Cell Reports Medicine

BackgroundThe antibody response to SARS-CoV-2 does not follow the immunoglobulin isotype pattern expected in a primary response and is inconsistent with the current interpretation of COVID-19 immunopathology as the result of a primary infection. To better understand the immune response to SARS-CoV-2, it is essential to determine whether it is primary or secondary (or recall). The analysis of highly granular immunological variable trajectories of a homogeneous cohort of patients receiving standar...

Persistent SARS-CoV-2 infection in immunocompromised patients creates a unique environment for the accumulation of mutations linked to immune evasion. This is due to prolonged virus-host interaction, coupled with the effects of diminished selective pressures resulting from suboptimal adaptive immunity. In this study, we investigated viral evolution and immune escape during a 2.5-year persistent SARS-CoV-2 infection in a patient with a history of multiple myeloma and rheumatoid arthritis on B ce...

Antibody-mediated rejection (AbMR), driven by donor-specific alloantibodies (DSAs), is a major cause of late-stage kidney allograft failure, leading to premature graft loss in over half of affected patients. Despite efforts to link DSA features (e.g., HLA-specific IgG titers) to rejection risk, the immune mechanisms distinguishing DSA+ patients who develop AbMR remain unclear. In this first-in-class study, we develop a sample-sparing and cost-effective technique to generate the most comprehensiv...

Despite advances in surgical techniques and immunosuppression, long-term survival after lung transplantation (LuTx) remains suboptimal due to high rates of rejection, infection and graft dysfunction. To address this, we investigated post-LuTx T cell dynamics--tracking repopulation, clonal distribution, alloreactivity, and microbial reactivity--through flow cytometry and TCR{beta} sequencing of serial bronchoalveolar lavage (BAL) and peripheral blood samples. Pre- transplant mixed lymphocyte reac...

Primary Epstein-Barr virus (EBV) infection can lead to post-transplantation lymphoproliferative disorder (PTLD) following renal transplantation (RTx). Despite EBV-driven PTLD (ePTLD) being rare, it is potentially lethal. CD8+ T-cells play a crucial role in controlling viral infections and malignant transformation of cells. We therefore hypothesized that aberrant EBV-specific CD8+ T cell maturation may contribute to ePTLD development. We performed multichannel flow cytometry on MHC class I tetram...

Immunosuppression in solid organ transplant recipients inhibits protective immune responsiveness to pathogens and vaccines. However, specific cell states that associate with failure to generate protective immunity are not known. Here, we perform scRNAseq and CyTOF analyses of PBMC from 12 pediatric solid organ transplant recipients and 8 healthy children revealing the full spectrum of immune cell states present in these individuals, and examine the association of these cell states with the gener...

Despite the obvious knowledge that infectious particles can be shared through respiration, whether other constituents of the nasal/oral fluids can be passed between hosts has surprisingly never even been postulated, let alone investigated. The circumstances of the present pandemic facilitated a unique opportunity to fully examine this provocative idea. The data we show provides evidence for a new mechanism by which herd immunity may be manifested, the aerosol transfer of antibodies between immun...

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). Yet, the exact feature of antibody responses that governs COVID-19 disease outcomes remain unclear. Here, we analysed humoral immune responses in 209 asymptomatic, mild, moderate and severe COVID-19 patients over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-Spike (S) IgG levels, length of hospitalization...

Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome in Chil...

IntroductionVery preterm birth (<32 weeks of gestation) disrupts key developmental programs and exposes infants to a highly vulnerable postnatal period. However, the molecular trajectories underlying early postnatal adaptation remain poorly characterized, largely due to limitations in longitudinal sampling and the need for minimally invasive approaches. MethodsHere, we applied an integrated longitudinal proteomic and lipidomic analysis to plasma extracellular vesicles (EVs) from very preterm in...

BackgroundDonor T cell reconstitution following allogeneic hematopoietic cell transplantation (HCT) is crucial for protective immunity against infections and cancer relapse. However, its use remains limited by the risk of graft-versus-host disease (GvHD), a serious complication arising when donor T cells target recipient tissues. Here we evaluate a novel metric--the T cell receptor beta (TRB) tolerant fraction--as a predictor of GvHD risk. MethodsWe analyzed TRB sequencing data from mouse model...

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocytosis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely impeding the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell R...

Identifying biomarkers in kidney transplant patients is essential for early detection of rejection, personalized treatment and improved overall outcomes. It improves our ability to monitor the health of the transplanted organ and tailor interventions to the specific needs of each patient. Here we compiled a multicenter, multiomic dataset of the kidney transplant landscape. Using multi-omics factor analysis (MOFA), we sought to uncover sources of biological variability in patients blood, urine an...

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of MIS-C patient samples (n=199) to identify a distinct set of host proteins that are differentially targeted by patient autoantibodies relative to matched controls. We identified an autoreactive epitope within SNX8, a protein expressed pri...

It is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of gut lymphocyte populations. Using polychromatic flow cytometry that includes HLA allele group-specific mAbs distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establish...

1.The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like pa...

Coronavirus disease 2019 (COVID-19) displays high clinical variability but the parameters that determine disease severity are still unclear. Pre-existing T cell memory has been hypothesized as a protective mechanism but conclusive evidence is lacking. Here we demonstrate that all unexposed individuals harbor SARS-CoV-2-specific memory T cells with marginal cross-reactivity to common cold corona and other unrelated viruses. They display low functional avidity and broad protein target specificitie...

Progress in detecting and understanding endometrial conditions in women of fertile age, such as endometriosis, has been hampered by the invasiveness of the sample collection procedure. Menstrual fluid (MF) can be sampled non-invasively and could provide a unique opportunity to study the physiological state of tissues in the reproductive system. Despite this potential, the use of MF for diagnostics and research has been limited. Here we establish protocols and assess the feasibility of collecting...

Over 2.5 million neonatal dried blood spots (DBS) are stored at the Danish National Biobank. These samples offer extraordinary possibilities for metabolomics research, including prediction of disease and understanding of underlying molecular mechanisms of disease development. Nevertheless, Danish neonatal DBS have been little explored in metabolomics studies. One question that remains is the long-term stability of the large number of metabolites typically assessed in untargeted metabolomics over...

BackgroundLack of knowledge on the processes driving endometriosis hinders early detection and therapy development. Our purpose was to identify key molecular events involved in lesion formation across diverse populations and to detect transcriptomic changes in eutopic endometrium that accompany endometriosis. MethodsWe searched Gene Expression Omnibus and ArrayExpress and performed differential gene expression analysis and a network meta-analysis on nine qualifying datasets. Those contained tra...