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IL-6-mediated endothelial injury impairs anti-viral humoral immunity

ABSTRACT: IL-6-mediated endothelial injury impairs anti-viral humoral immunity

PROVIDER: PRJNA1058435 | ENA |

REPOSITORIES: ENA

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IL-6-mediated endothelial injury impairs anti-viral humoral immunity

Project description:Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT) but how this affects immune responses broadly remains unknown. Using a preclinical model of cytomegalovirus (CMV) reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells resulting in sustained IFN secretion which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for immunoglobulin G (IgG) recycling, and rapid IgG loss. In contrast, recipient IgG producing cells are rapidly eliminated after BMT. T cell-specific deletion of IL-6R led to persistence of recipient-derived CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invokes IFN-dependent EC injury and consequent IgG loss leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury thereby preserving humoral immunity after immunotherapy.

2024-04-01 | GSE252180 | GEO

IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

Project description:Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.

| S-EPMC10977988 | biostudies-literature

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Project description:Cytidine diphosphate (CDP)-ethanolamine pathway of phospholipid metabolism coordinates metabolic programming of Tfh cell responses and humoral immunity.

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Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity

Project description:Immune cells can metabolize fatty acids (FAs) to generate energy. The source of different fatty acid species, and their impacts on humoral immunity remains poorly understood. Here we report that proliferating B cells require increased amount of monounsaturated fatty acids (MUFA) to maintain mitochondrial metabolism and mTOR activity, and to prevent excessive autophagy and endoplasmic reticular (ER) stress. Furthermore, B cell extrinsic Stearoyl-Coa desaturase (SCD) activity generates endogenous MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.

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Project description:Venous plexus-associated lymphoid hubs support meningeal humoral immunity