Immunology
Abstract
Accumulating evidence suggests the pathogenic role of immunity and metabolism in diabetic kidney disease (DKD). Herein, we aimed to investigate the effect of complement factor B (CFB) on lipid metabolism in the development of DKD. We found that in patients with diabetic nephropathy, the staining of Bb, CFB, C3a, C5a, and C5b-9 was markedly elevated in renal tubulointerstitium. Cfb-knockout diabetic mice had substantially milder tubulointerstitial injury and less ceramide biosynthesis. The in vitro study demonstrated that cytokine secretion, endoplasmic reticulum stress, oxidative stress, and cell apoptosis were ameliorated in HK-2 cells transfected with siRNA of CFB under high-glucose conditions. Exogenous ceramide supplementation attenuated the protective effect of CFB knockdown in HK-2 cells, while inhibiting ceramide synthases (CERS) with fumonisin B1 in CFB-overexpressing cells rescued the cell injury. CFB knockdown could downregulate the expression of NF-κB p65, which initiates the transcription of CERS3. Furthermore, C3 knockdown abolished CFB-mediated cytokine secretion, NF-κB signaling activation, and subsequently ceramide biosynthesis. Thus, CFB deficiency inhibited activation of the complement alternative pathway and attenuated kidney damage in DKD, especially tubulointerstitial injury, by inhibiting the NF-κB signaling pathway, further blocking the transcription of CERS, which regulates the biosynthesis of ceramide. CFB may be a promising therapeutic target of DKD.
Authors
Zi-jun Sun, Dong-yuan Chang, Min Chen, Ming-hui Zhao
Abstract
Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and anti-inflammatory pathways including IL10, which was lost after acute HFD feeding and intestinal injury. IL10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and Il10 induction. Milk fat globule-EGF factor-8 (MFGE8) is a bridging molecule that facilitates macrophage uptake of dead cells. MFGE8 also facilitates lipid uptake, and we demonstrate that dietary lipids interfere with MFGE8-mediated macrophage apoptotic neutrophil uptake and subsequent Il10 production. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to unresolved tissue damage.
Authors
Andrea A. Hill, Myunghoo Kim, Daniel F. Zegarra-Ruiz, Lin-Chun Chang, Kendra C. Norwood, Adrien Assié, Wan-Jung H. Wu, Michael C. Renfroe, Hyo W. Song, Angela M. Major, Buck S. Samuel, Joseph M. Hyser, Randy S. Longman, Gretchen E. Diehl
Abstract
CD4+ T cells play a critical role in anti-tumor immunity via recognition of peptide antigens presented on MHC class II (MHC-II). Although some solid cancers can be induced to express MHC-II, the extent to which this enables direct recognition by tumor-specific CD4+ T cells is unclear. We isolated and characterized T cell antigen receptors (TCRs) from naturally primed CD4+ T cells specific for two oncoproteins, HPV16 E6 and the activating KRASG12V mutation, from head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC) patients, respectively, and determined their ability to recognize autologous or human leukocyte antigen (HLA)-matched antigen-expressing tumor cells. We find in both cases that the TCRs are capable of recognizing peptide-loaded target cells expressing the relevant MHC-II or B cell antigen-presenting cells (APC) when the antigens are endogenously expressed and directed to the endosomal pathway but fail to recognize tumor cells expressing the source protein even after induction of surface MHC-II expression by IFN- or transduction with CIITA. These results suggest that priming and functional recognition of both a nuclear (E6) and a membrane-associated (KRAS) oncoprotein is predominantly confined to cross-presenting APC rather than via direct recognition of tumor cells induced to express MHC-II.
Authors
Spencer E. Brightman, Martin S. Naradikian, Rukman R. Thota, Angelica Becker, Leslie Montero, Milad Bahmanof, Ashmitaa Premlal, Jason A. Greenbaum, Bjoern Peters, Ezra E.W. Cohen, Aaron M. Miller, Stephen P. Schoenberger
Abstract
Although air pollutants such as fine particulate matter (PM2.5) are associated with acute and chronic lung inflammation, the etiology of PM2.5-induced airway inflammation remains poorly understood. Here we report that PM2.5 triggered airway hyperreactivity (AHR) and neutrophilic inflammation with concomitant increases in Th1 and Th17 responses and epithelial cell apoptosis. We found that γδ T cells promoted neutrophilic inflammation and AHR through IL-17A. Unexpectedly, we found that invariant natural killer T (iNKT) cells played a protective role in PM2.5-induced pulmonary inflammation. Specifically, PM2.5 activated a suppressive CD4– iNKT cell subset that coexpressed Tim-1 and programmed cell death ligand 1 (PD-L1). Activation of this suppressive subset was mediated by Tim-1 recognition of phosphatidylserine on apoptotic cells. The suppressive iNKT subset inhibited γδ T cell expansion and intrinsic IL-17A production, and the inhibitory effects of iNKT cells on the cytokine-producing capacity of γδ T cells were mediated in part by PD-1/PD-L1 signaling. Taken together, our findings underscore a pathogenic role for IL-17A–producing γδ T cells in PM2.5-elicited inflammation and identify PD-L1+Tim-1+CD4– iNKT cells as a protective subset that prevents PM2.5-induced AHR and neutrophilia by inhibiting γδ T cell function.
Authors
Christina Li-Ping Thio, Alan Chuan-Ying Lai, Jo-Chiao Wang, Po-Yu Chi, Ya-Lin Chang, Yu-Tse Ting, Shih-Yu Chen, Ya-Jen Chang
Abstract
NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4–/–) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband’s variant in Elf4–/– mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.
Authors
Sandra Andrea Salinas, Emily M. Mace, Matilde I. Conte, Chun Shik Park, Yu Li, Joshua I. Rosario-Sepulveda, Sanjana Mahapatra, Emily K. Moore, Evelyn R. Hernandez, Ivan K. Chinn, Abigail E. Reed, Barclay J. Lee, Alexander Frumovitz, Richard A. Gibbs, Jennifer E. Posey, Lisa R. Forbes Satter, Akaluck Thatayatikom, Eric J. Allenspach, Theodore G. Wensel, James R. Lupski, H. Daniel Lacorazza, Jordan S. Orange
Abstract
BACKGROUND Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects.METHODS This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab.RESULTS Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo.CONCLUSION The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes.TRIAL REGISTRATION ClinicalTrials.gov NCT02631538.FUNDING Funding was provided by GSK.
Authors
Xavier Mariette, Francesca Barone, Chiara Baldini, Hendrika Bootsma, Kenneth L. Clark, Salvatore De Vita, David H. Gardner, Robert B. Henderson, Michael Herdman, Karoline Lerang, Prafull Mistry, Raj Punwaney, Raphaele Seror, John Stone, Paul L.A. van Daele, André van Maurik, Nicolas Wisniacki, David A. Roth, Paul Peter Tak
Abstract
Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification. Furthermore, urinary TLS signature scores correlated with ICI-AIN diagnosis but not paired plasma. Urinary CXCL9 correlated best to tissue CXCL9 expression (rho 0.75, p < 0.001) and the ability to discriminate AIN vs. non-AIN (AUC 0.781, p-value 0.003). For the first time, we report the presence of TLS signatures in irAEs, define distinctive immune signatures, identify chemokine markers distinguishing ICI-AIN from common AKI etiologies and demonstrate that urine chemokine markers may be used as a surrogate for ICI-AIN diagnoses.
Authors
Shailbala Singh, James P. Long, Amanda Tchakarov, Yanlan Dong, Cassian Yee, Jamie S. Lin
Abstract
Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from severe COVID-19 patients every third to seventh day during hospitalization and every third month after recovery. We profiled the antigen-specific immune cell dynamics by combining single cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-Seq, B cell receptor (BCR)-Seq with oligo-tagged antigen baits. While the proportion of Spike Receptor Binding Domain-specific memory B cells (MBC) increased from 3 months after infection, the other Spike- and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen specific cells, which was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to one year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen specific B cell responses in longitudinally sampled COVID-19 infected patients.
Authors
Lydia Scharf, Hannes Axelsson, Aikaterini Emmanouilidi, Nimitha R. Mathew, Daniel J. Sheward, Susannah Leach, Pauline Isakson, Ilya V. Smirnov, Emelie Marklund, Nicolae Miron, Lars-Magnus Andersson, Magnus Gisslén, Ben Murrell, Anna Lundgren, Mats Bemark, Davide Angeletti
Abstract
Although glycogen synthase kinase β (Gsk3β) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution vs. inflammation activation is unclear. In a murine liver partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3β inhibitory phosphorylation increased at both the early activation and late resolution stages of the disease. Myeloid Gsk3β deficiency not only alleviated liver injuries, but also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells (KCs) prior to the onset of liver ischemia diminished the differences between the WT and Gsk3β KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in the Gsk3β KO mice. In CD11b-DTR mice, Gsk3β deficient bone marrow-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β deficiency promoted the reparative phenotype differentiation in vivo in liver infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK deficient, mice. Thus, Gsk3β regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the pro-resolving function of liver infiltrating macrophages in MerTK–dependent manner.
Authors
Hanwen Zhang, Ming Ni, Han Wang, Jing Zhang, Dan Jin, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Wei Li, Xuehao Wang, Yuan Zhai
Abstract
To determine the mechanisms that mediate resistance to Mycobacterium tuberculosis (M. tuberculosis) infection in household contacts (HHCs) of patients with tuberculosis (TB), we followed 452 latent TB infection–negative (LTBI–) HHCs for 2 years. Those who remained LTBI– throughout the study were identified as nonconverters. At baseline, nonconverters had a higher percentage of CD14+ and CD3–CD56+CD27+CCR7+ memory-like natural killer (NK) cells. Using a whole-transcriptome and metabolomic approach, we identified deoxycorticosterone acetate as a metabolite with elevated concentrations in the plasma of nonconverters, and further studies showed that this metabolite enhanced glycolytic ATP flux in macrophages and restricted M. tuberculosis growth by enhancing antimicrobial peptide production through the expression of the surface receptor sialic acid binding Ig-like lectin–14. Another metabolite, 4-hydroxypyridine, from the plasma of nonconverters significantly enhanced the expansion of memory-like NK cells. Our findings demonstrate that increased levels of specific metabolites can regulate innate resistance against M. tuberculosis infection in HHCs of patients with TB who never develop LTBI or active TB.
Authors
Deepak Tripathi, Kamakshi Prudhula Devalraju, Venkata Sanjeev Kumar Neela, Tanmoy Mukherjee, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Igor Dozmorov, Abhinav Vankayalapati, Mohammad Soheb Ansari, Varalakshmi Mallidi, Anvesh Kumar Bogam, Karan P. Singh, Buka Samten, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
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