Biology subjects

Gabay, C.

Publications and source records attributed to Gabay, C..

4 recordsLinked to original sources

bioRxiv2026

IL-23 licenses the transition from preclinical autoimmunity to inflammatory arthritis through IL-17A-dependent mechanisms

Objectives: The mechanisms driving transition from systemic autoimmunity to clinical rheumatoid arthritis (RA) remain poorly understood. We investigated the role of interleukin-23 (IL-23) in disease transition using a murine model of experimental arthritis, complemented by human transcriptomic analyses in individuals at risk of RA and RA synovial tissue. Methods: Collagen-induced arthritis (CIA) was induced in less susceptible C57BL/6 mice and combined with sustained systemic IL-23 overexpression. Disease severity, histopathology, immune responses, and tissue gene expression were evaluated. The contribution of IL-17A was assessed using a neutralizing anti-IL-17A antibody. Expression of IL-23 pathway-related genes was assessed in whole-blood transcriptomic data from a large cohort of first-degree relatives of patients with RA (n=1080) and in an independent synovial RNA-sequencing dataset (n=218). Results: In mice, sustained IL-23 overexpression converted a mild CIA phenotype into a highly penetrant arthritis characterized by increased expression of innate inflammatory mediators, and enhanced antigen-specific production of IL-17A and IFN-{gamma}, despite unchanged collagen-specific antibody responses. Neutralization of IL-17A prevented arthritis development. In human whole blood longitudinal analyses, lower RORC and KLRB1 expression was associated with a higher risk of RA onset. KLRB1 expression was persistently lower in progressors, whereas RORC expression showed a steeper decline before diagnosis, although this difference did not remain significant after correction for multiple testing. In RA synovium, IL23R, IL23A, and CCR2 expression was increased compared with controls, while IL23R expression was higher in early than established RA. Conclusions: IL-23 acts as a critical regulator of the transition from systemic autoimmunity to inflammatory arthritis by promoting IL-17A-dependent cellular and myeloid inflammatory pathways. The change in IL-23 pathway signatures in at-risk individuals and early RA supports the translational relevance of this pathway during disease initiation.

immunology↗

bioRxiv2026

Serum Calprotectin as predictor of Rheumatoid Arthritis disease severity and Mortality

Objective: To evaluate the clinical utility of serum calprotectin (sCAL) as a biomarker of disease activity, disease severity, cardiovascular risk, and mortality in inflammatory rheumatic diseases (IRDs). Methods: Serum calprotectin was measured in 2677 patients with IRDs, including 1472 rheumatoid arthritis (RA), 771 axial spondyloarthritis (axSpA), and 434 psoriatic arthritis (PsA) patients enrolled in the Swiss Clinical Quality Management in Rheumatic Diseases registry, as well as 248 healthy blood donors. Associations with disease activity, radiographic progression, cardiovascular biomarkers, incident major adverse cardiovascular events (MACE), and mortality were evaluated using receiver operating characteristic, Cox regression, and Kaplan-Meier models. Results: sCAL concentrations were significantly higher in RA than in axSpA, PsA, or healthy blood donors. Although diagnostic discrimination between IRDs was modest (Area under the curve (AUC): 0.56), elevated sCAL identified a subset of patients with RA characterized by higher disease activity, higher autoantibody levels, and accelerated radiographic progression, performing better than CRP for the assessment of inflammatory activity, particularly for the discrimination of active synovitis (SJC28[≥]4, AUC 0.67 vs 0.62, p=0.012), even in patients with normal CRP concentrations. Elevated sCAL was independently associated with increased all-cause mortality (HR:2.99; 95% confidence interval (95%CI):1.87-4.78), cardiovascular mortality (HR:7.49;95%CI:1.50-37.55), respiratory mortality (HR: 5.89; 95%CI:1.97-17.62), and incident MACE (HR: 2.10; 95%CI: 1.04-4.24). Furthermore, sCAL correlated with high-sensitivity cardiac troponin T and NT-proBNP concentrations, independently of lipid profile. Conclusions: Serum calprotectin is a clinically relevant biomarker in RA that reflects both disease activity and severity, independently identifying patients at increased cardiovascular risk and mortality, supporting its potential role in disease monitoring and risk stratification.

immunology↗

bioRxiv2023

Immunosuppression is a conserved driver of tuberculosis susceptibility

Mycobacterium tuberculosis (Mtb) causes 1.25 million deaths a year; however, tuberculosis (TB) pathogenesis remains poorly understood. Here we find that gene signatures from three different Mtb-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice, non-human primates, and humans, but largely absent from B6 mice, was Mtb-induced Spp1+ macrophage differentiation. Spp1+ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). Here we report that enhancement of IL-1 signaling via deletion of IL-1Ra promoted bacterial control across three susceptible mouse models. We found that IL-1 signaling promotes pulmonary control of Mtb infection through amplifying TNF production by uninfected bystander cells. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved mechanism limiting Mtb control in mice, non-human primates, and humans.

immunology↗

bioRxiv2022

Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein (IL-18BP) in inflammation and tumor immunity

Human Interleukin-18 (IL-18) is an omnipresent pro-inflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases, and serving as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase in COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18 Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors would be highly desirable. However, the structure of human IL-18BP in complex with IL-18 had remained elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP towards IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecule from different complexes, resulting in a novel complex with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings will provide a framework for innovative structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease. Significance statementElevated levels of interleukin-18 (IL-18) have long been implicated in numerous inflammatory diseases while also displaying potent anti-tumoral activities. Recent research on COVID-19 has now underscored the role of IL-18 and IL-18 binding protein (IL-18BP), a soluble receptor serving to regulate IL-18 activity, as key players in viral immunity and as promising biomarkers and predictors of disease severity. In this work, we present detailed structural insights into how human IL-18 and IL-18BP interact thereby completing the structural repertoire of IL-18 in complex with its cognate human receptors and viral decoy receptors. Our findings will support structure-based efforts to either disrupt or enhance the interactions of IL-18 with its cognate receptors for therapeutic purposes.

immunology↗