Editorial: Autoimmune diseases: from molecular mechanisms to therapy development

Autoimmune diseases comprise a heterogeneous group of disorders characterized by the immune system's failure to distinguish between self and non-self, leading to aberrant immune responses that target the body's own cells and tissues. This dysregulation manifests as chronic inflammation, tissue damage, and systemic dysfunction, with clinical presentations ranging from severe organ failure to subtle biochemical abnormalities. The pathogenesis of autoimmune diseases is shaped by complex interactions among genetic predisposition, environmental triggers, and epigenetic modifications, which together undermine immune self-tolerance.Given their wide-ranging effects on multiple organ systems and the overlap in clinical manifestations, diagnosing autoimmune disorders is inherently challenging. Proper diagnosis requires the identification of disease-specific biomarkers and the performance of tests to rule out other conditions. This research collection delves into the latest advances in understanding the molecular and cellular mechanisms underlying autoimmunity and current therapeutic approaches. These range from broadly used anti-inflammatory drugs to recent molecular-targeted therapies, such as Janus kinase (JAK) inhibitors, monoclonal antibodies, and emerging cellular therapies, including chimeric antigen receptor (CAR) T cell therapy and regulatory T cell (Treg) adoptive transfer or induction (1).At the core of autoimmune diseases lies the breakdown of immune self-tolerance, a process that drives the activation of autoreactive immune cells, especially T cells and B cells (2). In these diseases, an imbalance arises between effector T cells and Tregs, both locally at the site of tissue damage and systemically. The depletion or functional alteration of Tregs allows autoreactive cytotoxic CD8 + T cells to operate freely. They can migrate into affected tissues and directly interact with and destroy target cells. Additionally, CD4 + T cells exacerbate tissue damage by releasing large amounts of pro-inflammatory cytokines or activating B cells. These inflammatory signals draw many myeloid immune cells to the site of tissue injury. This initiates a localized immune response. Activated B cells mature into plasma cells, producing significant quantities of antibodies against selfantigens. These autoantibodies can activate the complement system, mediate cell destruction through antibody-dependent cell-mediated cytotoxicity (ADCC), or form immune complexes with various nucleic acids and related proteins. Immune complexes can deposit and trigger a strong inflammatory response, damaging organs and tissues. For example, in rheumatoid arthritis (RA), they contribute to osteocyte death and osteoarticular damage (2). In systemic lupus erythematosus (SLE), these complexes target the kidneys, leading to immune-mediated glomerulonephritis (3). Furthermore, the inflammatory response in autoimmune diseases is self-sustaining, driven by the release of pro-inflammatory cytokines and other signaling molecules (2). Notably, the Janus kinasesignal transducer and activator of transcription (JAK/STAT) pathway plays a pivotal role in sustaining this inflammatory cascade by regulating the expression of key pro-inflammatory genes.Dysregulation of the JAK/STAT pathway may promote the immune-mediated destruction of pancreatic beta-cells in type 1 diabetes (T1D) (4) and the intestinal epithelial cell death, along with intestinal barrier problems in inflammatory bowel disease (IBDs) in both humans and mice (5).The interplay between the innate and specific arms of immunity is complex and multifaceted, as illustrated by the case presented by Smertinaite et al. (6), in which an inflammatory stimulus, such as ectopic pregnancy, drives the relapse of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The authors demonstrate that the relapse was associated with increased IL-1 and that a potent B-cell-depleting therapy can hamper this process. Chronic overactivation of plasmacytoid dendritic cells through Toll-like receptors 7 and 9 and the cGAS-STING signaling pathway leads to sustained type I interferon production during inflammatory responses, which can serve as biomarkers of SLE progression and may contribute to disease propagation (7). The cGAS-STING pathway also plays a role in other autoimmune diseases, such as RA (8) and Sjögren syndrome (9).In response to chronic inflammation, the host attempts to limit tissue damage by producing antiinflammatory cytokines, such as interleukin (IL)-37 and IL-38. These cytokines have been extensively studied in conditions such as osteoarthritis and RA (10), where they play a key role in mitigating the inflammatory environment (11). Specifically, IL-37 acts early by inhibiting proinflammatory pathways like STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB, and by influencing macrophage polarization, particularly the balance between pro-inflammatory (M1) and antiinflammatory (M2) subsets. Conversely, IL-38 limits T helper 17 (Th17)-mediated response.Elevated levels of IL-37 and IL-38 have been found both systemically and locally in individuals with RA, and are linked to the Disease Activity Score (DAS28) and histological changes. As patients enter remission, the levels of IL-37 and IL-38 decline, suggesting their potential as biomarkers for disease progression and therapeutic response, as well as a guide for personalized therapy (11).Liang et al. review how histone deacetylase 6 (HDAC6) modulates, at least in part, immune system functions and inflammatory responses in RA, SLE, and psoriasis (12).The bidirectional dialogue between the immune system and the microbial world continues to recalibrate our understanding of autoimmune diseases. Beyond its classical role in maintaining barrier integrity and hemostatic balance, the host-microbe interface has emerged as a potent modulator of systemic immunity. Microbial products can subvert tolerance through molecular mimicry, reshape lymphocyte repertoires, and activate pattern-recognition pathways that imprint long-lasting inflammatory tone. In this context, Wang et al. proposed gut-derived metabolites as discriminative biomarkers of immune status in RA. Through fecal metabolite profiling the authors distinguished between naïve and remission RA patients (13), implicating gut-derived bioactive compounds in systemic inflammatory modulation.Converging evidence also underscores the importance of infectious triggers in autoinflammatory conditions such as synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome (14).The intersection of immune activation, hemostatic regulation, and inflammatory signaling represents an increasingly recognized axis in the pathobiology of autoimmune and autoinflammatory disorders.Sometimes immune and clotting responses can become simultaneously overly active, especially in diseases such as SLE, RA, and IBDs. Matsushita et al. (15) reported a rare case of retroperitoneal fibrosis with IgG4-expressing plasma cell infiltration. The patient experienced recurrent lifethreatening bleeding due to autoimmune coagulation factor XIII deficiency, which was successfully controlled through plasma exchange therapy. Mechanistic analysis revealed pathogenic autoantibodies targeting a structural component of the clotting factor, thereby impairing its function.This case underscores how immune dysregulation can directly undermine coagulation homeostasis, producing a dual burden of autoimmunity and hemorrhagic risk.Despite being classically immune-mediated, a subset of patients remains unresponsive to immunosuppressive therapies. In this context, the report by Sau et al. ( 16) is notable: the authors describe a case in which a thrombopoietin receptor agonist successfully restored platelet counts in a patient with immune thrombocytopenia resistant to multiple immunomodulatory regimens.The accelerating shift toward precision medicine in immunology is grounded in the rapid expansion of molecular diagnostics capable of guiding individualized therapeutic decisions. By integrating genetic, serologic, and transcriptional data, clinicians are increasingly able not only to predict disease risk but also to tailor interventions that improve efficacy, minimize toxicity, and optimize healthcare resources. Autoantibodies remain among the most informative biomarkers in autoimmune and immune-mediated disorders. Liu et al. (17) have illustrated this principle through an unusual anti-PL7-mediated syndrome in which a discrete serologic signature presaged unexpected pulmonary manifestations, with important therapeutic implications in the cure of early-stage disease. Similarly, the cases described by Qin and Yan (18) have shown how convergent autoantibody profiles may unify multiple disparate neurological autoimmune conditions, underscoring the diagnostic and pathogenic value of humoral signatures.Beyond serology, high-resolution transcriptional profiling is emerging as a powerful means of monitoring immune perturbations and therapeutic response. Royo et al. (19) provide a compelling example in SLE, delineating the miRNA and mRNA alterations induced by belimumab treatment.Their findings support the potential of miRNAs, such as miR-146a, as novel biomarkers capable of capturing both disease activity and response to therapy. Moreover, Xu et al. (20) show that even therapeutics may be revitalized through biomarker-based stratification. They demonstrated that rituximab, despite its established role across multiple autoimmune diseases, can achieve improved cost-effectiveness and sustained clinical benefit when guided by individualized biomarker thresholds.Over the past two decades, immunology has witnessed a decisive shift from broad immunosuppression toward precision manipulation of pathogenic pathways. Molecular-targeted agents, including JAK inhibitors and anticytokine monoclonal antibodies (mAbs), have redefined the standard of care in multiple autoimmune and inflammatory diseases by selectively extinguishing the signals that sustain chronic immune activation. The clinical success of TNF-α and IL-17 blockade in RA and psoriasis remains emblematic of this paradigm, demonstrating how interrupting a single cytokine axis can arrest the propagation phase of inflammation and induce durable remission. Indeed, the profound efficacy of TNF-α inhibition across RA and psoriatic arthritis underscores its role as a non-redundant driver of these disorders (21,22).Parallel advances in B-cell-targeted therapies have expanded the therapeutic armamentarium for antibody-mediated diseases. Deng et al. (23) have highlighted the potential of ofatumumab, a novel fully human monoclonal antibody that selectively eliminates B lymphocytes, in anti-N-Methyl-Daspartate receptors (NMDAR) encephalitis. They reported how next-generation mAbs may offer advantages in potency, tissue penetration, or safety relative to conventional B-cell-depleting agents.Similarly, the landscape of Graves' ophthalmopathy is rapidly evolving, with Wang and Chen (24) providing a panoramic view of emerging targeted therapies (such as mAbs targeting CD20, IL-6 R, and insulin-like growth factor-1 receptor) aimed at interrupting fibroblast activation and orbital tissue As computational power and multi-omic datasets continue to expand, in silico modeling is emerging as an indispensable counterpart to classical in vivo systems. Wei et al. (28) have highlighted the utility of bioinformatic approaches in identifying shared pathogenic pathways across coexisting autoimmune diseases within the same individual. Importantly, their findings illustrated that integrative computational analyses can yield clinically actionable insights, enabling more precise and individualized therapeutic strategies.Growing evidence suggests that nutraceuticals may confer therapeutic or preventive benefits across a variety of chronic conditions, including immune-mediated disorders. For instance, Ganoderma lucidum, a fungal product, component of traditional Chinese medicine, has garnered particular interest for its antioxidant and anti-inflammatory activities, and for the absence of reported toxicity (29)