ABSTRACT
Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.
Subject(s)
Adaptive Immunity , Immunity, Innate , Interferon-gamma/immunology , Mycobacterium/immunology , T-Box Domain Proteins/metabolism , Amino Acid Sequence , Base Sequence , Cell Lineage , Child, Preschool , Chromatin/metabolism , CpG Islands/genetics , DNA Methylation/genetics , Dendritic Cells/metabolism , Epigenesis, Genetic , Female , Homozygote , Humans , INDEL Mutation/genetics , Infant , Interferon-gamma/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Loss of Function Mutation/genetics , Male , Mycobacterium Infections/genetics , Mycobacterium Infections/immunology , Mycobacterium Infections/microbiology , Pedigree , T-Box Domain Proteins/chemistry , T-Box Domain Proteins/deficiency , T-Box Domain Proteins/genetics , T-Lymphocytes, Helper-Inducer/immunology , Transcriptome/geneticsABSTRACT
Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, in vitro T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.
Subject(s)
Hepatitis B Vaccines/immunology , Hepatitis B virus/physiology , Hepatitis B/diagnosis , Monitoring, Immunologic/methods , Vaccination/methods , Adult , Aged , Aged, 80 and over , Female , Hepatitis B/immunology , Humans , Male , Middle Aged , Prospective Studies , Systems Biology , Treatment OutcomeABSTRACT
Low socioeconomic status (SES) in early-life and adulthood independently contribute to increased risk for aging-related chronic diseases. One mechanistic hypothesis for these associations involves faster cellular aging of immune cells, which could plausibly contribute to chronic disease pathogenesis by compromising host resistance and/or up-regulating inflammation. However, little is known about the association between life-course SES and cellular aging. The present study examines the association of early-life and current SES with a novel biomarker of cellular aging termed the "epigenetic clock," in monocytes. Additionally, we examine health behaviors and depressive symptoms as potential explanatory pathways. The study involved 335 participants between the ages of 15 and 55 from Vancouver, Canada and surrounding areas. Enrolled participants had to fit into four life-course SES trajectories, corresponding to low-low, low-high, high-low and high-high combinations of early-life (ages 0 to 5) and current SES respectively. Cellular aging of monocytes was measured using Horvath's DNA methylation derived measure of epigenetic age acceleration. Results indicated that socioeconomic disadvantage during early-life, but not later in life, was associated with accelerated epigenetic aging of monocytes. No early-life SES by current SES interaction was detected, suggesting that socioeconomic mobility is unrelated to epigenetic age acceleration. In path analyses, neither current health behaviors nor current depressive symptoms emerged as mediators of the early-life SES effect. These findings suggest socioeconomic disadvantage in early-life is independently predictive of cellular aging of immune cells, with potential implications for aging-related diseases later in life.
