Objectives Preeclampsia (PE) is a pregnancy-associated hypertensive disorder characterized by maternal systemic inflammation and endothelial dysfunction. Although aberrant maternal-fetal immunotolerance plays a role in the pathogenesis, the breadth and specificity of maternal antibody responses remain poorly defined. Methods We performed phage immunoprecipitation sequencing (PhIP-Seq) to profile antibody reactivity against 42,692 peptides representing 16,296 proteins across 661 species in women with PE (n = 15) and control pregnancies (n = 33). Selected autoantigens were further evaluated using germline and placental expression datasets and RT-qPCR in independent placental samples. Results Maternal antibody repertoires in PE differed from controls at the level of individual antigens despite a similar overall number of antibody targets. Among 59 endogenous targets enriched in PE, 48 showed male germline associated expression, including CATSPERZ, DCAF8L2, and NBPF3. Many of these targets also showed expression in placental and vascular tissue, and placental expression of selected targets was confirmed by RT-qPCR in an independent cohort. In addition, selective differences in microbial and viral antibody reactivity were observed, including enrichment of Streptococcus dysgalactiae, EBV and influenza A virus antigens in PE, and reduced recognition of HSV-1 antigens. Conclusion PE is associated with an altered maternal antibody profile characterized by autoreactivity to placental and developmental antigens. The overlap between antibody targets and placental expression identifies a previously unrecognized pattern of maternal immune recognition involving shared placental and male germline-associated antigen programs in PE. These findings suggest that maternal immune responses are associated with disease pathophysiology.
Myasthenia gravis (MG) is an autoimmune neurological disease driven by the production of autoantibodies against components of the neuromuscular junction, resulting in fatigable muscle weakness, and in more severe cases, leading to life-threatening complications. This breakdown of immune tolerance has been associated with an impaired suppressive function and altered frequency of Regulatory T cells (Tregs) in autoimmune diseases, including MG. As key regulators of immune tolerance, Tregs play a pivotal role in maintaining immune homeostasis through their ability to suppress other immune cells, controlling inflammation. Nevertheless, the mechanisms underlying Tregs dysfunction in MG pathogenesis are not fully understood. Here, we reveal the impact of Treg N-glycosylation on their immunoregulatory activity and function in the MG context. Glycan profiling by flow cytometry of circulating Tregs from MG patients (n = 72) and healthy controls (HCs; n = 24) revealed increased presence of oligomannose N-glycans in disease. Moreover, this specific Treg N-glycome profile was associated with disease severity, distinguishing between active disease and remission, being more pronounced in MG patients with additional autoimmune diseases, highlighting its potential as a disease biomarker. Functionally, in vitro abrogation of the N-glycosylation pathway in Tregs (mimicking the oligomannose enrichment found in the patients) resulted in impaired suppressive capacity over conventional T cells. Consistently, in the Experimental Autoimmune Myasthenia Gravis (EAMG) model, mice with altered Treg N-glycosylation exhibited worse clinical features and a reduced frequency of effector Tregs compared to wild-type controls. Altogether, these findings identify N-glycosylation as a mechanism underlying Treg dysfunction in MG, in which abnormal expression of mannose-enriched N-glycans in Tregs associates with compromised Treg suppressive function and increased disease severity, proposing Treg N-glycosylation as both a mechanistic driver of MG pathogenesis and a potential avenue for therapeutic intervention.
Objectives The role of the sympathetic neurotransmitter norepinephrine (NE) in ulcerative colitis (UC) remains controversial. We aimed to elucidate NE's precise mechanisms in UC, focusing on colonic metabolism, diagnostic potential, and local immune interactions. Methods Colonic biopsies from active UC patients and DSS-colitis mice were profiled. Neurotransmitter levels, including NE, were quantified by targeted metabolomics. An NE-pathway diagnostic model was constructed from bulk RNA-seq data using machine learning. In vivo, NE was administered via enema or intraperitoneal injection at graded concentrations to assess its pro-inflammatory effects. Immune cells were characterized by flow cytometry, scRNA-seq and spatial transcriptomics. In vitro, NE's effects on neutrophils were verified with receptor inhibitors. Clinical relevance was evaluated using pre-treatment mucosal RNA-seq and therapeutic response data. Results UC patients and DSS mice exhibited elevated local NE levels, influenced by increased biosynthesis and reduced degradation. A machine learning classifier based on NE-pathway genes achieved high accuracy (AUC > 0.9) for UC detection. Experimentally, at low concentrations, NE enemas—but not intraperitoneal administration—aggravated acute colitis in DSS mice via colonic neutrophils. Mechanistically, NE exacerbated colitis by enhancing the pro-inflammatory phenotype of neutrophils through adrenergic receptor β2 (Adrb2)-mediated elevation of intracellular ROS. Subsequently, Adrb2+ neutrophils drove inflammatory crosstalk via TNF-TNFR1/2 signaling. Clinically, high ADRB2+ neutrophil infiltration predicted favorable responses to infliximab. Conclusions This study identifies localized NE accumulation as a neutrophil-dependent driver of UC progression via Adrb2-neutrophil-TNF inflammatory cascade, providing a mechanistic rationale that may help guide biologic agent selection and support strategies with selective ADRB2 antagonists in UC treatment.
Background Autoimmune gastritis (AIG) has long been considered a host-related autoimmune disease that results in oxyntic atrophy, leading to Pernicious Anemia and increasing neoplastic risk. Current evidence discloses that gastric autoimmunity includes a spectrum of inflammatory diseases (i.e., Autoimmune Gastritides) with distinct etiologies, comorbidities, clinical presentations, histological phenotypes, and outcomes. Aim To distinguish the clinical-pathological subtypes of immunomediated gastric disorders. Results Gastric autoimmune diseases comprise Type-1 and Type-2 variants. Type-1 atrophic AIG may lead to vitamin B12 malabsorption, resulting in pernicious anemia, and carries a high risk of Type-1 neuroendocrine gastric neoplasia. Type-1a AIG includes two subtypes. Type-1a is the canonical oxyntic-restricted AIG subtype with no history of exposure to H. pylori infection. In this subtype, a T-cell-rich, cytolytic infiltrate targets the corpus/fundus mucosa, resulting in oxyntic-restricted atrophic changes. Type-1b combines autoimmune etiology with prior or current exposure to H. pylori infection. The dual etiology of Type-1b AIG combines autoimmune oxyntic damage with H. pylori-related antral lesions. This condition may lead to extensive (antral and oxyntic) atrophy, necessitating cancer prevention strategies tailored to the histological stage of gastritis. Type-2 AIG is far less frequent than Type-1, presents with mucus-secreting (antral-pyloric) and oxyntic (corpus/fundus) erosive mucosal high-grade pangastritis, and involves symptomatic multiorgan immune-mediated comorbidities, irrespective of H. pylori status. Type-2 combines Type-1-like serology with a wide, variable spectrum of circulating organ-specific and non-organ-specific autoantibodies and requires targeted treatment. Conclusions The nosology of autoimmune gastritides should reflect their diverse etio-pathogenesis, clinicopathological presentations, and outcomes.
Objectives CD8 T cells co-expressing granzymes K and B (GzmK + B+) are enriched in the joint compared with peripheral blood and have been implicated in the pathogenesis of rheumatoid arthritis (RA). However, it remains unclear whether the enrichment of GzmK+B+ subsets is specific to RA. In addition, the mechanism underlying the generation of GzmK + B + CD8 T cells remains unknown. Methods Characteristics of CD8 T cells in the synovium of patients with RA and osteoarthritis (OA) were examined by a flow cytometer. Public database of single cell RNA sequence (scRNA-seq) of RA and OA synovium was analyzed, and the results were verified by in vitro culture experiments. Flow cytometric analysis of viral antigen-specific CD8 T cells identified by MHC class I tetramer was performed. Results GzmK+B+ subset in CD8 T cells was more enriched in RA than OA joint, whereas no difference was observed in the frequency of GzmK + B- subset. In silico analysis of public database recapitulated these results and suggested the transition from GzmK + B- to GzmK+B+ subset which is mediated by IL-15- but not TCR-signaling. IL-15 induced an increase in GzmK + B + CD8 T cells from RA and OA joints in vitro. Viral antigen specific bystander CD8 T cells in RA joints are also enriched of GzmK+B+ subset. Conclusions Our results suggest that increased IL-15 in RA joints promotes bystander activation of CD8 T cells, leading to the enrichment of GzmK + B + CD8 T cells, which are implicated in the pathogenesis of RA.
