Antibody Response to <scp>HML</scp>‐2 May Be Protective in Amyotrophic Lateral Sclerosis

García-Montojo, Marta; Simula, Elena Rita; Fathi, Saeed; McMahan, Cynthia; Ghosal, Anubrata; Berry, James; Cudkowicz, Merit; Elkahloun, Abdel G.; Johnson, Kory R.; Norato, Gina; Jensen, Philip J.; James, Tony D.; Sechi, Leonardo Antonio; Nath, Avindra

doi:10.1002/ana.26466

Cited by 13 publications

(19 citation statements)

References 46 publications

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“…It will therefore be important to investigate whether LINE-1 expression also can trigger TDP-43 pathology. Finally, a body of literature has established that RTEs and ERVs become inappropriately expressed not only in TDP-43 related disorders ALS and FTD [12][13][14][15][16][17][18][19][20][21]56,57 , but also in some disorders with Tau pathology (AD and Progressive supranuclear palsy) 58,59 and in Aicardi-Goutieres syndrome 60,61 . RTE and ERV expression has the potential to contribute to many of the cellular impacts that are thought to be at play across these disorders, including inflammatory signaling, DNA damage and defects in RNA metabolism and proteostasis [62][63][64][65] .…”

Section: Discussionmentioning

confidence: 99%

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Chang

Dubnau

2023

Nat Commun

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Inter-cellular movement of “prion-like” proteins is thought to explain propagation of neurodegeneration between cells. For example, propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) is proposed to underlie progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases, ALS and FTD are not infectious and injection of aggregated TDP-43 is not sufficient to cause disease. This suggests a missing component of a positive feedback necessary to sustain disease progression. We demonstrate that endogenous retrovirus (ERV) expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either Drosophila mdg4-ERV (gypsy) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Viral ERV transmission also triggers TDP-43 pathology in recipient cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism potentially underlies the TDP-43 proteinopathy-caused neurodegenerative propagation through neuronal tissue.

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Section: Discussionmentioning

confidence: 99%

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Chang

Dubnau

2023

Nat Commun

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“…Several studies observed the detection of HERV-K Env in the cerebrospinal fluid (CSF) and brain in amyotrophic lateral sclerosis (ALS) patients, noting its specific neurotoxic effect in vitro and in vivo [ 27 , 28 , 29 ]. Significantly increased levels of Abs targeting HERV-K Env in ALS patients were initially reported by our group [ 26 , 30 ].…”

Section: Discussionmentioning

confidence: 75%

“…HERVs-encoded proteins may be the principal trigger of the disease when they are expressed or overexpressed. It is possible that these proteins could induce the overproduction of anti-HERVs antibodies by B lymphocytes with a protective role, as observed in ALS recently [ 26 ]. Several studies observed the detection of HERV-K Env in the cerebrospinal fluid (CSF) and brain in amyotrophic lateral sclerosis (ALS) patients, noting its specific neurotoxic effect in vitro and in vivo [ 27 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…The potential involvement of HERVs in neurological conditions [ 26 , 27 , 28 ] and autoimmune disorders [ 29 ] has been extensively documented.…”

Section: Discussionmentioning

confidence: 99%

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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Antibody Response to HML‐2 May Be Protective in Amyotrophic Lateral Sclerosis

Cited by 13 publications

References 46 publications

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

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

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

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