Pemphigoid diseases (PDs) are antibody-mediated autoimmune blistering diseases caused by loss of tolerance to basement membrane proteins such as type VII collagen (COL7), triggering pathogenic T and B cell responses. The contribution of regulatory T cells (Tregs) to disease resistance remains unclear. Using a COL7 immunization-induced PD mouse model, we show that transient Treg depletion breaks tolerance and induces skin blistering in otherwise PD-resistant H2[b] mice. Disease occurred predominantly in females and was associated with impaired Treg recovery, early skin inflammation, altered B-cell homeostasis, and antigen-specific CD154[+] T cells. These findings identify Tregs as critical regulators of susceptibility to PD.

Neutrophils are increasingly recognized as key regulators of autoimmune responses; however, the mechanisms by which their heterogeneity is influenced across various tissues in autoimmunity remain insufficiently understood. Here, using experimental autoimmune encephalomyelitis (EAE), we show that splenic and bone marrow neutrophils acquire both CD4[+] T cell suppressive and Th17-promoting capacities. In contrast, lung neutrophils exhibit predominantly CD4[+] T cell suppressive activity. We further identify three distinct neutrophil subsets, comprising Ki67[+] N0, Acvrl1[+] N1, and CD300ld[+] N2 neutrophils. Functionally, CD300ld[-] neutrophils are characterized by a pro-inflammatory phenotype, whereas CD300ld[+] neutrophils demonstrate immunosuppressive activity, indicating tissue-specific properties of these cells. Mechanistically, EAE induces splenic extramedullary granulopoiesis, resulting in the generation of heterogeneous neutrophil subsets, with a notable enrichment of N2 neutrophils in the lung. Within this organ, a unique microenvironment further reprograms CD300ld[+] neutrophils toward a more immunosuppressive state through pathways associated with lipid metabolism. Notably, analogous subsets are also observed in animal models of rheumatoid arthritis and systemic lupus erythematosus, as well as in patients with multiple sclerosis. Collectively, our findings illustrate that splenic extramedullary granulopoiesis creates a heterogeneous neutrophil landscape, which is further shaped by tissue-specific microenvironments, driving the functional plasticity of neutrophils in EAE. This framework defines distinct neutrophil subsets as potential targets for immunomodulatory intervention in autoimmune diseases.

Autoimmune diseases are a major cause of acute and chronic kidney injury, driven by complex mechanisms involving autoantibodies and cellular immune responses that result in tissue damage. Intercalated cells (ICs), specialized renal epithelial cells responsible for proton secretion, are strategically positioned at the epithelial-immune interface, making them ideal sensors of stress signals and potential regulators of immune responses. To investigate the molecular mechanisms by which ICs crosstalk with immune cells during autoimmune kidney injury, we depleted Foxp3[+] regulatory T-cells (Tregs) by injecting diphtheria toxin (DT) into male and female Foxp3-DTR mice. This triggered robust renal autoimmune inflammation, characterized by infiltration of neutrophils, macrophages, and T- and B-cells, along with the formation of ectopic lymphoid-like structures. We found elevated renal autoantibodies in urine and serum, with antibody deposition in glomeruli and tubules. We identified several renal antigens targeted by autoantibodies, suggesting a potential role for these antigens in kidney injury. Damage included glomerular hypertrophy, proximal tubular injury, an increased urine albumin/creatinine ratio, and decreased urine output. Disruption of immune tolerance led to upregulation of inflammasome-related genes and IL-33 in ICs, which act as key alarmin signals that promote Treg activation and expansion. Despite their initial depletion, Tregs rebounded at 2 and 8 weeks, particularly the subsets expressing the IL-33 receptor and activation markers. Our findings reveal a novel IC-Treg crosstalk, a potential immune-regulatory mechanism mediated by the IL-33 pathway that promotes renal immune tolerance. Understanding the mechanisms behind autoimmune renal tubular injury is essential for developing targeted therapies and identifying suitable biomarkers.

Reduced IgG Fc galactosylation, reflected by elevated agalactosylated (G0) glycoforms, is a hallmark of autoimmune diseases and correlates with systemic inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Whether similar glycosylation alterations occur in disease-specific autoantibodies in the absence of systemic inflammation remains unknown. IgG Fc glycosylation was analyzed in systemic sclerosis (SSc), a disease characterized by fibrosis, vasculopathy, and autoimmunity rather than overt systemic inflammation. Anti-centromere protein B antibody-positive (ACA[+]) and anti-topoisomerase I antibody-positive (ATA[+]) SSc patients were studied in a discovery (n = 69) and validation dataset (n = 58), with age- and sex-matched healthy donors (HDs; n = 30 per dataset) as controls (total n = 187). Total and antigen-specific IgG were affinity-purified and analyzed by liquid chromatography-mass spectrometry. Fc glycosylation traits were quantified, and associations with CRP and ESR assessed. Compared with HDs, total IgG1 in SSc exhibited reduced galactosylation (p ≤ 0.01) and sialylation, and increased bisection. These alterations were more pronounced in antigen-specific IgG1, with both anti-CENP-B and anti-TOP1 IgG1 displaying increased fucosylation and bisection; and reduced galactosylation and sialylation compared with total IgG1 (all p ≤ 0.002). Anti-CENP-B IgG1 showed higher bisection than anti-TOP1 IgG1 (p = 0.001), whereas antigen-specific IgG2/3 and IgG4 glycoforms were predominantly detected in ATA[+] patients. Despite significantly elevated autoantigen-specific G0 glycoform frequencies compared with total IgG1 (p < 0.0001 to p = 0.013), no significant correlations with CRP or ESR were observed (rs < 0.24 for all). Findings were confirmed in the validation dataset. Autoantigen-specific IgG1 in SSc exhibits a proinflammatory Fc glycosylation profile in the absence of systemic inflammation, suggesting disease-specific or localized mechanisms underlying Fc glycan remodeling.

Pentraxin 3 (PTX3), the prototypical long pentraxin, is a locally inducible soluble pattern-recognition molecule that participates in complement regulation, efferocytosis, extracellular-matrix organization, vascular homeostasis, host defense, and tissue repair. These properties have made PTX3 an attractive candidate biomarker and regulatory molecule in rheumatic and autoimmune diseases. However, the interpretation of PTX3 in autoimmunity remains challenging because increased circulating or lesional expression may indicate local inflammation without necessarily proving pathogenic causality. This review provides a focused and critical synthesis of PTX3 in systemic lupus erythematosus, rheumatoid arthritis, immune-mediated vasculitis, and other autoimmune or autoinflammatory diseases. Particular emphasis is placed on advances from 2021 to 2025, anti-PTX3 autoantibodies, disease-specific mechanisms, and translational boundaries. Across diseases, the most consistent evidence supports PTX3 as a marker of local inflammatory activity, tissue involvement, and selected complications, especially when conventional hepatic acute-phase reactants such as C-reactive protein do not adequately reflect organ-specific inflammation. At the mechanistic level, PTX3 should not be regarded as a universal pro-inflammatory mediator. Studies using PTX3-deficient models often indicate protective or homeostatic roles, particularly in host defense, apoptotic-cell clearance, and vascular biology. Conversely, more direct evidence for pathogenic or disease-amplifying functions exists in selected settings, including rheumatoid arthritis synovium and complement-inflammasome interactions. Anti-PTX3 autoantibodies further add complexity, showing epitope-, isotype-, and disease-specific effects that may be protective in lupus nephritis but diagnostically or mechanistically relevant in rheumatoid arthritis and ANCA-associated vasculitis. We therefore propose an evidence-based framework separating biomarker association, tissue expression, mechanistic implication, and causal function, and argue that PTX3 should be translated cautiously as a precision biomarker before it is advanced as a therapeutic target.

Hypoxia-inducible factor 1α (HIF-1α) promotes T helper 17 (Th17) differentiation, but whether it regulates ADAM9 expression in Th17 cells during autoimmune nephritis remains unclear. Hypoxia enhanced Th17 differentiation and increased ADAM9 expression in a HIF-1α-dependent manner. HIF-1α deficiency reduced ADAM9 expression and impaired Th17 differentiation in vitro. In anti-glomerular basement membrane nephritis and B6.lpr lupus-prone mice, T cell-specific HIF-1α deletion attenuated renal pathology and reduced kidney-infiltrating CD4[+] and IL-17A-producing T cells. These findings identify ADAM9 as a HIF-1α-regulated target in Th17 cells that may contribute to autoimmune renal inflammation.