Immune Signatures
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2022 ◽  
Patrick Taeschler ◽  
Carlo Cervia ◽  
Yves Zurbuchen ◽  
Sara Hasler ◽  
Christian Pou ◽  

Background: Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. Objective: We longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19. Methods: We performed highly sensitive indirect immunofluorescence assays to detect anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed-up to one year after infection, eleven vaccinated individuals, and 41 unexposed controls. Results: Compared to healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B cell compartment after recovery. Conclusion: Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased anti-viral humoral immune responses and inflammatory immune signatures.

Xiaoyu Che ◽  
Mady Hornig ◽  
Michaeline Bresnahan ◽  
Camilla Stoltenberg ◽  
Per Magnus ◽  

2021 ◽  
Adam J H Newton ◽  
David Chartash ◽  
Steven H Kleinstein ◽  
Robert A McDougal

Objective: The accelerating pace of biomedical publication has made retrieving papers and extracting specific comprehensive scientific information a key challenge. A timely example of such a challenge is to retrieve the subset of papers that report on immune signatures (coherent sets of biomarkers) to understand the immune response mechanisms which drive differential SARS-CoV-2 infection outcomes. A systematic and scalable approach is needed to identify and extract COVID-19 immune signatures in a structured and machine-readable format. Materials and Methods: We used SPECTER embeddings with SVM classifiers to automatically identify papers containing immune signatures. A generic web platform was used to manually screen papers and allow anonymous submission. Results: We demonstrate a classifier that retrieves papers with human COVID-19 immune signatures with a positive predictive value of 86%. Semi-automated queries to the corresponding authors of these publications requesting signature information achieved a 31% response rate. This demonstrates the efficacy of using a SVM classifier with document embeddings of the abstract and title, to retrieve papers with scientifically salient information, even when that information is rarely present in the abstract. Additionally, classification based on the embeddings identified the type of immune signature (e.g., gene expression vs. other types of profiling) with a positive predictive value of 74%. Conclusions: Coupling a classifier based on document embeddings with direct author engagement offers a promising pathway to build a semi-structured representation of scientifically relevant information. Through this approach, partially automated literature mining can help rapidly create semi-structured knowledge repositories for automatic analysis of emerging health threats.

2021 ◽  
pp. clincanres.1816.2021
Adam J. Luginbuhl ◽  
Jennifer M. Johnson ◽  
Larry A. Harshyne ◽  
Alban J. Linnenbach ◽  
Sanket K. Shukla ◽  

2021 ◽  
Vol 4 (1) ◽  
Joern Pezoldt ◽  
Carolin Wiechers ◽  
Florian Erhard ◽  
Ulfert Rand ◽  
Tanja Bulat ◽  

AbstractOur understanding of the composition and functions of splenic stromal cells remains incomplete. Here, based on analysis of over 20,000 single cell transcriptomes of splenic fibroblasts, we characterized the phenotypic and functional heterogeneity of these cells in healthy state and during virus infection. We describe eleven transcriptionally distinct fibroblastic cell clusters, reassuring known subsets and revealing yet unascertained heterogeneity amongst fibroblasts occupying diverse splenic niches. We further identify striking differences in innate immune signatures of distinct stromal compartments in vivo. Compared to other fibroblasts and to endothelial cells, Ly6C+ fibroblasts of the red pulp were selectively endowed with enhanced interferon-stimulated gene expression in homeostasis, upon systemic interferon stimulation and during virus infection in vivo. Collectively, we provide an updated map of fibroblastic cell diversity in the spleen that suggests a specialized innate immune function for splenic red pulp fibroblasts.

2021 ◽  
Vol 5 (1) ◽  
Okan Gultekin ◽  
Jordi Gonzalez-Molina ◽  
Elin Hardell ◽  
Lidia Moyano-Galceran ◽  
Nicholas Mitsios ◽  

AbstractUterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.

2021 ◽  
Joann Diray-Arce ◽  
Helen E.R. Miller ◽  
Evan Henrich ◽  
Bram Gerritsen ◽  
Matthew P Mulè ◽  

Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern 'omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effects across studies, and the absence of multiple relevant studies from non-HIPC groups in ImmPort. To support comparative analyses across different vaccines, we have created the Immune Signatures Data Resource, a compendium of standardized systems vaccinology datasets. This data resource is available through ImmuneSpace, along with code to reproduce the processing and batch normalization starting from the underlying study data in ImmPort and the Gene Expression Omnibus (GEO). The current release comprises 1405 participants from 53 cohorts profiling the response to 24 different vaccines and includes transcriptional profiles and antibody response measurements. This novel systems vaccinology data release represents a valuable resource for comparative and meta-analyses that will accelerate our understanding of mechanisms underlying vaccine responses.

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S815-S815
Styliani Karanika ◽  
James Gordy ◽  
Pranita Neupane ◽  
Richard Markham ◽  
Petros Karakousis

Abstract Background Tuberculosis (TB) is one of the leading causes of death from a single infectious agent worldwide. The lengthy treatment regimen reflects the unique ability of a subpopulation of “persister” bacteria to remain in a nonreplicating state in the infected host through various adaptive strategies, including induction of the stringent response. The key stringent response enzyme, RelMtb, is essential for long-term Mycobacterium tuberculosis (Mtb) survival under physiologically relevant stresses in vitro and in animal lungs. Recently, our group has generated a therapeutic, parenteral, relMtb DNA vaccine, which induces RelMtb-specific cellular immunity and augments the activity of the first-line drug isoniazid against active TB in mice and guinea pigs. Our group also has applied a novel vaccination strategy involving the fusion of an antigen of interest with the immature dendritic cell (iDC)-targeting chemokine MIP-3α/CCL20, which significantly enhances antigen-specific T-cell responses. We sought to determine if this iDC-targeting strategy improves the immunogenicity of the therapeutic relMtb DNA vaccine. Methods We cloned the relMtb and chemokine MIP-3α genes into the eukaryotic expression plasmid pSectag2b. We conducted an immunogenicity study using C57BL/6J mice, comparing the T-cell responses between the relMtbvs. MIP-3α/relMtb DNA intramuscular vaccination groups. Results Intramuscular administration of the DNA vaccine expressing the MIP-3α/relMtb gene fusion induced increased production of various Mtb-protective cytokines (IL-17α, IL-2, TNF-α, IFN-γ) in various mouse tissues, including the spleen, draining lymph nodes and peripheral blood mononuclear cells, relative to the vaccine expressing relMtb alone. Conclusion Intramuscular immunization with a DNA vaccine expressing relMtb/MIP-3α induces robust in vivo Mtb-protective immune signatures, suggesting this may be a promising adjunctive approach in combination with standard anti-TB therapy. Disclosures All Authors: No reported disclosures

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A957-A957
Chai Gan ◽  
Bernard Kok Bang Lee ◽  
Shin Hin Lau ◽  
Thomas George Kallarakkal ◽  
Zuraiza Mohamad Zaini ◽  

BackgroundPatients with oral potentially malignant disorders (OPMD) having moderate or severe oral epithelial dysplasia (OED) have a greater risk of developing oral squamous cell carcinoma (OSCC) compared to mild OED with an odds ratio of 2.4.1 The involvement of specific immune cell types associated with malignant transformation have been reported, giving rise to clinical trials in immunoprevention. However, the immune landscape of OPMD remains understudied. In this study, we aimed to elucidate the immune landscape of high-risk OPMD by transcriptomic profiling for the identification of potential immunoprevention strategy.MethodsHistological evaluation was performed on hematoxylin and eosin (H&E)-stained tissues to investigate the differences of lymphocyte infiltration in benign lesions (n=16), high-risk OPMD consisted of moderate and severe OED (n=46) and early-stage OSCC (n=6). Formalin-fixed paraffin-embedded tissue sections of selected cases from each sample type were subjected to RNA sequencing. Weighted-gene-correlation network analysis (WGCNA) was used to identify key gene modules expressed in specific disease type.2 The immune landscape of high-risk OPMD was elucidated by the enrichment of immune signatures using single-sample gene set enrichment analysis.3–5 The response of high-risk OPMD to anti-PD1 treatment was predicted by the detection of T-cell-inflamed condition.6 Validation was performed by multiplex immunofluorescent (mIF) staining.ResultsOur H&E evaluation showed that lymphocyte infiltration into the epithelial was seen in 80% of high-risk OPMD and early-stage OSCC, compared to 9% of benign lesion. Gene modules identified from WGCNA analysis revealed that genes involved in immune-related pathways were overexpressed in high-risk OPMD and in early-stage OSCC when compared to benign lesion, but unchanged between high-risk OPMD and early-stage OSCC. We further demonstrated that immune signatures representing lymphocyte infiltration, MHC-I antigen presentation and cytotoxic immune responses were enriched in high-risk OPMD, indicating the presence of immune surveillance. High-risk OPMD can be grouped into the T-cell-inflamed and non-immune reactive subtypes. The T-cell-inflamed subtype is enriched with T cells, interferon signaling and PD-1/PD-L1 immune checkpoint proteins, suggesting that these lesions may be amenable to anti-PD1 treatment. Meanwhile, the non-immune reactive subtype demonstrated low enrichment in signatures for immune cell infiltration, indicating a need of intervention to induce lymphocyte infiltration. Using mIF staining, we observed an increase of CD45+ immune cell population expressing PD-L1 in high-risk OPMD.ConclusionsImmune surveillance is a prominent feature of high-risk OPMD. However, different subsets of high-risk OPMD exist, suggesting a need of different immunoprevention approaches to prevent disease progression which warrants further investigation.AcknowledgementsThis study was supported and funded by the Global Challenge Research Fund by the Medical Research Council, UK (MR/P024351/1) and Cancer Research Malaysia. We thank the Ong Heng Tiang & Ong Sek Pek Foundation for scholarship sponsorship.ReferencesIocca O, Sollecito TP, Alawi F, et al. Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck 2020;42:539–55.Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008;9:559.Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.Chen YP, Wang YQ, Lv JW, et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol 2019;30:68–75.Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018;48:812–30.Ayers M, Lunceford J, Nebozhyn M, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 2017;127:2930–40.Ethics ApprovalThe use of clinical specimens in this study has been approved by the Medical Ethics Committee, Faculty of Dentistry, University of Malaya [DF OS1624/0073(L)], and The National Medical Research Register, Malaysia [NMRR-16-1764-32566 (IIR)].

2021 ◽  
Vol 7 (42) ◽  
Supriya Ravichandran ◽  
Gabrielle Grubbs ◽  
Juanjie Tang ◽  
Youri Lee ◽  
Chang Huang ◽  

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