Appadurai et al. report a critical role for the sialyltransferase ST6GalNAc-I in immunosuppression and angiogenesis in non–small cell lung cancer (NSCLC) via sialyation of the glycoproteins NECTIN2 and MUC5AC. The cover image shows the distribution of MUC5AC in NSCLC tissue.
Graft endothelial cells (ECs) express donor alloantigens and encounter cytotoxic T lymphocytes (CTLs) but are generally spared during T cell-mediated rejection (TCMR), which predominantly affects epithelial structures. The mechanisms underlying this vascular immune privilege are unclear. Transcriptomic analyses and endothelial-mesenchymal transition assessments confirmed that the graft endothelium is preserved during TCMR. Co-culture experiments revealed that endothelial and epithelial cells are equally susceptible to CTL-mediated lysis, ruling out cell-intrinsic protection. Intravital microscopy of murine kidney grafts and single-cell RNA sequencing of human renal allografts demonstrated that CTL interactions with ECs are transient compared to epithelial cells. This disparity is mediated by a chemotactic gradient produced by graft stromal cells, guiding CTLs away from ECs toward epithelial targets. In vitro, chemotaxis overrode TCR-induced cytotoxicity, preventing endothelial damage. Finally, analysis of TCMR biopsies revealed that disruption of the chemotactic gradient correlates with endothelialitis lesions, linking its loss to vascular damage. These findings challenge the traditional view of cell-intrinsic immune privilege, proposing a cell-extrinsic mechanism where chemotaxis preserves graft vasculature during TCMR. This mechanism may have implications beyond transplantation, highlighting its role in maintaining vascular integrity across pathological conditions.
T. Barba, M. Oberbarnscheidt, G. Franck, C. Gao, S. This, M. Rabeyrin, C. Roufosse, L. Moran, A. Koenig, V. Mathias, C. Saison, V. Dubois, N. Pallet, D. Anglicheau, B. Lamarthée, A. Hertig, E. Morelon, A Hot, H. Paidassi, T. Defrance, A. Nicoletti, J.P. Duong-Van-Huyen, Y. Xu-Dubois, F.G. Lakkis, O. Thaunat
Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDS), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia, however its molecular mechanism of action is unclear. We found that the ACVR2B, its ligand GDF11, and effector, SMAD2, are upregulated in MDS patient samples. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at GATA1 intron. Intronic SMAD2 binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2 binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of gata1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-seq analysis of samples from the Phase 3 MEDALIST trial revealed that responders to Luspatercept had a higher proportion of GATA1s compared to non-responders. Moreover, the increase RBCs post-treatment was linked to a relative decrease in GATA1s isoform. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to Luspatercept in MDS.
Srinivas Aluri, Te Ling, Ellen Fraint, Samarpana Chakraborty, Kevin Zhang, Aarif Ahsan, Leah Kravets, Gowri Poigaialwar, Rongbao Zhao, Kith Pradhan, Anitria Cotton, Kimo Bachiashvili, Jung-In Yang, Anjali Budhathoki, Beamon Agarwal, Shanisha Gordon-Mitchell, Milagros Carbajal, Srabani Sahu, Jacqueline Boultwood, Andrea Pellagatti, Ulrich Steidl, Amittha Wickrema, Satish Nandakumar, Aditi Shastri, Rajasekhar N.V.S. Suragani, Teresa V. Bowman, John D. Crispino, Sadanand Vodala, Amit Verma
Air pollution is a serious environmental threat to public health; however, the molecular basis underlying its detrimental effects on respiratory fitness remains poorly understood. Here, we show that exposure to particulate matter ≤2.5 µm (PM2.5), a significant fraction of air pollutants, induces the generation of reactive aldehyde species in the airway. We identified aldehyde dehydrogenase 1A1 (ALDH1A1), which is selectively expressed in airway epithelium, as an enzyme responsible for detoxifying these reactive aldehyde species. Loss of ALDH1A1 function results in the accumulation of aldehyde adducts in the airway, which selectively impairs mucociliary clearance (MCC), a critical defense mechanism against respiratory pathogens. Thus, ALDH1A1-deficient mice pre-exposed to PM2.5 exhibited increased susceptibility to pneumonia. Conversely, pharmacological enhancement of ALDH1A1 activity promoted the restoration of MCC function. These findings elucidate the critical role of aldehyde metabolism in protecting against PM2.5 exposure, offering a potential target to mitigate the negative health consequences of air pollution.
Noriko Shinjyo, Haruna Kimura, Tomomi Yoshihara, Jun Suzuki, Masaya Yamaguchi, Shigetada Kawabata, Yasutaka Okabe
Immune and clinical outcomes to Mycobacterium tuberculosis (Mtb) infection vary greatly between individuals yet the underlying genetic and cellular mechanisms driving this heterogeneity remain poorly understood. We performed a cellular genome-wide association study (GWAS) to identify genetic variants associated with Mtb-induced monocyte transcriptional expression of IL1B, IL6, TNF, and IFNB1 via RNA-seq in a Ugandan cohort. Significantly associated variants were assessed for transferability in an independent Seattle cohort, further validated in vitro, and assessed for clinical phenotype associations. We identified 77 loci suggestively associated with Mtb-induced cytokine expression in monocytes in Uganda. SNPs associated with Mtb-induced TNF were enriched within alpha-linolenic acid metabolism pathway genes which was validated in vitro using PLA2 inhibitors. Four loci maintained significant associations in Seattle. We validated cytokine effect with siRNA knockdown for two of these loci which mapped to the genes SLIT3 and SLC1A1. Furthermore, exogenous treatment of macrophages with SLIT3 enhanced Mtb intracellular replication. Finally, SLC1A1 and SLIT3 variants were associated with susceptibility to tuberculous meningitis (TBM) and subsequent survival in a Vietnamese cohort, respectively. In sum, we identified multiple variants and pathways associated with Mtb-induced cytokine transcriptional responses that validated in vitro and were associated with clinical TB susceptibility.
Joshua J. Ivie, Kimberly A. Dill-McFarland, Jason D. Simmons, Glenna J. Peterson, Penelope H. Benchek, Harriet Mayanja-Kizza, Lily E. Veith, Moeko Agata, Dang T.M. Ha, Ho D.T. Nghia, W. Henry Boom, Catherine M. Stein, Chiea C. Khor, Guy E. Thwaites, Hoang T. Hai, Nguyen T.T. Thuong, Xuling Chang, Sarah J. Dunstan, Thomas R. Hawn
Germinal centre (GC) B cells are pivotal in establishing a robust humoral immune response and long-term serological immunity while maintaining antibody self-tolerance. GC B cells rely on autophagy for antigen presentation and homeostatic maintenance. However, these functions, primarily associated with the light zone, cannot explain the spatiotemporal autophagy upregulation in the dark zone of GCs. Here, we define a functional mechanism controlling chromatin accessibility in GC B cells during their dark zone transition. This mechanism links autophagy and nuclear Lamin B1 dynamics with their downstream effects, including somatic hypermutation and antibody affinity maturation. Moreover, the autophagy-Lamin B1 axis is highly active in the aberrant ectopic germinal centres in the salivary glands of Sjogren’s disease, defining its role in autoimmunity.
Marta C Sallan, Filip Filipsky, Christina H. Shi, Elena Pontarini, Manuela Terranova-Barberio, Gordon Beattie, Andrew Clear, Michele Bombardieri, Kevin Y. Yip, Dinis Parente Calado, Mark S. Cragg, Sonya James, Matthew J. Carter, Jessica Okosun, John G. Gribben, Tanya Klymenko, Andrejs Braun
The complement system executes an evolutionarily ancient innate immune response with important roles in many human diseases, including a variety of conditions involving the kidney, autoimmune disorders, age-related macular degeneration, and more. This series of reviews, curated by Dr. Claudia Kemper, highlights the latest discoveries in complement biology and examines ongoing efforts to target complement therapeutically. From the relatively newly uncovered functions of intracellular complement (complosome) to the complexities involved in using animal models of complementopathies, these reviews convey the challenges of studying complement and developing complement-targeted therapeutics as well as call attention to recent findings that supply momentum to the field.
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