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Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases—systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.

Human endogenous retroviruses (HERVs) constitute about 8% of the human genome. The overexpression of HERVs has been detected in various inflammatory disorders like neuro-inflammation disorders and cancer. Interestingly, it has been reported that stress conditions facilitate HERV expression. Space travel exposes astronauts to microgravity environments (a stress condition), which may result in the activation of HERVs and might influence pathogenic outcomes during and after space flight. This study aimed to elucidate the transcriptional activity of three HERV families (W, K, and H) and cytokine genes (IL-1, IL-6, and TNF-α) in different cell lines under microgravity (μg) conditions and compare them with the results obtained under normal gravity (ng; 1g). We evaluated the expression of HERVs (HERV-K env, HERV-K gag, HERV-W env, and HERV-H env) and cytokine gene expression (IL-1, IL-6, and TNF-α) in neuroblastoma (SH-SY5Y), HEp-2, and Caco-2 cell lines under simulated μg and 1g conditions. In SH-SY5Y cells, the expression level of the IL-1, IL-6, HERV-H env, HERV-K env, HERV-K gag, and HERV-W env genes was significantly increased when exposed to short-term μg (3 and 6 h). The expression of TNF-α remained unchanged throughout all time points. Additionally, in Caco-2 cells, the expression of the HERV-K env, HERV-K gag, and IL-1 genes was significantly higher after 6 h of incubation in μg conditions compared to 1g. There was no statistically significant difference in the expression levels of the HERV-W env, HERV-H env, IL6, and TNF-α genes between the μg and 1g conditions. Moreover, in HEp-2 cells, the expression of the IL-1, IL6, TNF-α, HERV-H env, HERV-K env, HERV-K gag, and HERV-W env genes significantly increased following short-term incubation in μg (3 h, 6 h) and then decreased to levels comparable to those observed in the 1g condition. Taken together, the dysregulation of cytokine and HERV gene expression was observed under the simulated μg condition. The patterns of these dysregulations varied throughout cell lines, which demands further investigation for human health protection in space.

Enterotoxigenic Bacteroides fragilis (ETBF) has emerged as a gut microbiome pathogen that can promote intestinal inflammation and contribute to colorectal cancer (CRC). Its principal virulence factor, the Bacteroides fragilis toxin (BFT), is a zinc-dependent metalloprotease that disrupts epithelial barrier integrity, initiates inflammatory signaling pathways, and enhances epithelial proliferation. Although growing evidence supports a link between ETBF and CRC, some inconsistencies across studies highlight the need for further investigation into the molecular mechanisms underpinning BFT-mediated pathogenesis. This review examines the biological structure and activity of BFT, with a focus on its role in epithelial injury, inflammatory responses, and tumorigenesis. In addition, we discuss current challenges in the detection and characterization of ETBF and BFT, including technical limitations in clinical diagnostics and methodological variability across studies. Recent advances in multi-omics technologies, molecular diagnostics, nanobody-based detection platforms, and probiotic intervention are also highlighted as promising avenues for improving ETBF identification and therapeutic targeting. Future research integrating systematic molecular profiling with clinical data is essential to enhance diagnostic accuracy, elucidate pathophysiological mechanisms, and develop effective interventions against ETBF-associated diseases.

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL 1 gene harbors a copy of the human endogenous retrovirus HML-2 , whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology. Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.

The human endogenous retrovirus-K (HERV-K) and TAR DNA-binding protein 43 (TDP-43) have been associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). Given these findings, we investigated the humoral response against HERV-K envelope surface (env-su) glycoprotein antigens and TDP-43 in the plasma of ALS patients and healthy controls (HCs). The measured levels of Abs against the different epitopes’ fragments were significantly elevated in ALS patients, both in long-survivor (LS) and newly diagnosed (ND) patients, compared to HCs. We observed a positive correlation between HERV-K and TDP-43 antibodies (Abs) levels, which seemed to strengthen with disease progression, that was not found in HCs. The TDP-43 and HERV-K epitopes identified in this study are highly immunogenic and recognized by the humoral response of ALS patients. Increased circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers.

A higher expression of human endogenous retroviruses (HERVs) has been associated with several malignancies, including prostate cancer, implying a possible use as a diagnostic or prognostic cancer biomarker. For this reason, we examined the humoral response against different epitopes obtained from the envelope protein of HERV-K (HERV-K env-su19–37, HERV-K env-su109–126), HERV-H (HERV-H env-su229–241, HERV-H env387–399) and HERV-W (HERV-W env-su93–108, HERV-W env-su248–262) in the plasma of patients affected by prostate cancer (PCa), and compared to that of benign prostate hyperplasia (BPH) and a borderline group of patients with atypical small acinar proliferation (ASAP) and prostate intraepithelial neoplasia (PIN) and healthy controls. A significant antibody response was observed against HERV-K env-su109–126 (p = 0.004) and HERV-H env-su229–241 (p < 0.0001) in PCa patients compared to HCs, BPH and borderline cohorts, whilst no significance difference was found in the antibodies against HERV-W env-su93–108 and HERV-W env-su248–262 in patients with PCa. Our results provided further proof of the association between HERV-K and PCa and added new evidence about the possible involvement of HERV-H in PCa pathogenesis, highlighting their possibility of being used as biomarkers of the disease.

Human Endogenous Retroviruses comprise approximately 8% of the human genome, serving as fragments of ancient retroviral infections. Although they are generally maintained in a silenced state by robust epigenetic mechanisms, specific HERV groups, particularly HERV-W and HERV-K, can become derepressed under specific pathological conditions, thereby contributing to the initiation and progression of neuroinflammatory and neurodegenerative processes. Preclinical studies and clinical trials, such as those investigating monoclonal antibodies, indicate that directly targeting these elements may offer a novel therapeutic strategy. In this review, we provide an overview of HERVs′ biology, examine their role in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer′s disease, and Parkinson′s disease, and explore their therapeutic prospects, highlighting both the challenges and the potential future research directions needed to translate these approaches into clinical interventions.

Crohn’s disease (CD) is a multifactorial polygenic inflammatory bowel disease linked to aberrant immune response. Mycobacterium paratuberculosis (MAP) has been associated with CD; however, detecting MAP in CD tissues remains highly challenging. Recently, Human Endogenous Retroviruses (HERVs) differential gene expression has been reported in CD, but little is known about the involvement of MAP and HERVs in CD pathology. This study aimed to characterize the humoral response against HERV-K, HERV-W, and MAP antigens using an indirect ELISA in plasma samples from CD patients and age- and gender-matched healthy controls (HCs). We observed a significant antibody response against HERV-K and HERV-W epitopes in CD patients in comparison to MAP epitopes, as well as a higher overall antibody response in patients compared to HCs. This study is the first to report the presence of humoral immune response against HERVs antigens in CD. Considering the pro-inflammatory nature of CD, HERVs may contribute to the development or progression of disease in genetically predisposed individuals. However, further research is needed to better understand the complex role of HERVs in CD.

Systemic rheumatic diseases, including conditions such as rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, and systemic lupus erythematosus, represent a complex array of autoimmune disorders characterized by chronic inflammation and diverse clinical manifestations. This study focuses on unraveling the genetic underpinnings of these diseases by examining polymorphisms in key genes related to their pathology. Utilizing a comprehensive genetic analysis, we have documented the involvement of these genetic variations in the pathogenesis of rheumatic diseases. Our study has identified several key polymorphisms with notable implications in rheumatic diseases. Polymorphism at chr11_112020916 within the IL-18 gene was prevalent across various conditions with a potential protective effect. Concurrently, the same IL18R1 gene polymorphism located at chr2_103010912, coding for the IL-18 receptor, was observed in most rheumatic conditions, reinforcing its potential protective role. Additionally, a further polymorphism in IL18R1 at chr2_103013408 seems to have a protective influence against the rheumatic diseases under investigation. In the context of emerging genes involved in rheumatic diseases, like PARK2, a significant polymorphism at chr6_161990516 was consistently identified across different conditions, exhibiting protective characteristics in these pathological contexts. The findings underscore the complexity of the genetic landscape in rheumatic autoimmune disorders and pave the way for a deeper understanding of their etiology and the possible development of more targeted and effective therapeutic strategies.

Human endogenous retroviruses (HERVs), as remnants of ancient exogenous retroviruses in the human genome, have received increased attention regarding their pathogenic effects caused by abnormal activation. In normal somatic cells, HERVs are tightly regulated by epigenetic mechanisms and are rarely expressed. In cancer cells, likely due to epigenetic dysregulation, HERVs become abnormally activated and are transcribed and expressed. The innate and adaptive immune responses triggered by HERV activation are closely associated with cancer initiation and progression. Melanoma, as a malignant tumor, often exhibits a poor prognosis in advanced-stage patients. HERVs have been found to be expressed in melanoma and linked to its malignant transformation. Here, we review the potential roles HERVs may play in melanoma development. As promising therapeutic targets for melanoma, research on HERVs could facilitate the development of novel treatment strategies.