Publications by authors named "Simon Mallal"

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. While there is no curative treatment, the immune system's involvement with autoimmune T cells that recognize the protein alpha-synuclein (α-syn) in a subset of individuals suggests new areas for therapeutic strategies. As not all patients with PD have T cells specific for α-syn, we explored additional autoantigenic targets of T cells in PD.

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Chronic inflammation contributes to the prevalence of cardiovascular disease in people living with HIV (PLWH). The immune mechanisms driving atherosclerosis progression in PLWH remain unclear. This study conducted comprehensive assessments of medium-sized coronary arteries and aorta from deceased PLWH and controls without HIV using DNA/RNA assays, spatial transcriptomics, and high-resolution mass spectrometry.

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Article Synopsis
  • Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe skin reactions to drugs, involving immune system responses from CD8 T cells.
  • Researchers analyzed skin and blister fluid from 15 SJS/TEN patients using various sequencing techniques, revealing 15 distinct cell types and noting active immune responses in affected areas.
  • Key findings indicate that certain T cell receptors and inflammatory markers in skin tissues could be targeted for new treatments, highlighting the role of keratinocytes and T cells in the disease's progression.
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Chronic systemic inflammation significantly increases myocardial infarction risk in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis, contributing to cardiovascular disease. We aimed to characterize endothelial cell (EC) chemokines, cytokine, and chemokine receptors of PLWH, hypothesizing that in our cohort, glucose intolerance contributes to their differential expression implicated in endothelial dysfunction.

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Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides.

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A strong genetic predictor of outcome following untreated HIV-1 infection is the carriage of specific alleles of human leukocyte antigens (HLAs) that present viral epitopes to T cells. Residual variation in outcome measures may be attributed, in part, to viral adaptation to HLA-restricted T cell responses. Variants of the endoplasmic reticulum aminopeptidases (ERAPs) influence the repertoire of T cell epitopes presented by HLA alleles as they trim pathogen-derived peptide precursors to optimal lengths for antigen presentation, along with other functions unrelated to antigen presentation.

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Context: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH.

Objective: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART.

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People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities.

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Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation.

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Objectives: Recent immunologic study of the adaptive immune repertoire in the subglottic airway demonstrated high-frequency T cell clones that do not overlap between individuals. However, the anatomic distribution and antigenic target of the T cell repertoire in the proximal airway mucosa remain unresolved.

Methods: Single-cell RNA sequencing of matched scar and unaffected mucosa from idiopathic subglottic stenosis patients (iSGS, n = 32) was performed and compared with airway mucosa from healthy controls (n = 10).

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Article Synopsis
  • Parkinson's disease (PD) is related to autoimmune T cells that target alpha-synuclein and other neuroantigens linked to PD pathology.
  • Researchers explored additional autoantigen targets by studying various proteins connected to PD, including GBA, SOD1, PINK1, and others.
  • The study found that T cells, particularly in male PD patients, reacted to the mitochondrial protein PINK1, suggesting that understanding these targets could lead to new diagnostics and treatments for PD.
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Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T-cells. To obtain an unbiased assessment of SJS/TEN cellular immunopathogenesis, we performed single-cell (sc) transcriptome, surface proteome, and TCR sequencing on unaffected skin, affected skin, and blister fluid from 17 SJS/TEN patients. From 119,784 total cells, we identified 16 scRNA-defined subsets, confirmed by subset-defining surface protein expression.

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Standard single-cell RNA-sequencing alignment pipelines exhibit a propensity for misassigning killer immunoglobulin-like receptor (KIR) transcripts, thereby giving rise to inaccuracies in quantifying KIR expression. Alves et al. elucidated that these default workflows frequently misclassify activating KIR transcripts as inhibitory KIR expression, resulting in a skewed representation of the KIR repertoire.

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Article Synopsis
  • - SJS/TEN is a severe, drug-induced skin condition with a high mortality rate of 15-20% and requires multidisciplinary expertise for effective treatment; it's rare, with an incidence of 1-5 cases per million annually in the U.S., but more common globally.
  • - The SJS/TEN 2021 research meeting, held virtually, aimed to build an international research network involving 428 scientists and 140 survivors and family members to enhance collaboration between science and the community.
  • - The workshop covered vital themes such as mental health, pediatric cases, long-term complications, skin care for diverse populations, and the impact of COVID-19 vaccines, identifying key areas for future research and clinical focus.
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Objectives: Recent translational scientific efforts in subglottic stenosis (SGS) support a disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. Given the observed immune cell infiltrate in SGS, we sought to test the hypothesis that SGS cases possessed a low diversity (highly clonal) adaptive immune response when compared with healthy controls.

Methods: Single cell RNA sequencing (scRNA-seq) of subglottic mucosal scar in iSGS (n = 24), iLTS (n = 8), and healthy controls (n = 7) was performed.

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Introduction: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population.

Methods: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health.

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Background: The Southern region of the United States has the highest HIV incidence, and new infections disproportionately affect Black Americans. The Tennessee Center for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI) program supports the training of individuals from groups underrepresented in medicine and science in multiple areas of research to increase the pool of HIV-focused investigators at early educational and career stages.

Setting: The Tennessee CFAR is a partnership between Vanderbilt University Medical Center, Meharry Medical College (one of the oldest historically Black medical colleges), Tennessee Department of Health, and Nashville Community AIDS Resources, Education and Services (a sophisticated community service organization, which emphasizes research training responsive to regional and national priorities).

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HIV-1 remains a global health crisis, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.

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The coronavirus (CoV) family includes several viruses infecting humans, highlighting the importance of exploring pan-CoV vaccine strategies to provide broad adaptive immune protection. We analyze T cell reactivity against representative Alpha (NL63) and Beta (OC43) common cold CoVs (CCCs) in pre-pandemic samples. S, N, M, and nsp3 antigens are immunodominant, as shown for severe acute respiratory syndrome 2 (SARS2), while nsp2 and nsp12 are Alpha or Beta specific.

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Background: Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis.

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An increased risk of cardiometabolic disease accompanies persistent systemic inflammation. Yet, the innate and adaptive immune system features in persons who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states.

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Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1, GPR56, and CD57 T cells (termed CGC) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART.

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Objective: Despite recent scientific inquiry, idiopathic subglottic stenosis (iSGS) remains an enigmatic disease. The consistent demographics of the affected population suggest genetic factors may contribute to disease susceptibility. Given the inflammation observed in the affected proximal airway mucosa, we interrogated disease association with human leukocyte antigen (HLA) polymorphisms.

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The Coronavirus (CoV) family includes a variety of viruses able to infect humans. Endemic CoVs that can cause common cold belong to the alphaCoV and betaCoV genera, with the betaCoV genus also containing subgenera with zoonotic and pandemic concern, including sarbecoCoV (SARS-CoV and SARS-CoV-2) and merbecoCoV (MERS-CoV). It is therefore warranted to explore pan-CoV vaccine concepts, to provide adaptive immune protection against new potential CoV outbreaks, particularly in the context of betaCoV sub lineages.

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