Cluster analysis and differential gene expression revealed markers of cellular bioenergetic stress in select immune cell populations with depletion. To define the role of OXPHOS in human immune cells, we began by performing single cell RNAseq in peripheral blood mononuclear cells from children with MtD. The immune phenotype of patients with MtD is emerging and manifests as susceptibility to infection and immune dysfunction ( 5), making this population ideal for translational immunometabolism investigations. Due to the ubiquity of the mitochondria, the clinical phenotype of MtD is pleiotropic, involving organs and systems with considerable energy needs. Primary mitochondrial dysfunction, known as mitochondrial disease (MtD), is a group of disorders caused by deleterious variants in nDNA or mtDNA genes involved in OXPHOS, the main pathway for energy generation in cells ( 4). Indeed, the study of rare diseases has greatly contributed to our understanding of biologic mechanisms and remains a viable model for defining complex disease pathophysiology ( 3). Despite the widespread availability of various models, the human system displays its own extensive assortment of phenotypes due to deleterious variants in genes, and thus represents the ultimate experimental model system ( 2). Since one of the main goals of biomedical research is to improve the health and well-being of humankind, all biomedical research utilizing model organisms and systems is directed at human translation. Moreover, the role of oxidative phosphorylation (OXPHOS) in human immune cell populations, specifically B cells, is nearly absent from the biomedical literature. To date, the majority of immunometabolism studies have been conducted in mouse models, emphasizing the need for translational immunometabolism. Over the past decade, the field has delivered significant advances, with mitochondria taking center stage. Immunometabolism as a discipline encompasses the interplay between metabolism and immunocyte proliferation, differentiation, and function ( 1).

Despite similar viral exposomes, MtD displayed antiviral antibodies with less robust fold changes and limited polyclonality.ĭiscussion: Overall, we show that children with MtD display perturbations in the B cell repertoire which may impact humoral immunity and the ability to clear viral infections. To determine the functional consequences of our findings on humoral immunity, we studied the antiviral antibody repertoire in children with MtD and controls using phage display and immunoprecipitation sequencing. Knockdown studies of mir4485 demonstrated its role in promoting survival by modulating apoptosis. mir4485, a miRNA contained in the intron of MTRNR2L8, was co-expressed. MTRNR2L8, a marker of bioenergetic stress, was significantly elevated in populations that were most depleted. Results: Via scRNAseq, we found marked reductions in select populations involved in the humoral immune response, especially antigen presenting cells, B cell and plasma populations, with sparing of T cell populations. To define B cell function we performed phage display immunoprecipitation sequencing on a cohort of children with MtD (N = 19) and controls (N = 16). Methods: scRNAseq analysis of peripheral blood mononuclear cells was performed on matched children with MtD (N = 4) and controls (N = 4). To understand the impact of oxidative phosphorylation (OXPHOS) deficiency on human immunity, we studied children with primary mitochondrial disease (MtD). Introduction: The majority of studies on oxidative phosphorylation in immune cells have been performed in mouse models, necessitating human translation. 4Department of Transfusion Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, MD, United States.3NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.2Bioinformatics and Scientific Programming Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.1Metabolism, Infection and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.Wolfsberg 2 NISC Comparative Sequencing Program 3 Willy A. Gordon-Lipkin 1† Payal Banerjee 1† Jose Luis Marin Franco 1† Tatiana Tarasenko 1 Shannon Kruk 1 Elizabeth Thompson 1 Derek E.

Primary antibody repertoire