Eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) are rare systemic inflammatory conditions associated with eosinophilia and end-organ damage. Therapeutic aims for these diseases should include achieving sustained remission, preventing relapse, minimizing disease and treatment-related organ damage, restoring and maintaining quality of life and reducing mortality. To achieve these treatment goals in clinical practice, there is a need for clearly defined clinical outcomes, in addition to early diagnosis to facilitate early therapeutic intervention. This narrative review examines how clinical outcomes are currently defined and assessed in EGPA and HES studies and discusses how related treatment goals can be achieved, including the challenges physicians may face when implementing them. Treatment comparisons between studies are complicated by differences in how treatment-related outcomes are defined. Remission and relapse outcomes are generally well reported, although heterogeneously defined, while treatment-free remission, treatment-related toxicity, target-organ damage, mortality and patient-reported outcomes require further study. Additionally, many assessment tools utilized in clinical research are unreliable, not standardized and/or not disease-specific. Consensus definitions of treatment goals and disease-specific desired outcomes would facilitate better assessment and comparison of treatment responses in clinical practice for both EGPA and HES, supporting clinicians to set ambitious and achievable treatment goals for their patients. TAKE HOME MESSAGE.

Inflammatory myopathies are clinically and molecularly heterogeneous autoimmune diseases in which sustained type I interferon (IFN-I) responses and inflammatory cell death both contribute to tissue injury, yet their functional relationship remains poorly integrated. We integrate patient, disease-model, and mechanistic evidence to propose an evidence-graded reciprocal regulatory model between pyroptosis and IFN-I. Self-DNA may initiate AIM2/inflammasome-caspase-1-GSDMD-mediated pyroptosis; pyroptosis and ongoing tissue injury may increase self-DNA release or cytosolic exposure, together with the release of damage-associated molecular patterns (DAMPs), thereby potentially engaging cGAS-STING-TBK1-IRF3 signaling and IFN-I production; sustained IFN-I may in turn alter subsequent pyroptotic susceptibility through IFNAR-JAK-STAT-dependent transcriptional priming. Importantly, the complete bidirectional regulatory model has not yet been directly demonstrated in human inflammatory myopathies. Model persistence is further shaped by IFN negative feedback, DNA clearance, mitochondrial homeostasis, and oxidative stress. Evidence converges most clearly in dermatomyositis (DM): anti-MDA5-positive DM shows convergence of neutrophil extracellular trap (NET)-derived DNA, macrophage pyroptosis, and lung inflammation, whereas anti-NXP2-positive DM provides human evidence for self-DNA-cGAS/STING coupling. In antisynthetase syndrome, immune-mediated necrotizing myopathy, and inclusion body myositis, the network appears more context dependent. We also outline a biomarker framework spanning DNA/DAMP burden, pyroptotic activity, and IFN-I responses, and discuss therapeutic opportunities at IFN/JAK, inflammasome/GSDMD, and cGAS-STING nodes. This model integrates cell death, DNA sensing, and interferon signaling into a testable framework for disease persistence, molecular stratification, longitudinal monitoring, and mechanism-based therapy in inflammatory myopathies. TAKE-HOME MESSAGE: The proposed Pyroptosis-IFN-I reciprocal regulatory model provides an evidence-graded framework linking inflammatory cell death, self-DNA sensing, and interferon signaling in inflammatory myopathies. By integrating disease-context specificity with biomarker and therapeutic evidence, this model may help explain persistent inflammation and molecular heterogeneity while providing a rationale for mechanism-based patient stratification and targeted therapeutic investigation.

The Hippo signaling pathway is traditionally regarded as a key regulator of cancer initiation and progression. However, accumulating evidence indicates that the Hippo signaling pathway is also closely associated with the onset and progression of autoimmune diseases. Dysregulation of Hippo signaling in immune cells may disrupt immune homeostasis, thereby increasing susceptibility to autoimmune disorders. This review summarizes recent advances in understanding the role of the Hippo signaling pathway in immune cells and autoimmune diseases, and highlights the potential of targeting Hippo signaling as a novel therapeutic strategy for autoimmune diseases.

Immune-mediated systemic diseases frequently produce oral and orofacial findings involving the mucosa, salivary glands, periodontium, temporomandibular joints, and masticatory or oropharyngeal function. These findings may precede systemic diagnosis, reflect disease activity or damage, result from treatment, or identify patients requiring urgent referral. This expert narrative review provides a phenotype-based diagnostic and management framework for oral and orofacial manifestations of major immune-mediated systemic diseases. We integrate disease-specific patterns with key mimics, required confirmatory investigations, diagnostic red flags, and referral urgency. Ulcerative, lichenoid/interface, vesiculobullous, sicca/salivary, periodontal, temporomandibular, vascular/ischemic, infectious, and drug-related presentations are distinguished according to whether diagnosis is primarily clinical or requires further investigation. Systemic-disease correlation is supported by microbiological, histopathological and imaging data. Characteristic examples include recurrent aphthous-pattern ulceration in Behçet disease, salivary hypofunction in Sjögren disease, microstomia in systemic sclerosis, strawberry gingivitis in granulomatosis with polyangiitis, jaw claudication in giant cell arteritis, and granulomatous oral disease in Crohn's disease. Management is organized around local symptomatic care, correction of trauma or secondary infection, topical treatment of confirmed local immune-mediated disease, guideline-directed systemic therapy when oral findings reflect active systemic disease, and urgent referral for suspected vascular ischemia, multisite blistering disease, airway or ocular involvement, progressive dysphagia, or rapidly enlarging salivary glands. This lesion-first approach is intended to improve early recognition and multidisciplinary coordination across rheumatology, internal medicine, immunology, dentistry, oral medicine and dermatology.

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystem autoimmune disease in which the breakdown of T-cell tolerance is increasingly recognized as a central and therapeutically tractable event. Herein, we synthesize the spectrum of T-cell abnormalities in SLE and elucidate the underlying molecular mechanisms. SLE T cells show expanded B-cell-helper (Tfh/Tph), Th17 and double-negative populations, deficient or dysfunctional regulatory T cells, an intrarenal Th1 bias, clonally expanded cytotoxic and tissue-resident memory CD8[+] cells, and expanded IL-10-producing Th10 and age-associated helper T-cell states. We propose that these phenotypes arise from four interacting layers of dysregulation: extracellular cues including cytokine and non-cytokine mediators and altered antigen presentation, T-cell receptor (TCR) and co-stimulatory signaling, immunometabolic reprogramming, and epigenetic remodeling spanning DNA methylation, RNA modifications and histone post-translational modifications (PTMs). We highlight an integrated metabolic-epigenetic axis, in which metabolites act as obligatory substrates or cofactors for the enzymes that write and erase chromatin marks, and we identify the PP2A signaling axis, CaMK4 and mTOR as hubs that act across several layers at once, so that the layers are bidirectionally coupled rather than arranged in a single causal direction. Finally, we discuss how these mechanisms inform an evolving therapeutic landscape.

Absent in melanoma 2 (AIM2) is a cytosolic pattern recognition receptor that functions as a critical sensor of double-stranded DNA (dsDNA) of microbial or host origin. Upon DNA recognition, AIM2 assembles into a multiprotein inflammasome complex that drives pyroptotic cell death and maturation of the pro-inflammatory cytokines IL-1β and IL-18. Beyond its canonical role in host defense, aberrant AIM2 activation by self-DNA has been increasingly implicated in the pathogenesis of various inflammatory autoimmune diseases. This comprehensive review synthesizes current understanding of AIM2 biology. We examine the role of AIM2 in different immune cell populations, its effects on multiple downstream signaling pathways, and its complex association with autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Finally, we discussed therapeutic prospects and remaining challenges in targeting AIM2 for the treatment of autoimmunity.

Anti-neutrophil cytoplasmic antibody (ANCA)-mediated vasculitis (AAV) with its most prevalent manifestation, pauci-immune necrotizing crescentic glomerulonephritis (ANCA GN), is a potentially life-threatening autoimmune disease. This unique disease is characterized by antibodies directly affecting the activity and behavior of innate immune cells. It is a chronic condition with substantial risk of relapsing disease. The initial hyperinflammatory state is dominated by the innate immune system, but ongoing crosstalk with the adaptive immune system and the balance between damage and repair are crucial during the course of disease. Although we recognize the importance of the adaptive immune system in the pathogenesis of AAV, in this narrative review we provide an overview of the leading role of neutrophils and macrophages and their interplay with other components of the innate immune system in the pathogenesis of AAV and ANCA GN. Their central involvement is substantiated by increasing numbers of in vitro, in vivo, clinicopathological, molecular, and genetic studies. Classical evidence that neutrophil degranulation and reactive oxygen species play a role in ANCA GN is being expanded by recent insights into the damaging and communicative effects of neutrophil extracellular traps in ANCA GN. Macrophages, one of the most prevalent inflammatory cell types at the site of early ANCA GN, differentially contribute to inflammation, resolution, and chronicity in ANCA GN. In this narrative review, we discuss the current knowledge pertaining to the role of the innate immune system in the development and progression of ANCA GN.

The liver serves as a pivotal metabolic and immunological hub, yet its homeostatic equilibrium is highly susceptible to mitochondrial dysfunction. Recent studies have implicated mitochondrial DNA (mtDNA) as an important damage-associated molecular pattern (DAMP) that links mitochondrial injury to sterile hepatic inflammation and KCs (KCs) activation. This review provides a comprehensive synthesis of the mtDNA mediated KCs across four major hepatic pathologies: Alcohol-associated Liver Disease (ALD), Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Hepatic Ischemia-Reperfusion Injury (IRI), and Hepatocellular Carcinoma (HCC). We discuss emerging evidence that Z-DNA-binding protein 1 (ZBP1) associated PANoptosis and nerve injury-induced protein 1 (NINJ1) mediated plasma membrane rupture may contribute to inflammatory cell death in severe liver injury, complementing rather than superseding canonical pyroptotic mechanisms. However, the extent to which mtDNA directly activates this axis remains unresolved. Furthermore, we delineate the cell-type-specific dichotomy of cyclic GMP-AMP synthase (cGAS) signaling, which fuels pro-inflammatory storms in KCs via the stimulator of interferon genes (STING) pathway while promoting protective mitophagy in hepatocytes through a STING-independent cGAS-Beclin-1 interaction. In the context of immunometabolism, we also summarize preclinical evidence linking cytidine/uridine monophosphate kinase 2 (CMPK2) dependent mtDNA synthesis to inflammasome activation and mitochondrial calcium uniporter (MCU) acetylation to age-associated mtDNA release during IRI. Finally, we evaluate the clinical translational potential of targeting these molecular hubs and the emergence of cell-free mitochondrial DNA (cf-mtDNA) fragmentomics-including 5' end motif analysis and diversity scoring as a transformative liquid biopsy tool for precision diagnosis. Collectively, available evidence positions mtDNA mediated KCs activation as an important, context-dependent contributor to liver disease and a potential therapeutic target, while underscoring the need for cell-specific and human validation.

The PD-1/PD-L1 immune checkpoint pathway serves as a core regulatory hub that maintains peripheral immune tolerance. In different disease contexts, this axis exhibits opposing outcomes. In cancer, sustained antigenic stimulation elevates PD-1 expression and locks T cells into an exhaustion phenotype-a state characterized by progressive loss of effector functions, coordinated upregulation of multiple inhibitory receptors, and a TOX-driven epigenetic landscape. Conversely, in lupus nephritis (LN)-a severe autoimmune complication of systemic lupus erythematosus (SLE)-PD-1[+] T cells (both CD8[+] and CD4[+] subsets) undergo clonal expansion, display a highly activated phenotype, and produce abundant granzyme B, perforin, and IFN-γ, thereby directly inflicting renal tissue damage. Importantly, LN-associated PD-1[+] T cells are not uniformly exhausted; single-cell studies suggest that activated and partially exhausted subsets can co-exist. This review systematically elucidates the molecular, cellular, and microenvironmental bases that determine the bidirectional nature of PD-1 signaling-driving T cells toward exhaustion in cancer while promoting T cell activation in LN. Key differentiating factors underlying this divergence include the intensity and persistence of antigen stimulation, activation of the TOX-dependent exhaustion epigenetic program, the cytokine milieu composition (type I interferons, IL-12, IL-6), the balance between co-stimulatory and co-inhibitory signals, and the strikingly different metabolic environments-a nutrient-deprived, hypoxic tumor microenvironment versus an inflamed, metabolically active kidney in LN. As a theoretical synthesis, we propose a conceptual "balancing window" model of PD-1 signal strength to describe this bidirectional regulatory mechanism; this model is hypothesis-generating and not clinically validated. Finally, we discuss the clinical translation implications of this framework, encompassing PD-1 agonistic strategies in autoimmune diseases (still largely preclinical/early clinical), PD-1 blockade in cancer therapy, and the iatrogenic lupus-like syndrome induced by immune checkpoint inhibitors-the latter providing biological plausibility rather than definitive proof of causality. All proposed biomarkers and algorithms are presented as investigational tools not yet ready for routine clinical practice. Moreover, LN pathogenesis involves multiple pathways beyond T cells-including immune complexes, complement, B cells, and innate immunity-and the PD-1 axis should be considered within this broader context.

Persistent autoantibody production after conventional immunosuppression or B-cell depletion has focused attention on antibody-secreting cells that survive without ongoing proliferation. Long-lived plasma cells (LLPCs) are indispensable for durable protective immunity, but autoreactive members of this compartment may also maintain pathogenic antibodies in selected autoimmune diseases. Interpretation is complicated because longevity is usually inferred from population kinetics, anatomical persistence, transcriptional state, or treatment resistance rather than demonstrated by lineage tracing in humans; neither CD19 loss nor any single surface phenotype is a definitive identifier. We conducted a structured narrative review focused on rheumatic diseases and selected antibody-mediated disorders. We integrate developmental routes, CXCR4-dependent homing, adhesion, BAFF/APRIL receptor biology, stromal contact, proteostatic and metabolic adaptation, and single-cell heterogeneity. Systemic lupus erythematosus and lupus nephritis receive dedicated consideration because renal antibody-secreting-cell signatures distinguish active plasmablast-rich inflammation from LLPC-like persistence in refractory disease. Across diseases, the evidence ranges from direct kinetic or tissue studies to indirect serological observations and therapeutic inference. Plasma-cell-directed therapies-including proteasome inhibition, CD38 depletion, BCMA-directed T-cell engagers or cellular therapy, and immune reconstitution-have produced clinically important signals, but most autoimmune data remain uncontrolled, early-phase, or disease-specific. Niche disruption, apoptosis or autophagy inhibition, and antigen-specific deletion remain preclinical or conceptual. A useful translational framework is therefore not that LLPCs are universal master drivers, but that persistent autoreactive plasma cells may constitute one treatment-relevant disease module whose importance should be demonstrated with tissue, clonal, and longitudinal evidence before intervention.

The adaptive immune receptor repertoire (AIRR), composed of T-cell receptors (TCRs) and B-cell receptors (BCRs), underpins antigen-specific immunity through extensive diversity generated by V(D)J recombination and junctional modification. Advances in high-throughput AIRR sequencing have enabled comprehensive characterization of clonal diversity, gene usage patterns, and antigen-driven selection at unprecedented resolution. In autoimmune diseases, breakdown of immune tolerance permits the persistence and expansion of autoreactive lymphocyte clones, and is associated with characteristic repertoire remodeling. Reported alterations include changes in repertoire diversity, oligoclonal expansion, biased V(D)J gene usage, and convergent CDR3 motifs. Notably, repertoire changes exhibit spatial and temporal heterogeneity across peripheral blood and target tissues, highlighting the compartmentalized nature of adaptive immune responses. This review synthesizes current evidence on TCR and BCR repertoire alterations across major autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, type 1 diabetes, and ankylosing spondylitis. We summarize emerging computational frameworks for AIRR analysis and highlight machine learning approaches for clonotype classification and antigen specificity prediction. Furthermore, we discuss the diagnostic, prognostic, and therapeutic implications of AIRR profiling, particularly the potential for identifying disease-associated clonotypes and guiding antigen-specific immunotherapies. Despite ongoing technical and biological challenges, continued advances in sequencing technologies and computational modeling are strengthening the role of AIRR analysis as a valuable framework for elucidating autoimmune pathogenesis and advancing precision immunology.

Immune dysregulation spans a continuum from autoinflammation to autoimmunity and primary immune disorders, and arises from the interplay between genetic lesions and multiple layers of biological regulation. Monogenic diseases have provided critical models to dissect this complexity, yet phenotype is not determined by DNA sequence alone. The same gene can give rise to distinct clinical entities depending on variant functional class, position within functional domains, residual activity, isoform usage and cell- or tissue-specific effects, while carriers of identical variants may have variable phenotype due to somatic mosaicism, clonal dynamics, allelic expression bias, modifier genetics or environmental buffering. This review examines the major determinants of penetrance and variable expressivity across mechanistically informative immune disorders. We first analyze variant-intrinsic mechanisms using archetypal genes including MEFV, NLRP3, PLCG2 and UBA1, highlighting how distinct functional classes reshape disease identity. We then discuss how cellular context, somatic variation, allelic expression and X-linked regulation modify effective gene dosage in vivo. We further integrate multilocus inheritance, common and rare modifiers, interferonopathies, monogenic lupus-like diseases and primary immune disorders characterized by blended autoimmunity, autoinflammation and host-defense defects. Finally, we examine epigenetic, environmental and life-course drivers and their implications for diagnosis, counseling and precision therapy. Together, these data support a model in which genotype defines a framework rather than a fixed outcome. A mechanism-based view of immune dysregulation is therefore required to move from genetic diagnosis to meaningful prediction of disease expression and therapeutic response.

Organellar communication between mitochondria and melanosomes serves as a cornerstone of pigment cell biology, orchestrating bioenergetics, ion dynamics, and organelle remodeling during melanogenesis. Recent mechanistic insights reveal that melanosomal STIM1 engages mitochondrial Mitofusin-2 (Mfn2) upon calcium depletion to channel localized ATP for V-type ATPase-driven acidification, enabling PMEL amyloidogenesis. Concurrently, mitochondrial fission factor (MFF) translocates to melanosomes to assemble an ARP2/3-dependent actin network required for organelle scission and structural integrity. In Alopecia Areata (AA)-an autoimmune disorder classically characterized by hair follicle immune privilege collapse-active bulb melanocytes represent a primary vulnerable locus, as illustrated by clinical hallmarks such as the selective loss of pigmented hair ("canities sparing") and initial white hair regrowth (poliosis). Here, we synthesize how environmental or genetic stressors destabilize this mitochondria-melanosome axis: mitochondrial Ca[2+] overload and respiratory uncoupling dismantle STIM1-Mfn2 tethers and disrupt MFF scission, resulting in bioenergetic crisis, "aborted" melanization, and melanosomal membrane peroxidation. The ensuing release of damage-associated molecular patterns (DAMPs) and carbonylated neoantigens activates the NLRP3 inflammasome and cGAS-STING pathway, driving ectopic MHC class I expression and recruiting autoreactive CD8[+] T cells to execute targeted follicular destruction. By critically stratifying histopathologically proven AA endpoints from extrapolated vitiligo and epidermal melanocyte data, this review reframes AA within an organelle-centric pathogenic paradigm and highlights emerging therapeutic interventions targeting the mitochondria-melanosome axis.

Systemic autoimmune diseases often require long-term immunosuppression to control disease activity and prevent organ damage. However, immunosuppressive drugs increase the risk of infections, which remain among the leading causes of hospitalization and premature mortality in these conditions. The persistent therapeutic dilemma between too low and too severe immunosuppression is a major challenge in rheumatology practice, and very few tools exist to evaluate and follow the degree of immunosuppression in patients with systemic autoimmune diseases. Torque teno virus (TTV) is a non-pathogenic single-stranded DNA virus, which infects virtually everybody. TTV has emerged as a candidate biomarker of the net state of immunosuppression. TTV replication is dynamically constrained by host immune surveillance; blood viral load rises when immune control is impaired and falls when immune competence is restored. In solid organ transplantation, high TTV loads have been associated with infectious complications, whereas low loads have been associated with graft rejection, supporting the concept that TTV reports the balance between over- and under-immunosuppression. This Review summarizes the biological rationale for TTV monitoring, critically appraises transplantation evidence, reviews emerging data in systemic autoimmune disease, and proposes a translational framework for TTV-guided precision immunomodulation in systemic autoimmune diseases to be evaluated in future studies.