Science Immunology

Desmoid fibromatosis (DF) is a rare mesenchymal neoplasm with an unpredictable clinical course, where spontaneous regression or progression occurs in a significant subset of patients through largely undefined mechanisms. The use of active surveillance (AS) offers the opportunity to investigate whether tumor- or host-driven systemic and local immune features may explain these divergent outcomes, improving patient management. A prospective observational study enrolled 55 patients with primary sporadic DF managed with AS. Clinical evolution was categorized as progression, regression, or stable disease according to RECIST 1.1. Immunomonitoring with multicolor flow cytometry identified distinct systemic T-helper polarization states stratifying clinical trajectories: regressors showed a Th2-skewed profile, while progressors displayed activated T-helper cells and Th1/Th9/Th17 subsets. Higher baseline Th2 levels associated with regression and longer progression-free survival. Plasma proteomic and whole-blood transcriptomic analyses confirmed coordinated IL-4/IL-13-linked pro-resolving programs in regressors and inflammatory, early T-cell activation signatures in progressors. Tumor transcriptomics revealed adaptive, antigen-presentation and restrained immune programs in regressing lesions versus innate inflammatory, interferon and TGF-{beta}-driven fibrotic pathways in progressing tumors. These findings identify systemic T-helper polarization as a biomarker of DF behavior and highlight coordinated systemic-tumoral immune programs underlying clinical outcomes, supporting more precise clinical management.

Fibroblasts play a dual role in shaping tissue homeostasis and immune responses during inflammatory perturbations. Manipulating fibroblast behavior has therefore emerged as a promising strategy for autoimmune diseases. Here, through integrated multimodal single-cell transcriptomic and proteomic profiling of synovial tissue combined with prospective clinical data from 54 patients with rheumatoid arthritis, we identify C-X-C motif chemokine 12 (CXCL12)hi Apolipoprotein C1 (APOC1)+ fibroblasts as a pathogenic cell population driving refractory synovitis. CXCL12hi APOC1+ fibroblasts construct local niche in spatial coordinates with plasmablasts via the CXCL12-CXCR4 axis. APOC1 orchestrates senescent inflammatory cancer-associated fibroblast(iCAF)-like properties of this cluster through activation of the STAT3-C/EBP pathway. Therapeutic elimination of senescent cells, either alone or in combination with TNF inhibition, significantly ameliorates experimental arthritis. Together, these findings uncover a mechanistic basis for treatment resistance in rheumatoid arthritis and highlight senescent iCAF-like fibroblasts as a promising therapeutic target.

NLRP3 is an innate immune sensor of a broad range of stimuli, which upon activation forms a multiprotein inflammasome complex triggering caspase-1 activation, IL-1{beta} and IL-18 maturation, and inflammatory cell death. The canonical NLRP3 activation pathway has been well characterized from a structural perspective. It involves the association of NLRP3 with membranes in the form of inactive oligomeric "cage" complexes, which, upon activation, convert to an active oligomeric NLRP3 disc. NLRP3 structural rearrangements during non-classical NLRP3 activation pathways, however, remain unknown. Here, we report a novel mode of NLRP3 activation utilized by the NLRP3 homolog from zebrafish. The cryo-EM structure of zebrafish NLRP3 shows that, unlike human NLRP3, it forms disc-shaped heptamers that undergo further trimerization, resulting in a 21-mer oligomeric arrangement. Surprisingly, a single zebrafish NLRP3 heptamer cannot arrange its PYD domains into a PYD helix and therefore requires a trimer of heptamers to form a PYD filament that enables ASC oligomerization. Furthermore, zebrafish NLRP3 does not associate with the Golgi network, nor does it form inactive "cage" oligomers or interact with NEK7. Thus, our data demonstrate an ancestral non-canonical structural mechanism of NLRP3 activation, which may shed light on alternative NLRP3 activation pathways present in humans.

Vaccination programs worldwide have effectively reduced the burden of childhood diseases, yet immune responses remain highly heterogeneous among individuals. While host characteristics such as age and sex are established determinants of vaccine immunogenicity, the timing of vaccination, specifically the calendar season of vaccination, remains largely underexplored. Although circadian rhythms are known to regulate daily immune function, evidence for long-term circannual patterns has been limited by the difficulty of collecting year-round vaccination data across diverse populations. Here, we show that the season of vaccination systematically shapes the immune response across a broad range of pediatric vaccines. By leveraging data from 96 randomized control trials worldwide, including over 48,000 children vaccinated against 14 pathogens, we demonstrate that immunogenicity after vaccination follows a pronounced latitudinal gradient, typically peaking during colder months in temperate regions and exhibiting distinct variability in the tropics. These findings suggest that the circadian human immune response might extend to a circannual scale, potentially synchronized by environmental cues. Incorporating the season of vaccination into the design of clinical trials and public health campaigns may optimize vaccine performance and enhance seroprotection.

Abstract / SummarySurvival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically "cold" tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding, PD1, TIGIT, LAG3 and HAVCR2/TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFN{gamma}) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children. SignificanceEBV-positive BL tumors contain functional, metabolically active CD8+ T cells. Circulating PD1+TIGIT+CD8+ T cells found in BL patients blood are a biomarker for those in the tumor microenvironment.

Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Damage of the blood-brain barrier (BBB) and endothelial dysfunction are established drivers of the disease pathology, however, whether astrocytes, a major constituent of the BBB, influence the disease outcome remains unclear. Using the murine model of experimental cerebral malaria (ECM), we show that astrocytes decisively regulate the outcome of ECM and the deubiquitinating enzyme OTUD7B in astrocytes fosters the disease. Mice lacking astrocytic OTUD7B showed reduced brain pathology and were protected from ECM compared with wildtype littermate controls. Transcriptomic profiling of ex vivo-isolated astrocytes revealed reduced proinflammatory chemokines and cytokines in the absence of OTUD7B. Plasmodium infection-associated microvesicles triggered a pro-inflammatory response in astrocytes, which was dependent on OTUD7B. Mechanistically, OTUD7B cleaved K48-linked ubiquitin chains from TRAF3 and TRAF6 upon stimulation with microvesicles or activation of TLR3/TLR9 by plasmodial nucleic acids. The OTUD7B-dependent TRAF3 and TRAF6 stabilization led to sustained NF-{kappa}B and p38 MAP kinase signaling and CXCL10 expression. Therapeutic silencing of CNS Otud7b or Cxcl10 expression after disease onset protected mice from ECM, identifying the cerebral OTUD7B-Cxcl10 axis as an attractive therapeutic target.

In multiple sclerosis (MS), autoreactive B cells play a central role in driving CD4 T cell-mediated inflammatory damage to myelin (1). Here we investigated how disrupting Brutons tyrosine kinase (BTK) signaling exclusively in B cells shapes the course of experimental autoimmune encephalomyelitis (EAE), a model for MS, through alterations in B cell development and activity. B cell-specific BTK deletion significantly ameliorated both human MOG (hMOG) induced EAE (p = 0.0087) as well as spontaneous disease in 2D2+IgHMOG mice (p = 0.0004). Additionally, MOG-specific cells were found to be more sensitive to loss of BTK than tolerant clones (p = 0.0002) and production of anti-MOG immunoglobulins was also found to be diminished (p < 0.004) while overall IgG was unchanged (p = 0.44). B cells isolated from conditional knockout mice did not upregulate expression of co-stimulatory receptors or MHC II to the same extent as controls when cultured alongside MOG-specific CD4 T cells (p < 0.005) and were inferior at driving T cell proliferation (p < 0.0001) in vitro. Lastly, while BTK deletion diminished the proliferative and survival response of B cells following mitogen stimulation, B cell trafficking to the leptomeninges and organization into ectopic lymphoid tissues (ELTs) in 2D2+IgHMOG mice continued unabated. We identified that BTK signaling regulates several features adopted by autoreactive B cells that contribute to EAE pathogenesis. This study provides mechanistic insights into the therapeutic benefits of BTK inhibitors observed in clinical trials exploring BTK as a therapeutic target in the context of MS. Significance statementAutoreactive B cells contribute to the neuroinflammation that drives multiple sclerosis (MS) and related diseases, yet the molecular mechanisms enabling their pathogenicity remain incompletely understood. This study demonstrates that B cell-specific deletion of Brutons tyrosine kinase (BTK) markedly reduces disease severity in two complementary versions of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Loss of BTK impairs autoreactive B cell survival, antibody production, antigen presentation to encephalitogenic T cells, and T cell activation, while leaving meningeal ectopic lymphoid tissue formation intact. These findings provide direct mechanistic evidence that BTK signaling in B cells promotes neuroinflammatory damage and supports the therapeutic targeting of BTK to limit B cell-driven pathology in MS.

Mucosa-associated invariant T (MAIT) cells have been paradoxically implicated in both tissue repair and fibrosis. However, when and how they modulate fibrogenesis in the injured liver remain unclear. Here, using the carbon tetrachloride-induced model of liver injury in MR1- and MAIT cell-sufficient and -deficient mice, we identify MAIT cells as an early driver of fibrogenesis. The presence of MAIT cells exacerbated hepatocellular injury, myofibroblast activation, and matrix deposition early in the course of fibrosis development, but not at later stages. This was accompanied by rapid polarization of hepatic MAIT cells toward a MAIT17 phenotype and enrichment of pro-fibrotic transcriptional programs. Concurrently, MAIT cells acquired an exhaustion-associated phenotype while still retaining their effector functions. Mechanistically, we demonstrate that MAIT cells limit hepatic regulatory T (Treg) cell accumulation, accompanied by reduced Ki-67 and CXCR3 levels in the latter population, suggesting their impaired proliferation and tissue recruitment. Furthermore, Treg cell inactivation reversed MAIT cell-dependent differences in the severity of fibrosis, establishing Treg cells as a key downstream mediator. Together, these findings identify MAIT cells as early orchestrators of fibrogenesis and reveal a novel MAIT-Treg axis that can be considered a potential therapeutic target in the early stages of fibrotic diseases.

Down syndrome (DS), caused by trisomy 21, confers a near-universal risk for Alzheimers disease (AD), yet individuals exhibit marked variability in cognitive decline, suggesting the presence of cellular mechanisms that modulate vulnerability and resilience. However, these mechanisms remain poorly defined in the human brain. Here, we integrate matched single-nucleus RNA-seq and ATAC-seq profiles from the prefrontal cortex (PFC) and amygdala (AMY) of age-matched individuals with DS with and without AD (DSAD), enabling direct comparison within a shared genetic background. We identify basal astrocytes in the PFC as a selectively vulnerable cell state in DSAD, characterized by both reduced abundance and coordinated transcriptional and regulatory reprogramming. This state exhibits a shift away from homeostatic support functions, with decreased cytokine signaling and lipid-handling programs, alongside increased steroid- and nuclear receptor-associated activity. Concomitantly, chromatin accessibility profiling reveals reduced engagement of immune- and stress-responsive transcription factor programs, including AP-1, STAT, and BACH families, with linked regulatory perturbations at loci such as ABCA1, DAB2IP, and IL1RAP. Together, these findings define a previously unrecognized astrocyte state marked by epigenetic constraint and diminished responsiveness to stress and inflammatory signals, distinguishing it from classical reactive astrocyte phenotypes. Our results nominate PFC basal astrocytes as a key locus of vulnerability in DSAD and suggest that failure to mount appropriate astrocyte responses, rather than overt activation alone, may contribute to neurodegenerative progression.

Serological diagnostics for tuberculosis rely on pathogen-derived antigens to detect infection-specific antibodies. Whether chronic TB infection also reshapes the global topology of the antibody repertoire remains largely unexplored. Here we profile serum antibody binding across 6,936 peptides in 105 individuals from three countries using two complementary libraries: Mycobacterium tuberculosis peptides (TBC) and a resemblance-ranking library representing the human self-proteome (RRL). We construct a five-dimensional immune state vector from distributional binding properties and map individual sera into an immune phase space. A remodeling classifier achieves virtually identical performance on pathogen-derived and host-derived peptides (AUC 0.63-0.73), demonstrating that the diagnostic signal arises from global repertoire restructuring rather than antigen-specific recognition. HIV co-infection partially masks this signal; restricting analysis to HIV-negative individuals increases AUC to 0.73 (permutation p = 0.005) and enables detection of smear-negative TB (AUC = 0.83, specificity 0.95 with three peptides). Phase-space projections reveal that TB severity maps onto a continuous remodeling gradient, with smear-negative patients occupying intermediate positions between healthy controls and smear-positive cases. These findings position high-density peptide arrays as sensors of antibody repertoire topology, enabling detection of chronic immune states beyond antigen-specific recognition.

HIV escapes sterilizing immunity through a variety of mechanisms, including the downregulation of MHC-I expression by HIV Nef and Vpu to counteract CD8+ T cell responses. While reduced MHC-I expression would be expected to support targeting by NK cells, a subpopulation of infected CD4+ T cells consistently resists multiple rounds of NK cell natural and antibody-dependent cytotoxicity. Studies further reveal that the HIV accessory protein Vpr induces expression of TNFRSF10B (TRAIL-R2) in CD4+ T cells, with survivors of NK cell targeting exhibiting relatively higher MHC-I and weaker expression of TRAIL-R2. In fact, reverse TRAIL signaling in NK cells leads to the release of perforin and granzymes, a pathway limited when TRAIL-R2 expression is diminished. Thus, independent of canonical death receptor signaling, TRAIL-R2 serves as an activating ligand that augments NK cell killing. These observations demonstrate that through Vpr, HIV can regulate the TRAIL/TRAIL-R2 axis to control NK cell functionality.

High-throughput B-cell receptor sequencing has transformed the analysis of adaptive immunity, but benchmarking clonal grouping and lineage reconstruction methods remains limited by the absence of datasets with known evolutionary histories. Here we present Ancestra, a lineage-explicit simulator of B-cell receptor heavy-chain affinity maturation. Ancestra models stochastic V(D)J recombination, context-dependent somatic hypermutation, affinity-based selection and clonal expansion while recording complete parent-child relationships and mutation events. The framework generates BCR heavy-chain sequence datasets together with their corresponding ground-truth lineage trees, enabling direct benchmarking of lineage-aware analytical methods. Across simulations, Ancestra recapitulates key properties of human repertoires, including complementarity-determining region 3 length distributions, amino-acid usage patterns, junctional mutation patterns consistent with IMGT criteria and heterogeneous branching topologies. Simulated lineages also reveal multi-label lineage trees, in which identical nucleotide sequences can arise independently along distinct evolutionary paths. Ancestra provides a practical foundation for rigorous benchmarking of lineage-aware immune repertoire analysis.

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by local invasion, lymph node metastasis, and therapeutic resistance. Chronic periodontal disease has been linked to HNSCC progression, yet the responsible pathogens and underlying molecular mechanisms remain unclear. Here, we show that the keystone periodontal pathogen Porphyromonas gingivalis promotes HNSCC metastasis and chemoresistance through two internalin proteins that are secreted via the type IX secretion system (T9SS). These internalin proteins specifically bind the EC1 domain of E-cadherin through their curved solenoid-like leucine-rich repeats (LRRs), facilitating bacterial invasion and inducing epithelial-to-mesenchymal transition (EMT). Mechanistically, internalin-E-cadherin engagement drives {beta}-catenin nuclear translocation and activates p38 and JNK1/2 MAP kinase signaling pathways, enhancing tumor cell migration, metastatic dissemination, and resistance to cisplatin-induced apoptosis. Tissue microarrays detect internalin antigens in HNSCC specimens, supporting their in vivo relevance. Together, these findings establish a direct mechanistic link between an oral pathogen and HNSCC progression and extend the paradigm of internalin-E-cadherin interactions from microbial pathogenesis to cancer biology.

In a confirmatory study, we evaluated the immunogenicity and protective efficacy of a heterologous prime-boost vaccination strategy against respiratory syncytial virus (RSV) in non-human primates. Building on prior evidence of protective mucosal immunity induced by intramuscular DNA priming followed by an oropharyngeal adenoviral boost, we conducted a randomized, blinded, dual-centre study across two European primate research facilities. Rhesus macaques received a codon-optimized RSV-F DNA vaccine via electroporation, followed by two mucosal administrations of a recombinant adenovirus serotype 5 vector encoding the same antigen. Control groups included animals vaccinated with irrelevant influenza antigens and a comparator group mimicking natural immunity induced by primary RSV infection. Systemic and mucosal immune responses, including RSV-F-specific antibodies and tissue-resident memory T cells, were monitored longitudinally. Here, we detected robust immune responses, but with some variability between the two centres. However, following experimental RSV challenge performed 22 weeks after the final immunization, RSV-vaccinated animals demonstrated markedly reduced viral replication in both upper and lower respiratory tracts. However, unexpected RSV-specific immunity in the control group at one single study site prevented confirmation of the predefined primary endpoint. Overall, these results support the potential of mucosal adenoviral boosting following DNA priming to induce protective immunity against RSV, while highlighting challenges associated with multi-centre preclinical vaccine studies.

Survival during infection depends on both pathogen clearance and the ability to tolerate infection-induced physiological changes. Metabolic adaptations are a central component of this tolerance, but the mechanisms underlying these responses remain incompletely defined. Here, we identify white adipose tissue (WAT) lipolysis as a central regulator of metabolic tolerance to infection. In patients with sepsis, higher circulating non-esterified fatty acid (NEFA) levels were associated with reduced mortality. In mouse models of polymicrobial sepsis, infection induced robust adipose lipolysis and increased circulating NEFAs. Genetic ablation of adipose triglyceride lipase (ATGL) in adipose tissue impaired lipolysis, leading to hypothermia, bradycardia, and increased mortality without altering immune cell populations or pathogen burden, consistent with a defect in tolerance rather than resistance. Mechanistically, lipolysis-derived NEFAs, but not glycerol, were required for protection, as restoring circulating NEFAs rescued autonomic stability and survival in adipose tissue ATGL-deficient mice. Infection-induced lipolysis was redundantly regulated and did not depend on any single upstream signaling pathway. Both pharmacologic activation of lipolysis using a {beta}3-adrenergic agonist and exogenous fatty acid supplementation increased circulating NEFAs, improved survival, and promoted tolerance in mice. Consistent with these findings, analysis of real-world electronic health record data demonstrated that septic patients receiving FDA-approved {beta}3-adrenergic agonists had reduced mortality or hospice discharge in a propensity-matched cohort. Together, these results identify WAT lipolysis and circulating fatty acids as key mediators of tolerance to infection and support a therapeutic strategy based on repurposing clinically available {beta}3-adrenergic agonists to improve outcomes in sepsis. One Sentence SummaryWhite adipose tissue lipolysis promotes metabolic tolerance to infection through circulating fatty acids and is associated with improved survival in sepsis

Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8 T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8 T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response. SignificanceTDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8 T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.

AO_SCPLOWBSTRACTC_SCPLOWThe biology that governs progression and therapeutic response in autoimmune disease is organized in affected tissue, but direct molecular readout of that biology requires invasive biopsy and is rarely repeated during clinical trials or routine care. Using paired blood-skin single-cell RNA-sequencing from a systemic sclerosis (SSc) cohort of 74 individuals (57 patients and 17 matched controls, 192,809 cells across 53 annotated cell states), we show that peripheral blood carries a recoverable projection of tissue-resident molecular state. Across 63 pathways scored in both compartments, 43 same-pathway blood-skin associations reach FDR < 0.05; at cell-type resolution, 212 cross-compartment associations survive residualization for disease status and sex. Per-patient classifiers recover tissue-defined molecular states out of fold with AUCs between 0.62 and 0.79, with the strongest recoveries on fibroblast subtype programs that have no direct circulating analog: fibroblast COMP at 0.79, COCH at 0.75, MYOC2 at 0.74, POSTN at 0.74. Tissue programs route through different blood compartments at different representational levels: fibroblast programs resolve through T-cell, Treg, monocyte and B-cell axes at compositional and distributional levels, while interferon resolves through expression state across multiple cell types. Within SSc alone, a cross-validated partial least squares model learns a shared blood-skin latent axis at r = 0.486 (permutation p = 0.006); the induced patient ranking recovers tissue-interferon-high patients at 86% precision at the top-20% screening threshold against a 50% base rate. A paired multiview autoencoder, trained on module-level dependency structure under contrastive alignment, paired reconstruction, neighborhood preservation and tissue-target supervision, learns a shared latent geometry in which blood-only projections land in the same tissue-state region as their matched tissue samples and supports recovery of held-out tissue targets above simpler baselines and above two permutation null families. These results map the empirical geometry of cross-compartment inference in autoimmune disease and position peripheral blood as a substrate for tissue-state inference at trial and clinical scale.

Severe hemolysis is a life-threatening condition with limited therapeutic options. Although haptoglobin and hemopexin sequester hemoglobin and heme, these protective systems are rapidly saturated during acute hemolysis, leading to the accumulation of cytotoxic free heme. In this study, we identify scavenger receptor BI (SR-BI) as a critical mediator of free heme clearance. SR-BI binds heme and facilitates its hepatic uptake under pathological conditions. Mice lacking hepatic SR-BI exhibit impaired heme clearance and increased susceptibility to heme- and hemolysis-induced lethality. Pharmacological upregulation of hepatic SR-BI via imatinib or adenoviral delivery confers protection against heme toxicity. Using a humanized model of sickle cell disease (SCD), we further demonstrate that sickle hepatopathy significantly reduces hepatic SR-BI expression compared to non-SCD littermates, potentially increasing vulnerability to heme-induced injury. Notably, adenoviral-mediated SR-BI upregulation rescues SCD mice from heme toxicity. These findings reveal a previously unrecognized mechanism of heme detoxification via hepatic SR-BI and identify a promising therapeutic target for hemolytic disorders. One-Sentence SummaryIdentification of scavenger receptor BI as a targetable scavenger of heme in hemolysis

Acinetobacter baumannii is a high-priority multidrug-resistant pathogen that survives within host cells by hijacking intracellular defense pathways. Here, we identify a previously unrecognized signaling axis linking bacterial invasion to host lysosomal regulation. We show that A. baumannii activates calcium-independent phospholipase A2 (iPLA2), leading to increased lysophosphatidylcholine (LPC) production and calcium influx through the ORAI1 channel, which together drive activation and nuclear translocation of the lysosomal transcription factor EB (TFEB). Pharmacological inhibition or genetic silencing of iPLA2 or ORAI1 markedly impaired TFEB activation and lysosomal biogenesis. Mechanistically, we demonstrate that this pathway is initiated by the outer membrane protein A (OmpA), which promotes bacterial invasion and enhances iPLA2 activity, LPC production, and downstream TFEB signaling. Despite induction of lysosomal biogenesis, A. baumannii persists intracellularly by producing ammonia and alkalinizing the lysosomal environment, thereby counteracting host antibacterial activity. In vivo, infection induces activation of HLH-30, the TFEB ortholog, in Caenorhabditis elegans in an OmpA-dependent manner. Together, our finding define an OmpA-iPLA2-LPC-ORAI1-TFEB signaling axis that coordinates host lipid and calcium signaling with lysosomal responses, while revealing a bacterial counterstrategy that promotes intracellular survival.