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LRBA balances antigen presentation and T-cell responses via autophagy through the binding to PIK3R4 and FYCO1 bioRxiv. Immunol. Pub Date : 2024-04-24 Elena Sindram, Marie Celine Deau, Laura Anne Ligeon, Pablo Sanchez-Martin, Sigrun Nestel, Sophie Jung, Stefanie Ruf, Pankaj Mishra, Michele Proietti, Stefan Guenther, Kathrin Thedieck, Eleni Roussa, Angelika Rambold, Christian Muenz, Claudine Kraft, Bodo Grimbacher, Laura Gamez-Diaz
Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the exact molecular mechanism and its impact on T-cell responses remain unknown. We identified two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1)
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Deep, unbiased and quantitative mass spectrometry-based plasma proteome analysis of individual responses to mRNA COVID-19 vaccine bioRxiv. Immunol. Pub Date : 2024-04-23 Ting Huang, Alex Rosa Campos, Jian Wang, Alexey Stukalov, Ramon Diaz, Svetlana Maurya, Khatereh Motamedchaboki, Daniel Hornburg, Laura R. Saciloto-de-Oliveira, Camila Innocente-Alves, Yohana P. Calegari-Alves, Serafim Batzoglou, Walter O. Beys-da-Silva, Lucelia Santi
Global campaign against COVID-19 have vaccinated a significant portion of the world population in recent years. Combating the COVID-19 pandemic with mRNA vaccines played a pivotal role in the global immunization effort. However, individual responses to a vaccine are diverse and lead to varying vaccination efficacy. Despite significant progress, a complete understanding of the molecular mechanisms driving
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Rigid, bivalent CTLA-4 binding to CD80 is required to disrupt the cis CD80 / PD-L1 interaction bioRxiv. Immunol. Pub Date : 2024-04-23 Maximillian A Robinson, Alan Kennedy, Carolina T Orozco, Hung-Chang Chen, Erin A Waters, Dalisay Giovacchini, Kay Yeung, Lily Filer, Claudia Hinze, Christopher Lloyd, Simon Dovedi, David Sansom
The CTLA-4 and PD-1 checkpoints control immune responses to self-antigens and are key targets in cancer immunotherapy. Both pathways are connected via a cis interaction between CD80 and PD-L1, the ligands for CTLA-4 and PD-1 respectively. This cis interaction prevents PD-1 binding to PD-L1 but is reversed by CTLA-4 trans-endocytosis of CD80. However, the mechanism by which CTLA-4 selectively removes
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Antigen affinity and site of immunization dictate B cell recall responses bioRxiv. Immunol. Pub Date : 2024-04-23 Manon Termote, Rafael C. Marques, Erik Hyllner, Mariia V. Guryleva, Mirthe Henskens, Andreas Brutscher, Isabel J.L. Baken, Xaquin Castro Dopico, Adria Dalmau Gasull, Benjamin Murrell, Leonidas Stamatatos, Lisa S. Westerberg, Pia Dosenovic
Protective antibodies against HIV-1 require unusually high levels of somatic hypermutations (SHMs) introduced in germinal centers (GCs). To achieve this, a sequential vaccination approach was proposed. Using HIV-1 antibody knock-in mice with fate-mapping genes, we examined if antigen affinity affects the outcome of the B cell recall response. Compared to high affinity boost, low affinity boost resulted
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Loss of self-tolerance leads to altered gene expression and IMD pathway activation in Drosophila melanogaster bioRxiv. Immunol. Pub Date : 2024-04-22 Pooja Kr, Ashley L Waring-Sparks, Nicholas M Bretz, Nathan T Mortimer
Immune self-tolerance is the ability of a host's immune system to recognize and avoid triggering immune responses against self-tissue. This allows the host to avoid self-directed immune damage while still responding appropriately to pathogen infection. A breakdown of self-tolerance can lead to an autoimmune state in which immune cells target healthy self-tissue, leading to inflammation and tissue damage
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Humoral immunogenicity comparison of XBB and JN.1 in human infections bioRxiv. Immunol. Pub Date : 2024-04-22 Fanchong Jian, Ayijiang Yisimayi, Weiliang Song, Jing Wang, Yanli Xu, Xiaosu Chen, Yuanling Yu, Xiao Niu, Sijie Yang, Peng Wang, Haiyan Sun, Lingling Yu, Jing Wang, Yao Wang, Ran An, Wenjing Wang, Tianhe Xiao, Qingqing Gu, Fei Shao, Youchun Wang, Zhongyang Shen, Ronghua Jin, Yunlong Cao
The ongoing evolution of SARS-CoV-2 continues to challenge the global immune barrier established by infections and vaccine boosters. Recently, the emergence and dominance of the JN.1 lineage over XBB variants have prompted a reevaluation of current vaccine strategies. Despite the demonstrated effectiveness of XBB-based vaccines against JN.1, concerns persist regarding the durability of neutralizing
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Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity bioRxiv. Immunol. Pub Date : 2024-04-22 Yaron Carmi, Leen Farhat-Younis, Manho Na, Amichai Zarfin, Nadine Santana-Magal, Alon Richter, Aseel Khateeb, Amit Gutwillig, Diana Rasoulouniriana, Annette Gleiberman, Lir Beck, Tamar Giger, Avraham Ashkenazi, Adi Barzel, Peleg Rider
Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive in these harsh conditions. While they are equipped with cell-killing abilities
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IMD-mediated innate immune priming increases Drosophila survival and reduces pathogen transmission bioRxiv. Immunol. Pub Date : 2024-04-22 Arun Prakash, Florence Fenner, Biswajit Shit, Tiina S Salminen, Katy M Monteith, Imroze Khan, Pedro F Vale
Invertebrates lack the immune machinery underlying vertebrate-like acquired immunity. However, in many insects past infection by the same pathogen can prime the immune response, resulting in improved survival upon reinfection. Here, we investigated the generality, specificity and mechanistic basis of innate immune priming in the fruit fly Drosophila melanogaster when infected with the gram-negative
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Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response bioRxiv. Immunol. Pub Date : 2024-04-22 Harshavardhan Lingegowda, Katherine B Zutautas, Yuhong Wei, Priyanka Yolmo, Danielle J Sisnett, Alison McCallion, Madhuri Koti, Chandrakant Tayade
Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease
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Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia bioRxiv. Immunol. Pub Date : 2024-04-22 Farnaz Barneh, Joost B. Koedijk, Noa E. Wijnen, Tom Meulendijks, Minoo Ashtiani, Ester Dunnebach, Noel Dautzenberg, Annelisa M. Cornel, Anja Krippner-Heidenreich, Kim Klein, C. Michel Zwaan, Jurgen Kuball, Stefan Nierkens, Jacqueline Cloos, Gertjan J.L. Kaspers, Olaf Heidenreich
In contrast to patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL), patients with acute myeloid leukemia (AML) have not yet benefited from recent advances in targeted immunotherapy. Repurposing immunotherapies that have been successfully used to target other hematological malignancies could, in case of a shared target antigen, represent a promising opportunity to expand the immunotherapeutic
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Nrf2 regulates the activation-driven expansion of CD4+ T-cells by differentially modulating glucose and glutamine metabolism bioRxiv. Immunol. Pub Date : 2024-04-22 Aprajita Tripathi, Debolina Dasgupta, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Ben H.Y. Choi, shailendra Giri, Kalyani Pyaram
Upon antigenic stimulation, CD4+T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional
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Thymic stromal lymphopoietin contributes to endometriotic lesion proliferation and disease-associated inflammation. bioRxiv. Immunol. Pub Date : 2024-04-22 Stanimira Aleksieva, Harshavardhan Lingegowda, Danielle J Sisnett, Alison McCallion, Katherine B Zutautas, Timothy Childs, Bruce Lessey, Chandrakant Tayade
Endometriosis is a chronic disorder in which endometrial-like tissue presents outside the uterus. Patients with endometriosis have been shown to exhibit aberrant immune responses within the lesion microenvironment and in circulation which contribute to the development of endometriosis. Thymic stromal lymphopoietin (TSLP) is an alarmin involved in cell proliferation and the induction of Th2 inflammation
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Differential antigenic imprinting effects between influenza H1N1 hemagglutinin and neuraminidase in a mouse model bioRxiv. Immunol. Pub Date : 2024-04-22 Huibin Lv, Qi Wen Teo, Chang-Chun D Lee, Weiwen Liang, Danbi Choi, Kevin J. Mao, Roberto Bruzzone, Ian A. Wilson, Nicholas C Wu, Chris KP Mok
Understanding how immune history influences influenza immunity is essential for developing effective vaccines and therapeutic strategies. This study investigates the antigenic imprinting of influenza hemagglutinin (HA) and neuraminidase (NA) using a mouse model with sequential infection by four seasonal H1N1 strains. Our findings reveal that, among pre-2009 H1N1 strains, the extent of infection history
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KIRA6 is an effective and versatile mast cell inhibitor of IgE-mediated activation bioRxiv. Immunol. Pub Date : 2024-04-21 Thomas Wilhelm, Veronika Wunderle, Shatha Boukeileh, Jonas Gossen, Michael A. Margreiter, Roman Sakurov, Sandro Capellmann, Maike Schwoerer, Nabil Ahmed, Gina Bronneberg, Michel Arock, Christian Martin, Thomas Schubert, Francesca Levi-Schaffer, Giulia Rossetti, Boaz Tirosh, Michael Huber
Incidents of IgE-mediated, mast cell (MC)-driven allergic diseases are constantly rising and there is an urgent need for the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation of MCs via crosslinking of the high-affinity receptor for IgE (FcεRI) is regulated, amongst others, by the coordinated action of various cytosolic tyrosine kinases of the SRC family
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Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer bioRxiv. Immunol. Pub Date : 2024-04-21 Oluwagbemiga A Ojo, Hongxing Shen, Jennifer T Ingram, James A Bonner, Robert S Welner, Georges Lacaud, Allan J Zajac, Lewis Z Shi
During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108−CX3CR1+ effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit
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Advancing Tolerogenic Immunotherapy: A Multi-Epitope Vaccine Design Targeting the CYP2D6 Autoantigen in Autoimmune Hepatitis Through Immuno-Informatics bioRxiv. Immunol. Pub Date : 2024-04-20 Harish Babu Kolla, Anuj Kumar, Roopa Hebbandi Nanjunadappa, Briley Hilyard, Mansi Dutt, Deepak Chauhan, Jean Marshall, David Kelvin, Channakeshava Sokke Umeshappa
Juvenile autoimmune hepatitis (JAIH) is a rare autoimmune disorder affecting children, characterized by the immune system's misguided attack on liver cells, primarily targeting the CYP2D6 autoantigen. This repeated attack leads to hepatic inflammation, fibrosis, and eventual liver failure. Current therapeutic strategies predominantly rely on immunosuppressive agents or whole B cell depletion antibodies
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Leptospira seroprevalence in dogs, cats and horses: the effect of cross-reactivity between serovars and vaccination status on seroprevalence estimates bioRxiv. Immunol. Pub Date : 2024-04-20 Kellie A. McCreight, Liana N. Barbosa, Odoi Agricola, Porsha Reed, Sreekumari Rajeev
In this study, we estimated the Leptospira seroprevalence in dogs (n = 376), horses (n = 88), and cats (n = 169) using Microscopic Agglutination Test (MAT) against 12 Leptospira serovars. We observed a Leptospira seroprevalence of 29.41%, 47.73%, and 12.35% in dogs, horses, and cats, respectively. The highest seroprevalence was observed for serovar Autumnalis (74.55%) in dogs, and Bratislava in horses
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Circular DNA vcDNA-S7 derived from segmented-dsRNA virus BmCPV attenuated viral infection through RNase H1 bioRxiv. Immunol. Pub Date : 2024-04-20 Jun Pan, Xinyu Tong, Yuming Ding, Chao Lei, Shulin Wei, An Xu, Yaxuan Han, Qunnan Qiu, Huilin Pang, Xiaolong Hu, Chengliang Gong, Min Zhu
Viral circDNA derived from insect positive-sense single-stranded RNA viruses plays a crucial role in regulating viral infections depending on the RNAi pathway. Our previous research has revealed that Bombyx mori cypovirus (BmCPV), a segmented-dsRNA virus, can generate viral circDNA vcDNA-S7, which can be transcribed to form RNA and further processed into small RNAs to defend against the virus through
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A Membrane Lipid Signature Unravels the Dynamic Landscape of Group 1 ILCs bioRxiv. Immunol. Pub Date : 2024-04-20 Halle Frey, Xin Sun, Fatima Oudeif, Darleny Corona, Zijun He, Taejoon Won, Tracey L Schultz, Vern B. Carruthers, Amale Laouar, Yasmina Laouar
In an era where the established lines between cell identities are blurred by intra-lineage plasticity, distinguishing between stable and transitional states becomes imperative. This challenge is particularly pronounced within the Group 1 ILC lineage, where the similarity and plasticity between NK cells and ILC1s obscure their classification and the assignment of their unique contributions to immune
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Tissue factor-dependent colitogenic CD4+ T cell thrombogenicity is regulated by activated protein C signalling. bioRxiv. Immunol. Pub Date : 2024-04-20 Gemma Leon, Paula A. Klavina, Aisling M. Rehill, Shrikanth Chomanahalli Basavarajappa, James S. O'Donnell, Seamus Hussey, Patrick T. Walsh, Roger J.S. Preston
Inflammatory bowel disease (IBD) patients experience up to 6-fold increased risk of venous thromboembolism (VTE) compared to the general population, although the mechanistic basis for this increased risk remains poorly defined. We found that colitogenic CD4+ T cells express tissue factor (TF) and promote rapid TF-dependent plasma thrombin generation in T cell-dependent calibrated automated thrombinography
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Loss of circulating CD8α+ NK cells during human Mycobacterium tuberculosis infection bioRxiv. Immunol. Pub Date : 2024-04-20 Nezar Mehanna, Atul Pradhan, Rimanpreet Kaur, Theodota Kontopoulos, Barbara Rosati, David Carlson, Nai-Kong Cheung, Hong Xu, James Bean, Katherine Hsu, Jean-Benoit Le Luduec, Charles Kyriakos Vorkas
Natural Killer (NK) cells can recognize and kill Mtb-infected cells in vitro, however their role after natural human exposure has not been well-studied. To identify Mtb-responsive NK cell populations, we analyzed the peripheral blood of healthy household contacts of active Tuberculosis (TB) cases and source community donors in an endemic region of Port-au-Prince, Haiti by flow cytometry. We observed
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Heterogeneity of foam cell biogenesis across diseases bioRxiv. Immunol. Pub Date : 2024-04-20 Valentina Guerrini, Brendan Prideaux, Rehan Khan, Selvakumar Subbian, Yina Wang, Evita Sadimin, Siddhi Pawar, Rahul Ukey, Eric A Singer, Chaoyang Xue, Maria Laura Gennaro
Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of diverse origin. The long-standing paradigm that foam cells are cholesterol-laden derives from atherosclerosis research. We previously showed that, in tuberculosis, foam cells surprisingly accumulate triglycerides. Here, we utilized bacterial (Mycobacterium tuberculosis), fungal (Cryptococcus neoformans), and
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Giardia Increases Macrophage Production of the Anti-Inflammatory Cytokine Interleukin-10 in Response to Lipopolysaccharide via Macrophage Galactose Binding Lectin (MGL1) bioRxiv. Immunol. Pub Date : 2024-04-20 Vanessa Angelova, Matthew Darmadi, Eleanor Miskovsky, Marc Fink, Samantha Menegas, Haley Wexelblatt, Steven M Singer
Giardia duodenalis is an intestinal protozoan parasite, common in low- and middle-income countries. Infection is frequently subclinical, even when it is associated with other pathologies like growth stunting in children. Recent longitudinal cohort studies have found Giardia more frequently in patients with milder symptoms and have even suggested that Giardia reduces rotavirus symptom severity. One
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Human natural killer cells can activate NLRP1 and NLRP3 inflammasomes and drives pyroptosis bioRxiv. Immunol. Pub Date : 2024-04-19 Antonio Astorga-Gamaza, Ines Muela-Zarzuela, Juan M. Suarez-Rivero, Juan Lopez-Perez, Raquel de la Varga-Martinez, Auxiliadora Mazuecos, Mario D. Cordero
Innate immunity relies on inflammasomes as key components, defending the host against diverse harmful stimuli by orchestrating the release of pro-inflammatory cytokines and initiating pyroptosis. While extensively studied in myeloid cells, the involvement of natural killer (NK) cells in inflammatory responses through inflammasome signaling remains underexplored. In this study, we elucidate the activation
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A generalized framework to identify SARS-CoV-2 broadly neutralizing antibodies bioRxiv. Immunol. Pub Date : 2024-04-18 Fanchong Jian, Anna Z. Wec, Leilei Feng, Yuanling Yu, Lei Wang, Peng Wang, Lingling Yu, Jing Wang, Jacob Hou, Daniela Montes Berrueta, Diana Lee, Tessa Speidel, LingZhi Ma, Thu Kim, Ayijiang Yisimayi, Weiliang Song, Jing Wang, Lu Liu, Sijie Yang, Xiao Niu, Tianhe Xiao, Ran An, Yao Wang, Fei Shao, Youchun Wang, Simone Pecetta, Xiangxi Wang, Laura M. Walker, Yunlong Cao
Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain (RBD) showed high efficacy in the prevention and treatment of COVID-19. However, the rapid evolution of SARS-CoV-2 has rendered all clinically authorized mAbs ineffective and continues to stymie the development of next-generation mAbs. Consequently, the ability to identify broadly neutralizing antibodies (bnAbs) that neutralize
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Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C) bioRxiv. Immunol. Pub Date : 2024-04-18 Jenna K Dick, Jules A Sangala, Venkatramana D Krishna, Aaron Khaimraj, Lydia Hamel, Spencer M Erickson, Dustin Hicks, Yvette Soigner, Laura E Covill, Alexander Johnson, Michael J Ehrhardt, Keenan Ernste, Petter Brodin, Richard A Koup, Alka Khaitan, Carly Baehr, Beth K Thielen, Christine M Henzler, Caleb Skipper, Jeffrey S Miller, Yenan T Bryceson, Jianming Wu, Chandy C John, Angela Panoskaltsis-Mortari
Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore
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A co-opted ISG15-USP18 binding mechanism normally reserved for deISGylation controls type I IFN signalling bioRxiv. Immunol. Pub Date : 2024-04-18 Andri Vasou, Katie Nightingale, Vladimira Cetkovska, Jonathan Scheler, Connor GG Bamford, Jelena Andrejeva, Ulrich Schwarz-Linek, Richard E Randall, John McLauchlan, Michael P Weekes, Dusan Bogunovic, David J Hughes
Type I interferon (IFN) signalling induces the expression of several hundred IFN-stimulated genes (ISGs) that provide an unfavourable environment for viral replication. To prevent an overexuberant response and autoinflammatory disease, IFN signalling requires tight control. One critical regulator is the ubiquitin-like protein ISG15, evidenced by autoinflammatory disease in patients with inherited ISG15
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OCA-B promotes autoimmune demyelination through control of stem-like CD4+ T cells bioRxiv. Immunol. Pub Date : 2024-04-17 Erik P Hughes, Amber R Syage, Elnaz Mirzaei Mehrabad, Thomas E Lane, Benjamin T Spike, Dean Tantin
Stem-like T cell populations can selectively contribute to autoimmunity, but the activities that promote and sustain these populations are incompletely understood. Here, we show that T cell-intrinsic loss of the transcription cofactor OCA-B protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to CNS infection. In adoptive transfer EAE models driven by multiple
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Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine bioRxiv. Immunol. Pub Date : 2024-04-17 Essi Y. I Tchalla, Anagha Betadpur, Andrew Khalil, Manmeet Bhalla, Elsa N. Bou Ghanem
Vaccine-mediated protection and susceptibility to Streptococcus pneumoniae (pneumococcus) infections are influenced by biological sex. The incidence of invasive pneumococcal disease remains higher in males compared to females even after the introduction of the pneumococcal conjugate vaccine (PCV). However, sex-based differences in the immune response to this conjugate vaccine remain unexplored. To
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Structural and biochemical requirements for secretory component interactions with dimeric Immunoglobulin A bioRxiv. Immunol. Pub Date : 2024-04-17 Sonya Kumar Bharathkar, Beth M. Stadtmueller
Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody that protects host epithelial barriers and promotes microbial homeostasis. SIgA production occurs when plasma cells assemble two copies of monomeric IgA and one joining chain (JC) to form dimeric (d) IgA, which is bound by the polymeric Ig receptor (pIgR) on the basolateral surface of epithelial cells and transcytosed to the apical
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β-glucan induced trained immunity enhances antibody levels in a vaccination model in mice bioRxiv. Immunol. Pub Date : 2024-04-17 Jainu Ajit, Qing Chen, Trevor Ung, Matthew G Rosenberger, Jeremiah Kim, Ani Solanki, Jingjing Shen, Aaron P Esser-Kahn
Trained immunity improves disease resistance by strengthening our first line of defense, the innate immune system. Innate immune cells, predominantly macrophages, are epigenetically and metabolically rewired by β-glucan, a fungal cell wall component, to induce trained immunity. These trained macrophages exhibit increased co-stimulatory marker expression and altered cytokine production. Signaling changes
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T follicular helper cell profiles differ by malaria antigen and for children compared to adults bioRxiv. Immunol. Pub Date : 2024-04-16 Catherine Suzanne Forconi, Christina Nixon, Hannah W Wu, Boaz Odwar, Sunthorn Pond-Tor, John M Ong'echa, Jonathan D Kurtis, Ann M Moormann
Background: Circulating T-follicular helper (cTFH) cells have the potential to provide an additional correlate of protection against Plasmodium falciparum (Pf) as they are essential to promote B cell production of long-lasting antibodies. Assessing the specificity of cTFH subsets to individual malaria antigens is vital to understanding the variation observed in antibody responses and identifying promising
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Universal protection against SARS-CoV-2 viruses by multivalent mRNA vaccine in mice bioRxiv. Immunol. Pub Date : 2024-04-16 Zhengyang Lei, Shiyao Zhai, Xi Yuan, Runming Wang, Pengyun Wang, Vijay Pandey, Cang Yang Zhang, Jiansong Ji, Dongmei Yu, Zhenglin Chen, Sumin Bian, Peiwu Qin
The continual emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges available SARS-CoV-2 vaccines for adequate control of outbreaks. Currently, universal vaccines capable of obviating the need for exact strain matching between mRNA vaccines and circulating viruses are absent. In this study, we designed, manufactured, and evaluated a nucleoside-modified lipid
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CD4-mediated immunity shapes neutrophil-driven tuberculous pathology bioRxiv. Immunol. Pub Date : 2024-04-16 Benjamin H Gern, Josepha M Klas, Kimberly A Foster, Sara B Cohen, Courtney R Plumlee, Fergal J Duffy, Maxwell L Neal, Mehnaz Halima, Andrew T Gustin, Alan H Diercks, Alan Aderem, Michael Gale, John D Aitchison, Michael Y Gerner, Kevin B Urdahl
Pulmonary Mycobacterium tuberculosis (Mtb) infection results in highly heterogeneous lesions ranging from granulomas with central necrosis to those primarily comprised of alveolitis. While alveolitis has been associated with prior immunity in human post-mortem studies, the drivers of these distinct pathologic outcomes are poorly understood. Here, we show that these divergent lesion structures can be
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Regulation of host metabolism and defense strategies to survive neonatal infection bioRxiv. Immunol. Pub Date : 2024-04-16 Ziyuan Wu, Nguyen Tran Nam Tien, Ole Baek, Jingren Zhong, Bjorn Klabunde, Tinh Thu Nguyen, Nguyen Thi Hai Yen, Nguyen Phuoc Long, Duc Ninh Nguyen
Two distinct defense strategies, resistance and tolerance, enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on tolerance to cope with infection. However, this approach may fail as pathogen levels surpass a critical threshold, prompting a shift to resistance that can lead to dysregulated immune responses and sepsis. The mechanisms governing
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Cross-reactivity of rPvs48/45, a recombinant Plasmodium vivax protein, with sera from Plasmodium falciparum endemic areas of Africa bioRxiv. Immunol. Pub Date : 2024-04-15 Myriam Arévalo-Herrera, Saidou Balam, Kazutoyo Miura, Imen Ayadi, Drissa Konaté, Nathan C. Incandela, Valentina Agnolon, Merepen A Guindo, Seidina A.S. Diakité, Sope Olugbile, Issa Nebie, Sonia M Herrera, Carole Long, Andrey V. Kajava, Mahamadou Diakité, Giampietro Corradin, Socrates Herrera
Background: Ps48/45, a Plasmodium gametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we explored the cross-reactivity and TB activity of a recombinant P. vivax Ps48/45 protein (rPvs48/45) with sera from P. falciparum-exposed African donors. Methods: rPvs48/45 was produced in Chinese hamster ovary cell
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Hepatitis E Virus-induced antiviral response by plasmacytoid dendritic cells is modulated by the ORF2 protein bioRxiv. Immunol. Pub Date : 2024-04-15 Garima Joshi, Elodie Decembre, Jacques Brocard, Claire Montpellier, martin Ferrie, Omran Allatif, Ann-Kathrin Menhert, Johann Pons, Delphine Galiana, Viet Loan Dao Thi, Nolwenn Jouvenet, Laurence Cocquerel, Marlene Dreux
Type I and III interferons (IFN-I/III) are critical to protect the host during viral infection. IFN-mediated antiviral responses against hepatitis E virus (HEV) are suppressed and defeated by viral escape mechanisms at play in infected hepatocytes. Here, we studied the anti-HEV function of IFN secreted by plasmacytoid dendritic cells (pDCs), which are specialized producers of IFNs. We showed that pDCs
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Influenza virus antibodies inhibit antigen-specific de novo B cell responses in mice bioRxiv. Immunol. Pub Date : 2024-04-15 Eileen Goodwin, James S. Gibbs, jonathan yewdell, Laurence C Eisenlohr, Scott E. Hensley
Antibody responses to influenza vaccines tend to be focused on epitopes encountered during prior influenza exposures, with little production of de novo responses to novel epitopes. To examine the contribution of circulating antibody to this phenomenon, we passively transferred a hemagglutinin (HA)-specific monoclonal antibody (mAb) into mice before immunizing with whole inactivated virions. The HA
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Analysis of emergent bivalent antibody binding identifies the molecular reach as a critical determinant of SARS-CoV-2 neutralisation potency bioRxiv. Immunol. Pub Date : 2024-04-15 Anna Huhn, Daniel Allen Nissley, Daniel B Wilson, Mikhail A Kutuzov, Robert Donat, Tiong Kit Tan, Ying Zhang, Michael I Barton, Chang Liu, Wanwisa Dejnirattisai, Piyada Supasa, Juthathip Mongkolsapaya, Alain Townsend, William S James, Gavin Screaton, Philip Anton van der Merwe, Charlotte Deane, Samuel Isaacson, Omer Dushek
Key functions of antibodies, such as viral neutralisation, depend on bivalent binding but the factors that influence it remain poorly characterised. Here, we develop and employ a new bivalent model to mechanistically analyse binding between >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. Our method reproduces the monovalent on/off-rates and enables measurements of the
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Fetal protection against bovine viral diarrhea virus types 1 and 2 after vaccination of the dam with the DIVENCE vaccine bioRxiv. Immunol. Pub Date : 2024-04-15 Ester Taberner, Marta Gibert, Carlos Montbrau, Irene Munoz, Joaquim Mallorqui, Hector Santo Tomas, Antoni Prenafeta, Ricard March
The aim of this study was to demonstrate the efficacy of DIVENCE, a vaccine against BVDV types 1 and 2 (BVDV 1 and BVDV 2) transplacental infection, following a booster regimen in heifers. Calves of two to three months of age were given two intramuscular doses three weeks apart and a booster vaccine six months later. Efficacy was evaluated by means of a challenge with virulent BVDV 1 or BVDV 2 administered
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Unleashing the Immune Arsenal: Development of Broad-spectrum Multiepitope Bluetongue Vaccine Targeting Conserved T Cell Epitopes of Structural Proteins bioRxiv. Immunol. Pub Date : 2024-04-15 Harish Babu Kolla, Anuj Kumar, Mansi Dutt, Roopa Hebbandi Nanjunadappa, Karam Pal Singh, Peter Paul Clement Mertens, David Kelvin, Channakeshava Sokke Umeshappa
Bluetongue (BT) is a severe arboviral disease affecting sheep, cows, and other wild ruminants, caused by the Bluetongue virus (BTV). The virus has evolved into over 32 serotypes, rendering existing vaccines less effective. While the structural proteins of this virus represent promising targets for vaccine development, they unfortunately exhibit high amino acid polymorphism and are laden with numerous
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Defining mononuclear phagocyte distribution and behaviour in the zebrafish heart bioRxiv. Immunol. Pub Date : 2024-04-15 Bethany Moyse, Joanna J Moss, Laura Bevan, Aaron Scott, Valerie Wittamer, Rebecca Richardson
Mononuclear phagocytes (MNPs) are recognised as highly plastic, multifunctional cells that influence multiple physiological and pathophysiological states. In the heart, they support homeostatic functions, contribute to disease progression and play multiple roles in reparative and regenerative processes following tissue damage. Understanding the heterogeneous populations of cells that contribute to
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A protective role for B-1 cells and oxidation-specific epitope IgM in lung fibrosis bioRxiv. Immunol. Pub Date : 2024-04-15 Jeffrey Michael Sturek, Riley T Hannan, Aditi Upadhye, Eva Otoupalova, Edwin T Faron, Amr A.E. Atya, Cassidy Thomas, Vernerdean Johnson, Andrew Miller, James C Garmey, Marie D Burdick, Thomas H Barker, Alexandra Kadl, Yun Michael Shim, Coleen A McNamara
Idiopathic pulmonary fibrosis (IPF) is a morbid fibrotic lung disease with limited treatment options. The pathophysiology of IPF remains poorly understood, and elucidation of the cellular and molecular mechanisms of IPF pathogenesis is key to the development of new therapeutics. B-1 cells are an innate B cell population which play an important role linking innate and adaptive immunity. B-1 cells spontaneously
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Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease bioRxiv. Immunol. Pub Date : 2024-04-15 Mohini Mendiratta, Meenakshi Mendiratta, Shuvadeep Kumar Ganguly, Sandeep Rai, Ritu Gupta, Lalit Kumar, Sameer Bakhshi, Vatsla Dadhwal, Deepam Pushpam, Prabhat S Malik, Raja Pramanik, Mukul Aggarwal, Aditya Kumar Gupta, Rishi Dhawan, Tulika Seth, Manoranjan Mahapatra, Baibaswata Nayak, Thoudam Debraj Singh, Sachin Kumar Singla, Mayank Singh, Chandra Prakash Prasad, Hridayesh Prakash, Sujata Mohanty
Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. In this context, we here demonstrate that hypoxia preconditioned apoptotic MSCs
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Vimentin regulates mitochondrial ROS production and inflammatory responses of neutrophils bioRxiv. Immunol. Pub Date : 2024-04-15 Thao N Huynh, Jody Toperzer, Allison Scherer, Anne Gumina, Tonya Brunetti, Michael K Mansour, David M Markovitz, Brian C Russo
The intermediate filament vimentin is present in immune cells and is implicated in proinflammatory immune responses. Whether and how it supports antimicrobial activities of neutrophils is not well established. Here, we developed an immortalized neutrophil model to examine the requirement of vimentin. We demonstrate that vimentin restricts the production of proinflammatory cytokines and reactive oxygen
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Mutations in the IgG B cell receptor associated with class-switched B cell lymphomas bioRxiv. Immunol. Pub Date : 2024-04-15 Laabiah Wasim, Sin Wah Tooki Chu, Ben Sale, Lucy Pickard, Simon Leonard, Lingling Zhang, Helena Tolarova, Zhang Sung Tean, Niklas Engels, Dinis P. Calado, Karin Tarte, Jessica Okosun, Francesco Forconi, Pavel Tolar
Immunoglobulin class-switching from IgM to IgG enhances B cell receptor (BCR) signalling and promotes germinal centre (GC) B cell responses to antigens. In contrast, non-Hodgkin lymphomas derived from GC B cells typically avoid IgG BCR expression and retain the unswitched IgM BCR, suggesting that IgG BCR may protect B cells from malignant transformation. However, the mechanism of this phenomenon and
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Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection bioRxiv. Immunol. Pub Date : 2024-04-14 Qiaowei Xie, Mark D Namba, Lauren A Buck, Kyewon Park, Joshua G Jackson, Jacqueline M Barker
HIV infection is an ongoing global health issue despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter immune state, though this is difficult to
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SHP-1 interacts with NFκB1 to inhibit its phosphorylation and nuclear translocation to suppress excessive bacterial inflammation bioRxiv. Immunol. Pub Date : 2024-04-14 Ningning Wang, Suxu Tan, Muyuan Wang, Hongning Liu, Sen Han, Zhendong Wu, Jie Ma, Songlin Chen, Zhenxia Sha
The protein tyrosine phosphatase SHP-1 is a key negative regulator in cancer by dephosphorylating multiple target molecules. Specially in the NFκB signaling, where NFκB1/Rela dimer translocate to the nucleus and activate target gene transcription, SHP-1 inhibits the phosphorylation of Rela, while its regulation on NFκB1 has been unknown, especially in pathogen-induced inflammation. Chinese tongue sole
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Systematic perturbation screens decode regulators of inflammatory macrophage states and identify a role for TNF mRNA m6A modification bioRxiv. Immunol. Pub Date : 2024-04-14 Simone M Haag, Shiqi Xie, Celine Eidenschenk, Jean-Philippe Fortin, Marinella Callow, Mike Costa, Aaron Lun, Chris Cox, Sunny Z Wu, Rachana N Pradhan, Jaclyn Lock, Julia A Kuhn, Loryn Holokai, Minh Thai, Emily Freund, Ariane Nissenbaum, Mary Keir, Christopher J Bohlen, Scott Martin, Kathryn Geiger-Schuller, Hussein A Hejase, Brian L Yaspan, Sandra Melo Carlos, Shannon J Turley, Aditya Murthy
Macrophages adopt dynamic cell states with distinct effector functions to maintain tissue homeostasis and respond to environmental challenges. During chronic inflammation, macrophage polarization is subverted towards sustained inflammatory states which contribute to disease, but there is limited understanding of the regulatory mechanisms underlying these disease-associated states. Here, we describe
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Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways bioRxiv. Immunol. Pub Date : 2024-04-14 Gantseg Tumurkhuu, Richard Moore, Graziela Perri, Gabriela De Los Santos, Duygu E Laguna, David Gibb, Jessica Carriere, Christian Stehlik, Caroline Jefferies
Background. Patients with systemic lupus erythematosus (SLE) experience photosensitivity, with exposure to ultraviolet light B (UVB) driving lupus flares and triggering symptoms like joint pain, fatigue, and cutaneous lesions. Although the mechanism(s) linking UVB exposure to systemic effects are unclear, type I interferons (IFNs) are known to play a role. Our previous work has shown that TRIM21, an
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PIM kinase control of CD8 T cell protein synthesis and cell trafficking bioRxiv. Immunol. Pub Date : 2024-04-14 Julia Mary Marchingo, Laura Spinelli, Shalini Pathak, Doreen A Cantrell
Integration of a large network of kinase signalling pathways co-ordinates changes in the transcription, translation and metabolic events required for T cell activation and differentiation. The present study explores the role of the Serine/Threonine kinases PIM1 and PIM2 in controlling murine CD8 T lymphocyte antigen receptor-mediated activation and differentiation in response to the cytokines Interleukin
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Antiviral RNA interference targets viral transcripts but not genomes of RNA viruses in Drosophila melanogaster bioRxiv. Immunol. Pub Date : 2024-04-13 Emanuele Silva, Ferreira Alvaro, Thiago Leite, Isaque Faria, Juliana Armache, Gabrielle Hass, Franck Martin, Jean-Luc Imler, Joao Marques
RNA interference (RNAi) mediated by the small interfering RNA (siRNA) pathway is a major antiviral mechanism in insects. This pathway is triggered when double-stranded RNA (dsRNA) produced during virus replication is recognized by Dicer-2, leading to the formation of virus-derived siRNA duplexes. These siRNAs are loaded onto the programmable nuclease Argonaute-2 (AGO2), with one strand serving as a
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Impact of Obesity on the CCR6-CCL20 Axis in Epidermal γδ T Cells and IL-17A Production in Murine Wound Healing and Psoriasis bioRxiv. Immunol. Pub Date : 2024-04-13 William Lawler, Tanya Castellanos, Emma Engel, Cristian Alvizo, Antolette Kasler, Savannah Bshara-Corson, Julie Jameson
Obesity is associated with comorbidities including type 2 diabetes, chronic nonhealing wounds and psoriasis. Normally skin homeostasis and repair is regulated through the production of cytokines and growth factors derived from skin-resident cells including epidermal γδ T cells. However epidermal γδ T cells exhibit reduced proliferation and defective growth factor and cytokine production during obesity
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Cytomegalovirus inhibitors of programmed cell death prevent a contribution of antigen cross-presentation to the priming of antiviral CD8 T cells bioRxiv. Immunol. Pub Date : 2024-04-13 Stefan Ebert, Verena Böhm, Julia K. Büttner, Wolfram Brune, Melanie M. Brinkmann, Rafaela Holtappels, Matthias J. Reddehase, Niels AW Lemmermann
CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen
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Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns bioRxiv. Immunol. Pub Date : 2024-04-13 Joseph Stevens, Erica Culberson, Jeremy Kinder, Alica Ramiriqui Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-yu Shao, Faris Al Gharabieh, Laura Peterson, Shelby Steinmeyer, William J Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh
The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8+ T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression
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HIV-1 controllers possess a unique CD8+ T-cell activation phenotype and loss of control is associated with increased expression of exhaustion markers bioRxiv. Immunol. Pub Date : 2024-04-12 Amber D Jones, Zachary Capriotti, Erin Santos, Angel Lin, Rachel Van Duyne, Stephen M Smith, ZACHARY KLASE
HIV-1 controllers are a rare population of individuals that exhibit spontaneous control of HIV-1 infection without antiretroviral therapy. These controllers can be categorized based on the level and mechanism of control. Understanding the mechanisms by which controllers maintain and eventually lose this ability would be highly valuable in HIV-1 cure or vaccine research. We explored whether CD8+ T cell
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High-Dimensional Imaging of Vestibular Schwannoma Reveals Distinctive Immunological Networks Across Histomorphic Niches in NF2-related Schwannomatosis bioRxiv. Immunol. Pub Date : 2024-04-12 Adam P Jones, Michael J Haley, Grace E Gregory, Cathal J Hannan, Ana K Simmons, Leoma D Bere, Daniel G Lewis, Pedro Oliveira, Miriam J Smith, Andrew T King, D Gareth Evans, Pawel Paszek, David Brough, Omar N Pathmanaban, Kevin Couper
NF2-related Schwannomatosis (NF2 SWN) is a rare tumour-predisposition syndrome characterised by the growth of multiple central and peripheral nervous system neoplasms. The drivers of NF2 SWN are pathogenic variants in the tumour suppressor gene NF2, encoding the protein Merlin, leading to development of bilateral vestibular schwannoma (VS) in >95% of patients. VS tumours are characterised by infiltration
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Monoclonal antibodies derived from B cells in subjects with cystic fibrosis reduce Pseudomonas aeruginosa burden in mice bioRxiv. Immunol. Pub Date : 2024-04-12 Malika Hale, Kennidy K. Takehara, Christopher D. Thouvenel, Dina A. Moustafa, Andrea Repele, Mary F. Fontana, Jason Netland, Sharon McNamara, Ronald L. Gibson, Joanna B. Goldberg, David J Rawlings, Marion Pepper
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations
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IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells bioRxiv. Immunol. Pub Date : 2024-04-12 Kelsey S Heavener, Khushbu Kabra, Maedot Yidenk, Elizabeth Bradshaw
The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer′s disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding
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Synergistic innate immune activation and anti-tumor immunity through combined STING and TLR4 stimulation bioRxiv. Immunol. Pub Date : 2024-04-12 Emily F. Higgs, Thomas F. Gajewski
Previous work has shown that innate immune sensing of tumors involves the host STING pathway, which leads to IFN-B production, dendritic cell (DC) activation, and T cell priming against tumor antigens. This observation has led to the development of STING agonists as a potential cancer therapeutic. However, despite promising results in mouse studies using transplantable tumor models, clinical testing