aPAP may not be lifelong: in three long-term cases, anti-GM-CSF autoantibodies peaked early then declined with exponential kinetics, disappearing after 7-16 years, suggesting eventual immune quiescence via attrition of long-lived plasma cells https://bit.ly/4n2m9No.

Modern disease-modifying therapy has transformed rheumatoid arthritis. Even so, many patients cycle through biological and targeted synthetic drugs of distinct mechanisms without achieving sustained remission. This is the difficult-to-treat phenotype defined by the European Alliance of Associations for Rheumatology. We argue that in a large fraction, refractory disease is not simply inflammation that is too strong or too drug-resistant. It is better understood as an active failure of the program meant to end inflammation. Single-cell and spatial dissection of the synovium lets us recast the rheumatoid joint as a niche of failed resolution. In this niche, imprinted pathological fibroblasts and a macrophage compartment stripped of its pro-resolving, efferocytic subsets both work against resolution. Their reciprocal, largely feed-forward signaling, we propose, assembles a self-sustaining stromal-myeloid circuit: a "failed-resolution switch". Lipid-mediator, metabolic, and epigenetic determinants reinforce it, and synovial microarchitecture stabilizes it. A switch built from redundant, mutually reinforcing arms would explain the therapeutic ceiling in refractory disease. Blocking any single mediator can lower inflammatory output while leaving resolution unrestored. Because the framework describes failed resolution rather than every route to refractoriness, it applies most directly to the persistent-inflammatory subset of difficult-to-treat disease. For that subset, it defines a measurable mechanistic state that can be stratified and which is open to intervention. It also motivates resolution-restoring strategies: pro-resolving mediators, macrophage reprogramming, and fibroblast- and crosstalk-directed interventions. Early clinical evidence, from the instructive failure of the granulocyte-macrophage colony-stimulating factor (GM-CSF) blockade to a proof-of-concept signal for programmed cell death protein 1 (PD-1) agonism, points toward reversing the disease rather than only suppressing it.

Anti-cytokine autoantibodies are increasingly recognized as modulators of immune function and determinants of disease risk, yet their genetic basis and population-level impact remain unclear. Here we perform genome-wide association studies of autoantibodies against IL-1α, IL-6, IL-10, IFN-α, IFN-β, IFN-γ and GM-CSF in 15,000 individuals from the Danish Blood Donor Study. We identify 52 genome-wide significant loci, implicating genes enriched in antigen-presentation pathways. Using these data, we derive cytokine-specific polygenic risk scores and evaluate their associations across 300,000 individuals in the Copenhagen Hospital Biobank. Genetic predisposition to IL-1α autoantibodies is associated with reduced risk of rheumatoid arthritis and certain cancers, whereas genetic predisposition to IL-6 autoantibodies is associated with increased risk of diabetes, mirroring prior clinical observations. These findings define the genetic architecture of anti-cytokine autoantibodies and indicate their divergent effects on human disease risk at population scale, providing a framework for mechanistic investigation and potential clinical stratification.

Type 3 innate lymphoid cells (ILC3s) constitute key components of mucosal innate immunity and serve key roles in maintaining mucosal barrier homeostasis and regulating inflammatory responses. The present review summarizes the biological characteristics and regulatory mechanisms of ILC3s, while discussing their interactions with the gut microbiota and pathological functions in mucosa‑associated disorders. Derived from bone marrow‑resident common lymphoid progenitors, ILC3s differentiate under the transcriptional control of retinoid‑related orphan receptor γ‑t into distinct functional subsets, including natural cytotoxicity receptor (NCR)+ ILC3s, NCR‑ ILC3s and lymphoid tissue inducer cells. ILC3s maintain epithelial barrier integrity, enhance antimicrobial defense and support lymphoid tissue development through the production of effector molecules such as IL‑22, IL‑17 and granulocyte‑macrophage colony‑stimulating factor. These subsets can undergo phenotypic conversion in response to microenvironmental signals. ILC3 activity is tightly regulated by transcription factors, metabolic pathways, neuroimmune interactions and the circadian clock system. In addition, ILC3s establish bidirectional interactions with the gut microbiota: Microbial metabolites regulate ILC3 activity, whereas ILC3s influence microbial composition through IL‑22‑dependent antimicrobial peptide production and IgA responses. Depending on subset composition, local cytokine networks and tissue microenvironment, ILC3s may exert either pathogenic or protective effects in a number of diseases. Future investigations should aim to further elucidate the molecular mechanisms underlying ILC3 subset plasticity, tissue‑specific interaction networks and clinically translatable strategies for targeted intervention. Building upon these findings, the present review proposes a spatiotemporal‑quantitative framework and three regulatory axes that may account for disease‑specific variations in ILC3 responses, providing a basis for understanding distinct ILC3 functions and developing targeted therapeutic strategies. Systematic investigation of the regulatory principles governing ILC3 biology will not only deepen the understanding of innate immune homeostasis but also provide potential targets and strategies for precision immunotherapy in diseases such as inflammatory bowel disease and colorectal cancer.

The objectives of this study were to characterize the diffusion-perfusion properties of the parasagittal dura (PSD) using high-resolution intravoxel incoherent motion (IVIM) MRI and to explore whether PSD-specific IVIM metrics reflect distinct fluid-transport-related signal behavior compared with CSF and brain parenchyma. Ten healthy volunteers underwent 3 T MRI, including high-resolution 3D T2-FLAIR for anatomical localization and multi-b-value diffusion-weighted imaging using MUSE and FOCUS IVIM sequences. Apparent diffusion coefficients (ADCs) and IVIM parameters-true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f)-were quantified in the PSD, CSF, gray matter (GM), and white matter (WM). A pseudo-diffusion residual analysis was performed to estimate the perfusion-related b-value transition. Tissue-specific differences were assessed using nonparametric statistics. The PSD showed diffusion-perfusion characteristics distinct from those of both CSF and brain parenchyma. ADC values decreased with increasing b values and were intermediate between those of CSF and GM/WM. IVIM analysis demonstrated higher perfusion fractions and pseudo-diffusion coefficients in the PSD than in GM and WM, indicating substantial microcirculatory or fluid-transport contributions. The perfusion-related b-value transition thresholds in the PSD were higher than those in CSF but lower than those in GM and WM, supporting its intermediate perfusion behavior. MUSE and FOCUS acquisitions produced comparable quantitative metrics, with MUSE demonstrating reduced geometric distortion and FOCUS providing higher signal-to-noise ratios. In conclusion, the PSD exhibits a distinct diffusion-perfusion profile consistent with its role as a transitional interface among CSF pathways, dural lymphatics, and venous outflow. PSD-specific IVIM metrics may provide a rapid, noncontrast approach for characterizing dural fluid-transport-related signal behavior at the interface between CSF spaces, meningeal lymphatics, and venous outflow.

Pulmonary alveolar proteinosis is a rare lung disease characterized by the accumulation of surfactant lipids and proteins within the alveolar space, leading to impaired gas exchange and progressive respiratory dysfunction. In most cases, pulmonary alveolar proteinosis arises from disruption of GM-CSF (granulocyte-macrophage colony-stimulating factor) signaling, resulting in defective alveolar macrophage maturation and a failure of surfactant clearance. Emerging work has reframed pulmonary alveolar proteinosis as a disorder of macrophage lipid handling, linking impaired cholesterol efflux and surfactant catabolism to both disease initiation and progression. In this review, we synthesize current understanding of pulmonary alveolar proteinosis pathophysiology, highlighting GM-CSF-dependent regulation of alveolar macrophage function, insights from animal and cellular models, and the evolving therapeutic landscape. We further discuss how targeting macrophage lipid homeostasis may offer new disease-modifying strategies.