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BackgroundAutoantibodies against envelope (Env) protein encoded by human endogenous retrovirus group K (HERV-K) are prevalent in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but it remains unclear which proviruses are responsible for this autoantigen. It also remains poorly understood how the transcription of HERV-K loci is regulated in cells that can produce Env.ResultsWe aligned our neutrophil RNA sequencing data to the new telomere-to-telomere reference genome and found uniquely mapping transcripts from HERV-K101, K102, K104, K108, K109, K117 and ERVK5, of which only K102, K108, and K109 encode an intact Env. Expression of K102 and K108 were higher in SLE than in healthy donors or RA (padj?<?0.05). Transcripts from these proviruses increased in response to interferon-¦Á in monocytes and neutrophils from RA patients and healthy donors, but not in SLE, presumably because they have chronically elevated type I interferons in vivo. Indeed, HERV-K expression was significantly higher in SLE patients with high type I interferon gene signature. Tumor necrosis factor-¦Á and other cytokines and TLR ligands also induced HERV-K102 and K108 transcripts. Interferon-¦Á also increased detectable Env protein in monocytes, macrophages, and neutrophils from RA patients. Among the genes for epigenetic silencers of HERV-K, only TRIM28 was significantly decreased in SLE patients with high interferons (padj?=?0.00024).ConclusionsOur data establish a role for interferons in maintaining increased HERV-K expression in SLE and suggest that interferons or other cytokines can upregulate HERV-K to similar levels in RA. A transient increase may also accompany normal immune responses, suggesting that endogenous retroviruses may have been co-opted for efficient immune responses.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13100-025-00371-y. Key points Expression of HERV-K provirus is elevated in neutrophils from IFN-positive SLETNF¦Á, IFN, and other cytokines induce similar HERV-K expression also in RAHealthy donor myeloid cells respond only transiently with HERV-K transcription Supplementary InformationThe online version contains supplementary material available at 10.1186/s13100-025-00371-y.

BackgroundIn persons living with HIV, antiretroviral therapy (ART) reduces HIV RNA in their plasma and increases CD4?+?T lymphocytes, thus restoring their immune function and reducing mortality rates.MethodsThe heavy and light chains of B cell receptor (BCR) were amplified, sequenced, analyzed, and determined to be anti-CD4 mAb. The cytotoxicity of NK cells mediated by the anti-CD4 mAb was assessed using CCK-8, flow cytometry, ELISA, and western blotting. Detecting the viability/regulation of CD4 cells involved inhibiting the attachment of autoantibodies against CD4 to crucial receptors and detecting the inhibition of key molecules in B cells to produce anti-CD4 mAb in patients with immune non-responders (INR). Furthermore, through Phage Random Peptide Library Screening, we discovered that the AAPMFHSSVQLP-CD4 peptide has an affinity for the anti-CD4 mAb.ResultsAdministering anti-CD4 mAb enhanced NK cytotoxicity. The simultaneous administration of anti-CD4 mAb alongside GST-CD4 alleviated the harmful impacts of anti-CD4 mAb on the CD3?+?population in humanized mice, and HIV virus (p24). Individuals diagnosed with INR displayed abnormal B cell activity, particularly with elevated BAFFR expression and increased levels of anti-CD4 mAb. Nevertheless, suppression of BAFFR hindered B cell function and decreased the production of anti-CD4 mAb. In HIV-infected individuals, the dysregulation of B-cells led to the production of anti-CD4 mAb, which in turn facilitated NK cell cytotoxicity and the CD4?+?T effect by upregulating the expression of BAFFR.ConclusionThe dysregulation of B-cells in person living with HIV increased the production of anti-CD4 mAb, which in turn promoted NK cell cytotoxicity and the CD4?+?T effect.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10020-025-01286-3. Highlights1) B-cell dysregulation increased anti-CD4 mAb levels.2) B cells are abnormally active in patients with INR.3) Knockdown of BAFFR obviously reduced the secretion of anti-CD4 mAb.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10020-025-01286-3.

BACKGROUND Two opposing B cell subsets have been defined based on their cytokine profile: IL-6 producing effector B cells (B-effs) versus IL-10 producing regulatory B cells (B-regs) that respectively positively or negatively regulate immune responses. B-regs are decreased and/or impaired in many autoimmune diseases and inflammatory conditions. Since there is increasing evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD, the aim of this study was to investigate the presence and function of B-regs in COPD. METHODS First, presence of IL-10 producing regulatory B cells in human lung tissue was determined by immunohistochemistry. Secondly, quantification of IL-10??+??B-regs and IL-6??+??B-effs in peripheral blood mononuclear cells (PBMCs) from healthy controls, smokers without airflow limitation, and COPD patients (GOLD stage I-IV) was performed by flow cytometry. Thirdly, we exposed blood-derived B cells from COPD patients in vitro to cigarette smoke extract (CSE) and quantified IL-10??+??B-regs and IL-6??+??B-effs. Furthermore, we aimed at restoring the perturbed IL10 production by blocking BAFF. Fourthly, we determined mRNA expression of transcription factors involved in IL-10 production in FACS sorted memory- and naive B cells upon exposure to medium or CSE. RESULTS The presence of IL-10 producing regulatory B cells in parenchyma and lymphoid follicles in lungs was confirmed by immunohistochemistry. The percentage of IL-10??+??B-regs was significantly decreased in blood-derived memory B cell subsets from smokers without airflow limitation and patients with COPD, compared to never smokers. Furthermore, the capacity of B cells to produce IL-10 was reduced upon in vitro exposure to CSE and this could not be restored by BAFF-blockade. Finally, upon CSE exposure, mRNA levels of the transcription factors IRF4 and HIF-1$\alpha$, were decreased in memory B cells. CONCLUSION Decreased numbers and impaired function of B-regs in smokers and patients with COPD might contribute to the initiation and progression of the disease.