revealed high levels of autoantibodies in myasthenia gravis patients directed against the HERV-K-env-su(19–37), HERV-K-env-su(109–126), HERV-K-env-su(164–186), HERV-W-env(93–108), HERV-W-env(129–14), and HERV-W-env(248–262) epitopes. Notably, these results remained highly significant even when patients were subdivided into MG-AchR Ab+ and MG-DSN subgroups. Correlation analysis further revealed significant positive associations between the antibody levels against HERV-K and HERV-W families in patients, suggesting a synergistic action of the two HERVs in the pathology context since this correlation is absent in the control group. This study marks the first identification of a specific humoral response directed against defined epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis patients. These findings lay the foundation for future investigations aimed at elucidating the molecular mechanisms driving this immune response. The detection of these autoantibodies suggests the potential for novel biomarkers, especially within the MG-DSN patient subgroup, addressing the need for new biomarkers in this population.

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Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 96%

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

Simula,

Zarbo,

Arru

et al. 2023

IJMS

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wenzlau,

Gu,

Michels

et al. 2023

Diagnostics

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Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing b cells of the pancreatic islets. Autoantibodies to b cell proteins typically appear in the circulation years before disease onset, and serve as the most accurate biomarkers of T1D risk. Our laboratory has recently discovered novel b cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides (IAPP). T cells from a diabetic mouse model and T1D patients are activated by these hybrid peptides. In this study, we asked whether these hybrid molecules could serve as antigens for autoantibodies in T1D and prediabetic patients. We analyzed sera from T1D patients, prediabetics and healthy age-matched donors. Using a highly sensitive electrochemiluminescence assay, sera were screened for binding to recombinant proinsulin:IAPP probes or truncated derivatives. Our results show that sera from T1D patients contain antibodies that bind larger hybrid proinsulin:IAPP probes, but not proinsulin or insulin, at significantly increased frequencies compared to normal donors. Examination of sera from prediabetic patients confirms titers of antibodies to these hybrid probes in more than 80% of individuals, often before seroconversion. These results suggest that hybrid insulin peptides are common autoantigens in T1D and prediabetic patients, and that antibodies to these peptides may serve as valuable early biomarkers of the disease.

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Antibodies against endogenous retroviruses

Chisca,

Larouche,

Xing

et al. 2024

Immunological Reviews

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SummaryThe human genome harbors hundreds of thousands of integrations of ancient retroviruses, amassed over millions of years of evolution. To reduce further amplification in the genome, the host prevents transcription of these now endogenous retroviruses (ERVs) through epigenetic repression and, with evolutionary time, ERVs are incapacitated by accumulating mutations and deletions. However, several members of recently endogenized ERV groups still retain the capacity to produce viral RNA, retroviral proteins, and higher order structures, including virions. The retention of viral characteristics, combined with the reversible nature of epigenetic repression, particularly as seen in cancer, allow for immunologically unanticipated ERV expression, perceived by the adaptive immune system as a genuine retroviral infection, to which it has to respond. Accordingly, antibodies reactive with ERV antigens have been detected in diverse disorders and, occasionally, in healthy individuals. Although they are part of self, the retroviral legacy of ERV antigens, and association with and, possibly, causation of disease states may set them apart from typical self‐antigens. Consequently, the pathogenic or, indeed, host‐protective capacity of antibodies targeting ERV antigens is likely to be context‐dependent. Here, we review the immunogenicity of typical ERV proteins, with emphasis on the antibody response and its potential disease implications.

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

Cited by 5 publications

References 35 publications

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

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

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

Antibodies against endogenous retroviruses

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