Systemic relapse remains a major cause of morbidity in eosinophilic granulomatosis with polyangiitis (EGPA), but widely available prognostic markers are lacking. We retrospectively assessed 83 EGPA patients with rheumatoid factor (RF) tested at diagnosis. Systemic relapse was defined as new or worsening systemic disease activity and treatment escalation, excluding isolated asthma and rhinosinusitis exacerbations. RF-positive patients (45.8%) had higher C-reactive protein levels, more frequent mononeuritis multiplex, and more frequent systemic relapses (39.5% vs. 2.2%, q = 0.002). In the penalised Cox analysis, RF positivity was associated with shorter time to systemic relapse (HR 10.05, 95% CI 2.43-92.57; p < 0.001) and remained associated after adjustment for MPO-ANCA and treatment intensity. RF positivity may support closer surveillance in EGPA.

Spondyloarthritis (SpA) represents a heterogeneous group of chronic inflammatory rheumatologic diseases, including axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and SpA associated with inflammatory bowel disease (IBD). These conditions share overlapping clinical manifestations, genetic predisposition-particularly a strong association with HLA-B27-and common immunopathogenic pathways, notably the IL-23/IL-17 axis and tumor necrosis factor (TNF) signaling. Understanding SpA pathophysiology has been greatly facilitated by animal models, which have provided critical mechanistic insights and served as indispensable tools for preclinical drug testing. Among these, rodent models have been particularly informative. However, despite their contributions, no single model reproduces the full clinical spectrum of SpA, which includes axial inflammation, enthesitis, peripheral arthritis, and extra-articular manifestations such as uveitis, psoriasis, and gut involvement. This review provides a comprehensive analysis of rodent SpA models, focusing on their mechanistic underpinnings, key discoveries, and translational relevance. We first summarize the major categories of models before examining the strengths and limitations of each. We highlight how these models have advanced our understanding of the gut-joint axis, IL-23-driven entheseal inflammation, and TNF-dependent pathways, which are now major therapeutic targets. Finally, we discuss emerging strategies to enhance translational fidelity, including humanized mice, microbiome engineering, and integration of multi-omic approaches. These developments are essential to bridge the current gap between experimental findings and clinical applications in SpA.

The expansion and pathogenic differentiation of intermediate monocytes (IMs) are critical yet poorly understood events in psoriasis pathogenesis. Here, we identify the transcription factor PU.1 (encoded by SPI1) as a master regulator driving IM-mediated psoriasiform inflammation. Single-cell RNA sequencing and flow cytometry of peripheral blood mononuclear cells revealed expansion of IMs in psoriasis patients, with PU.1 uncovered as its specific regulator. Myeloid-specific ablation of Spi1 in mice ameliorated imiquimod-induced psoriasiform dermatitis. Mechanistically, PU.1 promoted IMs differentiation into pro-inflammatory M1 macrophages by transcriptionally upregulating Dectin-1, thereby activating the SYK/NF-κB pathway. We further discovered that the clinical-stage bromodomain and extra-terminal domain inhibitor NHWD-870 effectively suppressed PU.1 expression. Oral administration of NHWD-870 demonstrated potent efficacy in murine psoriasis models by disrupting this PU.1-dependent IMs differentiation. Our findings establish PU.1 as a novel therapeutic target for psoriasis and propose that pharmacologic inhibition of PU.1 represents a promising treatment strategy.

Inhalation of respirable crystalline silica (c-silica), an occupational hazard, has been associated with the development of systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, it is unclear if c-silica-mediated autoimmune disease requires pre-existing subclinical autoimmunity or to what extent the severity of existing subclinical autoimmunity influences the spectrum and severity of c-silica-induced autoimmune phenotypes. Sixty-one naïve Collaborative Cross (CC) strains, a multiparental panel of recombinant inbred (RI) mouse strains derived from eight founder strains, were assessed for the presence of subclinical autoimmunity via autoantibodies and inflammatory markers. These studies revealed a broad spectrum of subclinical autoimmune responses in naïve CC RI strains. Six strains, chosen to represent the range of subclinical autoimmunity, were exposed to c-silica or saline and studied for development of lung inflammation, autoantibodies, inflammatory markers, and the presence of connective tissue disease. Silica exposure resulted in the development of strain-selective systemic autoimmune disease phenotypes of varying severity. Specifically, c-silica exposure triggered inflammatory arthritis in female CC039 mice and lupus nephritis in CC061 mice. Other strains demonstrated lupus-like disease features without clear tissue involvement. The presence of subclinical autoimmunity dramatically influences the severity and specific disease phenotype of c-silica-induced systemic autoimmunity. These observations identify CC RI mice as a valuable resource to study the influence that subtle genetic differences and pre-existing subclinical autoimmune phenotypes have on the development and severity of autoimmune diseases linked to occupational and environmental exposures.

Liver damage in autoimmune hepatitis (AIH) is perpetrated by T-effector lymphocytes that are not adequately restrained by regulatory T cells (Tregs). The goal of AIH treatment is to control inflammation and induce disease remission through administration of immunosuppressive drugs including corticosteroids, azathioprine, and, in difficult-to-treat cases, mycophenolate mofetil or tacrolimus (TAC). Despite TAC being a potent immunosuppressant, its use has been hampered by a narrow therapeutic window and systemic toxicity. In this study, we have tested the effects of lipid-core nanoformulations encapsulating TAC (NC-TAC) as a novel drug delivery system that would enable potentially favorable immunomodulatory effects compared with unencapsulated TAC. NC-TAC properties were assessed in vitro, in CD4 T cells and Tregs isolated from the peripheral blood of AIH patients and controls; and in vivo through a model of T cell-mediated liver injury induced by Concanavalin-A (Con-A) in NOD/scid/gamma mice, pre-emptively reconstituted with human CD4 T lymphocytes. Compared to unencapsulated TAC, NC-TAC favored a regulatory phenotype in CD4 T cells of AIH patients, enhanced the suppressive function and preserved AIH Treg phenotype in the presence of an inflammatory stimulus. Systemic administration of NC-TAC ameliorated liver injury in vivo, as indicated by decreased ALT levels, reduced lymphocyte infiltration on histology, and an increased frequency of intrahepatic CD4[+]FOXP3[+] lymphocytes. NC-TAC could therefore be considered as a novel drug delivery system to be possibly explored for the treatment of AIH, having a beneficial immunomodulatory profile and effectively favoring Treg immune responses.

Muscle-specific kinase (MuSK) is a pivotal player in forming and maintaining healthy neuromuscular junctions (NMJ). In MuSK myasthenia gravis (MG), autoantibodies targeting MuSK disrupt its function, impairing neuromuscular transmission and causing fatigable skeletal muscle weakness. MuSK autoantibodies predominantly belong to the IgG4 subclass, which bind in a monovalent fashion due to Fab-arm exchange, although autoantibodies of other subclasses also exist. Polyclonal autoreactive IgG from patients may therefore harbor a variety of monovalent and bivalent MuSK antibodies with potentially distinct effects on MuSK signaling. To further unravel the pathomechanisms underlying MuSK MG, we have investigated how MuSK antibody-binding affects MuSK functioning with a diverse panel of (patient-derived) monoclonal MuSK antibodies. Our findings reveal that the valency of antibody-binding influences binding kinetics to MuSK, inhibition of agrin-induced MuSK activation, Dok7 binding to MuSK and NMJ gene expression. Monovalent binding to the frizzled domain of MuSK did not inhibit agrin-induced MuSK activation, while monovalent binding to the Ig-like domain 1 does. Moreover, the kinetics of Dok7 degradation induced by bivalent MuSK antibodies appear to depend on binding-epitope of MuSK. Surprisingly, none of the clones tested (both bivalent and monovalent) increased MuSK internalization. Taken together, the cumulative pathogenic effect of polyclonal MuSK antibodies in individual MuSK MG patients thus likely depends on autoantibody titer, affinity and the unique composition of MuSK autoantibodies varying in epitope and valency. This research enriches our understanding of the intricate interactions between antibodies and MuSK in MuSK MG and offers potential insights into novel therapeutic strategies using MuSK antibodies.

Somatic mutations can generate neoantigens recognized by CD8[+] T cells, enabling targeted elimination of mutated cells. Currently established B cell-targeting therapies in human B cell-mediated autoimmune diseases lack specificity and fail to achieve durable remission. Since autoreactive B cells often express B cell receptors (BCRs) that have undergone extensive somatic hypermutations (SHM), we hypothesized that mutated BCR-derived neoantigens could be exploited to selectively target these autoreactive B cells. However, the identification, validation, and extent to which autoreactive BCR-derived neoepitopes are presented and immunogenic remains poorly understood. Here, we investigated the immunological targetability of autoreactive B cells producing anti-citrullinated protein antibodies (ACPAs) - the hallmark antibody response in rheumatoid arthritis (RA). By using an integrated approach combining in silico MHC class I binding analysis, peptide-elution mass spectrometry, and CD8[+] T cell-activation assays, we studied 9 common HLA class I alleles and 150-patient derived BCRs. Our results predict that all autoreactive BCRs harbor sequences presentable by at least 3 HLA class I alleles. Notably, 85% of these sequences contain SHMs that introduce amino-acid changes compatible with candidate neoepitopes. Mass spectrometric analysis of HLA class I-eluted peptides from three BCR-transduced cell lines confirmed the presence of multiple predicted neoepitopes and revealed additional unpredicted, BCR-derived peptides. Importantly, several of these neoepitopes were endogenously processed, presented, and recognized by primary human CD8[+] T cells, while their unmutated counterparts were not recognized by the same CD8[+] T cell clones. These findings highlight that an integrative strategy, combining MHC isolation, peptide identification, and BCR sequencing, serves as a powerful platform for uncovering neoantigens presented by autoreactive B cells in a major human autoimmune disease. Likewise, they reveal a novel approach for the specific targeting of autoreactive B cells, paving the way for personalized immunotherapeutic interventions in RA and potentially other B cell-driven autoimmune diseases.