Low CC16 plasma levels are linked to accelerated lung function decline in COPD patients. Cigarette smoke (CS)-exposed Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-kB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-kB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 protein solution (rhCC16) or a NF-kB inhibitor (IMD0354) versus vehicle beginning at the mid-point of the exposures. COPD-like disease and NF-kB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic-bronchitis-like disease in WT and Cc16-/- mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-kB activation in CS-exposed Cc16-/- lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16-/- lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16-/- mice. rhCC16 treatment reduced NF-kB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-kB activation and represents a novel therapeutic approach for COPD.
Joselyn Rojas-Quintero, Maria E. Laucho-Contreras, Xiaoyun Wang, Quynh-Anh Fucci, Patrick R. Burkett, Se-Jin Kim, Duo Zhang, Yohannes Tesfaigzi, Yuhong Li, Abhiram R. Bhashyam, Li Zhang, Haider Khamas, Bartolome Celli, Aprile L. Pilon, Francesca Polverino, Caroline A. Owen
Neutrophils (PMN) are the first immune responders to infection/injury playing a critical role in clearing invading microbes and promoting tissue repair. However, dysregulated trafficking of PMNs across mucosal surfaces is a pathological hallmark of numerous diseases characterized by persistent or intermittent bursts of mucosal inflammation. The critical final step in PMN trafficking into mucosal lined organs (including the lungs, kidneys, skin and gut) involves transepithelial migration (TEpM). The glycoprotein CD11b/CD18 is the predominant β2 integrin that mediates PMN TEpM. Furthermore, CD11b/CD18 also regulates key PMN inflammatory effector functions that are implicated in the pathogenesis of chronic mucosal inflammation including superoxide release and degranulation. Recent studies have shown that terminal Fucose and GlcNAc glycans on CD11b/CD18 can be targeted to reduce PMN trafficking across intestinal epithelium, highlighting the importance of glycosylation in regulating PMN inflammatory function in mucosal settings. Previous studies have also demonstrated that the most abundant terminal glycan on human and murine PMN is sialic acid (Sia). However, the role of Sia in regulating PMN epithelial influx and mucosal inflammatory function is not well understood. Here we demonstrate that inhibiting sialidase mediated removal of α2-3 linked Sia from CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo. Sialylation was also found to regulate critical PMN inflammatory effector functions including degranulation and superoxide release. Finally, we demonstrate that sialidase inhibition reduces bacterial peptide mediated CD11b/CD18 activation in PMN and blocks downstream intracellular signaling mediated by Spleen tyrosine kinase (Syk) and p38 MAP kinase. Taken together, these data demonstrate that sialylated glycans on CD11b/CD18 represent novel targets for ameliorating PMN mediated tissue damage and reducing inflammation in mucosal inflammatory disorders.
Veronica Azcutia, Matthias Kelm, Dylan Fink, Richard D. Cummings, Asma Nusrat, Charles A. Parkos, Jennifer C. Brazil
Reactivation of human cytomegalovirus (HCMV) from latency is a frequent complication following hematopoietic stem cell transplantation (HSCT). The development of acute graft-versus-host disease (GVHD) is a significant risk factor for HCMV disease. Using a murine GVHD model in animals latently infected with murine CMV (MCMV) we studied preventive and therapeutic interventions in this high-risk scenario of HSCT. Mice latently infected with MCMV reactivated MCMV and developed disseminated MCMV infection concomitant with the manifestations of GVHD. Dissemination was accompanied by accelerated mortality. We demonstrate that MCMV reactivation and dissemination was modulated by MCMV-specific antibodies, thus demonstrating in vivo protective activity of antiviral antibodies. However, the efficacy of serum therapy required repetitive doses of high titer immune serum secondary to the shortened serum half-life of IgG in animals with GvHD. In a complementary approach, treatment of GVHD by adoptive transfer of donor-derived regulatory T cells facilitated production of MCMV-specific antibodies from newly developing donor-derived B cells. Together, our findings strongly suggest that antibodies play a major role in controlling recurrent MCMV infection that follows GVHD and argue for reassessing the potential of antibody treatments as well as therapeutic strategies that enhance de novo antibody development against HCMV.
Martina Seefried, Nadine Hundhausen, Irena Kroeger, Maike Büttner-Herold, Petra Hoffmann, Matthias Edinger, Evelyn Ullrich, Friederike Berberich-Siebelt, William J. Britt, Michael Mach, Thomas H. Winkler
The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.
Bindu Singh, Chivonne Moodley, Dhiraj K. Singh, Ruby A. Escobedo, Riti Sharan, Garima Arora, Shashank R. Ganatra, Vinay Shivanna, Olga Gonzalez, Shannan Hall-Ursone, Edward J. Dick Jr., Deepak Kaushal, Xavier Alvarez, Smriti Mehra
Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) — using AS01B-adjuvanted RH5.1 malaria antigen — substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells.
Carolyn M. Nielsen, Jordan R. Barrett, Christine Davis, Jonathan K. Fallon, Cyndi Goh, Ashlin R. Michell, Catherine Griffin, Andrew Kwok, Carolin Loos, Samuel Darko, Farida Laboune, Mehmet Tekman, Ababacar Diouf, Kazutoyo Miura, Joseph R. Francica, Amy Ransier, Carole A. Long, Sarah E. Silk, Ruth O. Payne, Angela M. Minassian, Douglas A. Lauffenburger, Robert A. Seder, Daniel C. Douek, Galit Alter, Simon J. Draper
A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.
Anna Woestemeier, Pasquale Scognamiglio, Yu Zhao, Jonas Wagner, Franziska Muscate, Christian Casar, Francesco Siracusa, Filippo Cortesi, Theodora Agalioti, Simone Müller, Adrian Sagebiel, Leonie Konczalla, Ramez Wahib, Karl-Frederick Karstens, Anastasios D. Giannou, Anna Duprée, Stefan Wolter, Milagros N. Wong, Anne K. Mühlig, Agata A. Bielecka, Vikas Bansal, Tianran Zhang, Oliver Mann, Victor G. Puelles, Tobias B. Huber, Ansgar W. Lohse, Jakob R. Izbicki, Noah W. Palm, Stefan Bonn, Samuel Huber, Nicola Gagliani
Ocular surface diseases, including conjunctivitis, are recognized as a common comorbidity in atopic dermatitis (AD) and also occur at an increased frequency in AD patients treated with biologics targeting interleukin-4 receptor alpha (IL-4Rα) or IL-13. However, the inflammatory mechanisms underlying this pathology are unknown. Here, we developed a novel mouse model of skin inflammation-evoked conjunctivitis and showed that it is dependent on CD4+ T cells and basophils. Blockade of IL-4Rα partially attenuated conjunctivitis development, downregulated basophil activation and led to a reduction in expression of genes related to type 2 cytokine responses. Together, these data suggest that an IL-4Rα-basophil axis plays a role in the development of murine allergic conjunctivitis. Interestingly, we found a significant augmentation of a number of genes that encode tear proteins and enzymes in anti-IL-4Rα-treated mice, which may underlie the partial efficacy in this model and may represent candidate mediators of the increased frequency of conjunctivitis following dupilumab in AD patients.
Hongwei Han, Sheila Cummings, Kai-Ting C. Shade, Jennifer Johnson, George Qian, Joseph Gans, Srinivas Shankara, Javier M. Escobedo, Erik Zarazinski, Renee Bodinizzo, Dinesh S. Bangari, Paul Bryce, Alexandra Hicks
HIV non-progression despite persistent viraemia is rare among antiretroviral therapy (ART)-naïve adults, but relatively common among ART-naïve children. Previous studies indicate that ART-naïve paediatric slow-progressors (PSPs) adopt immune evasion strategies similar to those described in the SIV natural hosts. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8+ T-cells immediately prior to ATI was the main predictor of slow progression during ATI (r=0.77, p=0.002). PD-1+ CD8+ T-cell frequency was also negatively correlated with CCR5 (r=-0.74, p=0.005) and HLA-DR (r=-0.63, p=0.02) expression on CD4+ T-cells and predicted stronger HIV-specific T-lymphocyte responses. In the CD8+ T-cell compartment of PSPs, we identified an enrichment of stem-like TCF-1+PD-1+ memory cells, whereas paediatric progressors and viraemic adults were populated with a terminally exhausted PD-1+CD39+ population. TCF-1+PD-1+ expression on CD8+ T-cells was associated with higher proliferative activity (r=0.41, p=0.03) and stronger Gag-specific effector functionality. These data prompt the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in early-ART-treated infants with a preserved and non-exhausted T-cell compartment.
Vinicius Adriano Vieira, Nicholas Lim, Alveera Singh, Ellen Leitman, Reena R. D'Souza, Emily Adland, Maximilian Muenchhoff, Julia Roider, Miguel Á. Marín Lopez, Julieta Carabelli, Jennifer Giandhari, Andreas Groll, Pieter Jooste, Julia G. Prado, Christina Thobakgale, Krista Dong, Photini Kiepiela, Andrew J. Prendergast, Gareth Tudor-Williams, John Frater, Bruce D. Walker, Thumbi Ndung'u, Veron Ramsuran, Alasdair Leslie, Henrik N. Kløverpris, Philip Goulder
Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.
Catherine M. Biggs, Anna Cordeiro-Santanach, Sergey V. Prykhozhij, Adam P. Deveau, Yi Lin, Kate L. Del Bel, Felix Orben, Robert J. Ragotte, Aabida Saferali, Sara Mostafavi, Louie Dinh, Darlene Dai, Katja G. Weinacht, Kerry Dobbs, Lisa Ott de Bruin, Mehul Sharma, Kevin Tsai, John J. Priatel, Richard A. Schreiber, Jacob Rozmus, Martin C.K. Hosking, Kevin E. Shopsowitz, Margaret L. McKinnon, Suzanne Vercauteren, Michael Seear, Luigi D. Notarangelo, Francis C. Lynn, Jason N. Berman, Stuart E. Turvey
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.
Zi-jun Sun, Dong-yuan Chang, Min Chen, Ming-hui Zhao
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