Editorial: [Autoimmunity: novel insights and future perspectives]

Constantin Caruntu^1*Monica Neagu^2*Mihaela Adriana Ilie^3*Ancuta MIHAI^4*

• ¹Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
• ²Institutul National de Cercetare-Dezvoltare in Domeniul Patologiei si Stiintelor Biomedicale Victor Babes Bucuresti, Bucharest, Romania
• ³Dermatology Department, Kalmar County Hospital, Kalmar, Sweden
• ⁴Spitalul Universitar de Urgenta Militar Central Dr Carol Davila, Bucharest, Romania

promotes the activation of proinflammatory and prothrombotic pathways, contributing to disease progression [52,53]. The summarized in vivo studies suggest that low dose proteasome inhibitors may alleviate the clinical manifestations of APS by reducing inflammatory mediators [54,55]. These results indicate that targeting the UPS could represent a novel therapeutic strategy for controlling the inflammatory and thrombotic processes associated with this condition.Expanding the scope of autoimmune interactions, Duan et al. employed bidirectional Mendelian Randomization to elucidate causal relationships between psoriasis, psoriatic arthritis, and multiple autoimmune diseases, including systemic lupus erythematosus (SLE), Crohn's disease (CD), Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA), vitiligo, and ankylosing spondylitis (AS). Their analysis revealed that CD and vitiligo increase the risk of developing psoriasis (PsO), whereas bullous pemphigoid appears to reduce it. For PsA, risk factors extended to CD, HT, RA, AS, SLE, and vitiligo. These results underscore the interconnectivity of autoimmune disorders and highlight the importance of careful monitoring for disease progression, particularly in patients presenting with coexisting autoimmune conditions. The study exemplifies how genetic epidemiology can contribute to risk stratification and early intervention strategies, guiding personalized patient management.Proteome-wide analyses complement genetic studies by identifying causal proteins that may serve as biomarkers or therapeutic targets. Similarly, in AS, a chronic immune-mediated arthritis with a not fully understood pathogenesis, primarily affecting the axial joints [56][57][58], Zhao et al. identified eight plasma proteins causally associated with disease risk, including AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13.Colocalization analyses confirmed these as shared causal variants, while phenome-wide assessments highlighted potential adverse effects, offering guidance for drug development.Together, these studies illustrate the power of multi-omics approaches to unravel the molecular mechanisms underlying autoimmune diseases and to support the design of targeted therapies.The role of the microbiome is emerging as a critical modifier of autoimmune pathogenesis [59][60][61][62][63][64][65][66] Coupled with mechanistic and molecular insights from the other studies, such platforms can accelerate translational research, bridging the gap between bench and bedside.Collectively, these contributions highlight a unifying theme: autoimmunity is a multidimensional process shaped by immune dysregulation, genetic predisposition, proteomic signatures, microbial interactions, and systemic consequences. Across RA, PsA, PsO, AS, and APS, the studies underscore the importance of integrating molecular, microbiological, and clinical data to contribute to risk stratification, biomarker discovery, and targeted interventions.The convergence of genetic epidemiology, proteomics, microbiome research, and advanced modelling technologies emphasize autoimmune disease not as a single organ pathology but as a networked, systemic phenomenon. Furthermore, the research presented in this issue emphasizes translational and clinical implications. Targeted immunotherapies, such as lowdose IL-2 in D2T RA, demonstrate the potential to restore immune balance with precision.Proteomic analyses identify actionable biomarkers and druggable targets in PsA and AS, paving the way for personalized therapeutics. Microbiota interventions illustrate the potential for disease prevention or modulation of progression, while organ-on-a-chip platforms provide realistic preclinical models to optimize drug development and predict adverse effects. Together, these advances signify a paradigm shift toward integrated, precision medicine approaches in autoimmune disease management.Lupus is another chronic autoimmune disease presented in our special issue. It is characterized by dysregulated immune responses leading to inflammation and immune-mediated injury that may affect various organs [67][68][69]. There are 4 original papers dedicated to lupus. Serological profile of Systemic Lupus Erythematosus (SLE) was explored by Nicola et al. and Anti-dsDNA antibodies were found to be statistically significant for both malar rash and proteinuria; anti-Ro/SSA antibodies showed an association with photosensitivity and pericarditis; additionally, association was found between anti-Ro antibodies and proteinuria, but only if anti-dsDNA antibodies were present as well. A similar study focusing on another circulatory marker, Mycinduced nuclear antigen (Mina) 53 The analysis of 26 publications revealed a lack of consensus regarding markers and criteria for assessing immune resolution but identified associations between T-cell regulatory biomarkers and clinical remission. The study highlights the potential of the "immune resolution" concept as marker of durable remissions, as well as the urgent need for methodological standardization in clinical studies.Pemphigus vulgaris, an autoimmune disease affecting the skin and mucous membranes [87][88][89][90][91], was studied by Zakrzewicz et al. and their original study focused on IgG autoantibodies directed against desmosomal adhesion proteins, (e.g. desmoglein-3 and -1) cause loss of keratinocyte adhesion. The paper shows that FcRn binding is compulsory for the pathogenicity of recombinant anti-desmoglein-3 antibodies in keratinocytes. The data suggest that the role of FcRn in autoimmune diseases is versatile and cell-type dependent. The report of Hou and Chen describes a rare case of pemphigus vegetans, a distinct form of pemphigus characterized by vegetative lesions in intertriginous areas, in which the most common autoantibodies target desmoglein 3 [92,93]. The case underscores the importance of prompt diagnosis and appropriate immunosuppressive therapy, demonstrating the effectiveness of modern therapeutic approaches in severe forms of pemphigus.Severe burn injury can generate autoantigens and on this topic Turan et al. focus on the liverderived selenium (Se) transporter selenoprotein P (SELENOP) as a marker of heavy inflammation in acute post-burn phase. The study presents SELENOP-aAb presence correlated with severe burn injury that can be relevant for severely affected patients.Our special issue also host several insightful reviews on this topic. Thus, Gong et al. have reviewed the hypoxic microenvironment, and the role of hypoxia-inducible factor-1 (HIF-1), involved in RA, SLE, multiple sclerosis (MS), and dermatomyositis (DM). Therapeutic strategies that aim at targeting the hypoxic pathways can highlight potential avenues for therapeutic intervention. Immune tolerance is a hot topic in autoimmunity [94][95][96][97][98] and Wixler et al. have reviewed the role of small spleen polypeptides (SSPs) regulators of peripheral immune tolerance. For example in animal models SSPs have reduced the progression of experimental psoriasis or arthritis [99]. Complex mechanisms triggered by SSPs induce the tolerogenic state in dendritic cells, generating Foxp3+ immunosuppressor Treg cells. Also T cells are the subject of the review of Dwyer et al. but in autoimmune diabetes. Key antigenic T lymphocyte epitopes were identified as contributors to this autoimmune pathology and the role of islet-specific T lymphocyte populations.An interesting opinion paper by Mustelin and Andrade presents the reader with a different angle on the 'loss of tolerance' concept in autoimmunity. The paper discusses 4 dilemmas regarding the loss of tolerance were their neoantigen hypothesis brings a critical rethinking and reexamination of the current loss of tolerance concept.Gut microbiota involvement is a recent important topic in autoimmunity [61,[100][101][102][103][104][105][106][107][108][109] and Wang et al. have reviewed its influence in this domain. The paper shows the complex interplay between the gut microbiota and the host and the immune system mainly in diseases like SLE, RA, Sjögren's syndrome, T1DM, ulcerative colitis and Pso [110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125].Also gut microbiota topic is highlighted in the paper of Freuchet et al. that addresses the importance of inflammation and biological variability in synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This review highlights the central role of neuroinflammation -mediated by central nervous systemresident cells, peripheral immune cells, and gut dysbiosis -in triggering and progression of neurodegeneration [126][127][128][129]. Sex-based differences in prevalence and immune response are also emphasized, with major therapeutic implications. The article supports the need for personalized approaches and specific biomarkers for the diagnosis and tailored treatment of synucleinopathies.The role of one type of mesenchymal cells, fibroblasts, in autoimmune diseases was reviewed by Shi et al. and their involvement in dermatological autoimmune conditions such as Pso, vitiligo, and atopic dermatitis. The fibroblasts heterogeneity, is highlighted in each of the autoimmune diseases implying new future research directions and possibly new therapeutic targets. Also in the dermatological area Ungureanu et al. review the autoimmune mechanisms in melanoma [130][131][132], the most severe form of skin cancer [133], with a very complex pathogenesis [134][135][136][137][138][139][140]. They underlie the fact that patients with vitiligo have a lower incidence to develop melanoma [141,142]. Moreover, their paper highlights that Drugassociated leukoderma (DAL) is a prolonged disease-free survival marker in melanoma patients treated with immune checkpoint inhibitors [143,144].In a more exotic form of autoimmunity, acute non-biliary pancreatitis patients (ANBP), is studied in an original paper by Anılır et al. Gene polymorphisms of Toll Like Receptor 4 (TLR4) and Toll Like Receptor 2 (TLR2) was studied their research findings point to TLR-4 Rs4986790 polymorphism groups that can have diagnostic value in ANBP.The study of Barzilai et al. investigates the role of vasculitis as a potential marker of disease severity in familial Mediterranean fever (FMF), a genetic autoinflammatory disorder [145,146]. A comparative analysis of 27 FMF patients with vasculitis and 100 without vasculitis revealed an association with earlier disease onset, increased severity, higher colchicine doses, and a higher frequency of homozygosity for the M694V mutation. Although vasculitis was not identified as an independent factor of severity, its presence may indicate a more aggressive disease course. The results highlight the clinical value of vasculitis as a monitoring and risk stratification indicator in the management of FMF patients.The study of Li et al. explores the role of ferroptosis -a form of cell death dependent on oxidative stress [147,148], in the pathogenesis of thyroid-associated orbitopathy (TAO), a complex autoimmune inflammatory disorder [149,150]. Through bioinformatic analysis of gene datasets and experimental validation, the genes ACO1 and HCAR1 were identified as significant molecular markers, showing reduced expression in the orbital adipose tissue of patients. Correlations with immune cell infiltration suggest a pathogenic mechanism in which macrophages play a key role. These findings provide new insights into the pathophysiological processes underlying TAO and propose ACO1 and HCAR1 as optimal feature genes (OFGs) of ferroptosis, suggesting their potential as diagnostic and therapeutic molecular targets in TAO. patients with IgA nephropathy, a major cause of chronic kidney disease [151][152][153]. Based on a retrospective analysis of 547 cases, predictive factors such as age, mean arterial pressure, eGFR, and serum uric acid were identified. The model demonstrated good performance (Cindex 0.72-0.78) and accuracy in predicting arteriolar damage. This tool provides a simple and reliable method for assessing renal prognosis, enabling early intervention in the management of patients with IgA nephropathy. Also in the nephropathy domain the review of Zhang et al.synthesizes the evidence regarding the involvement of the complement system in antiglomerular basement membrane glomerulonephritis (anti-GBM GN), a rare autoimmune disease that often progresses to end-stage renal disease [154]. Studies demonstrate activation of all three complement pathways and a correlation between complement-related proteins and lesion severity. The identification of biomarkers of complement activation enables risk stratification for renal deterioration and paves the way for the use of complement inhibition as a novel therapeutic strategy [155][156][157][158][159]. The findings support the importance of complement function assessment in the prognosis and management of patients with anti-GBM GN.In the therapy domain the paper of Zhang and Sun evaluate the potential of genetically engineered T-cell therapies (CAR-T and CAR-Treg) in treating autoimmune kidney diseases that are refractory to conventional therapies. By reprogramming T cells to target autoreactive B cells or antibody-secreting plasma cells, these therapies can modulate inflammation and prevent tissue damage [160,161]. The review summarizes recent fundamental and clinical research, highlighting the efficacy of precise targeting in immune regulation. These advances open revolutionary therapeutic perspectives in immune-mediated kidney diseases, marking a transition toward personalized cellular medicine.In conclusion, this research topic captures the dynamic landscape of autoimmune research, emphasizing mechanistic understanding, biomarker discovery, and innovative therapeutic strategies. By linking immunology, genetics, proteomics, microbiology, and technology, the studies collectively advance our understanding of autoimmune pathogenesis and offer new avenues for personalized interventions. As the field moves forward, such interdisciplinary approaches will be essential to translate mechanistic discoveries into clinical impact, ultimately improving patient outcomes and fostering the development of novel, targeted therapies for autoimmune diseases.