RESUMEN
Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.
RESUMEN
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.
Asunto(s)
Autoinmunidad , Linfocitos Intraepiteliales , Glicoproteínas de Membrana , Receptores de Antígenos de Linfocitos T alfa-beta , Humanos , Autoinmunidad/genética , Diferenciación Celular , Homocigoto , Linfocitos Intraepiteliales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Glicoproteínas de Membrana/genética , Mutación con Pérdida de Función , Recuento de Linfocitos , Alelos , Infecciones/inmunología , Trastornos Linfoproliferativos/inmunología , Linaje , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
Inborn errors of immunity (IEIs) are a group of more than 450 monogenic disorders that impair immune development and function. A subset of IEIs blend increased susceptibility to infection, autoimmunity, and malignancy and are known collectively as primary immune regulatory disorders (PIRDs). While many aspects of immune function are altered in PIRDs, one key impact is on T-cell function. By their nature, PIRDs provide unique insights into human T-cell signaling; alterations in individual signaling molecules tune downstream signaling pathways and effector function. Quantifying T-cell dysfunction in PIRDs and the underlying causative mechanisms is critical to identifying existing therapies and potential novel therapeutic targets to treat our rare patients and gain deeper insight into the basic mechanisms of T-cell function. Though there are many types of T-cell dysfunction, here we will focus on T-cell exhaustion, a key pathophysiological state. Exhaustion has been described in both human and mouse models of disease, where the chronic presence of antigen and inflammation (e.g., chronic infection or malignancy) induces a state of altered immune profile, transcriptional and epigenetic states, as well as impaired T-cell function. Since a subset of PIRDs amplify T-cell receptor (TCR) signaling and/or inflammatory cytokine signaling cascades, it is possible that they could induce T-cell exhaustion by genetically mimicking chronic infection. Here, we review the fundamentals of T-cell exhaustion and its possible role in IEIs in which genetic mutations mimic prolonged or amplified T-cell receptor and/or cytokine signaling. Given the potential insight from the many forms of PIRDs in understanding T-cell function and the challenges in obtaining primary cells from these rare disorders, we also discuss advances in CRISPR-Cas9 genome-editing technologies and potential applications to edit healthy donor T cells that could facilitate further study of mechanisms of immune dysfunctions in PIRDs. Editing T cells to match PIRD patient genetic variants will allow investigations into the mechanisms underpinning states of dysregulated T-cell function, including T-cell exhaustion.
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Sistemas CRISPR-Cas , Neoplasias , Animales , Citocinas/genética , Edición Génica , Humanos , Ratones , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Black/African Americans, Hispanic/Latinxs, and Native Americans remain chronically underrepresented in science, technology, engineering, and math (STEM). Values misalignment, implicit/explicit bias, and hypercompetition in the funding climate disproportionately affect underrepresented minority (URM) postdoctoral fellows transitioning into faculty positions. URM scientists must increase and be given opportunities to establish independent research programs.
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Movilidad Laboral , Docentes , Grupos Minoritarios , Selección de Profesión , Ingeniería , Humanos , Matemática , Investigadores , Ciencia , Tecnología , Estados UnidosRESUMEN
Idiopathic CD4+ T cell lymphocytopenia (ICL) is a heterogeneous syndrome presenting with persistent CD4+ T cell lymphopenia of unknown origin, and opportunistic infections in some patients. The underlying pathogenesis and appropriate management remain understudied. In this issue of the JCI, Perez-Diez and Wong et al. assessed the prevalence of autoantibodies from the sera of 51 adult ICL patients (out of a cohort of 72). Some patients showed high levels of IgG and IgM autoantibodies against numerous autoantigens, and some autoantibodies were specific for lymphocytes. The researchers implicate these autoantibodies as a possible pathogenic mechanism responsible for the reduction in circulating CD4+ T cells. This study goes beyond defining a mechanism in a complex, poorly defined disease; it also brings a renewed focus on ICL that will likely result in improved diagnostic evaluation and treatment.