RESUMEN
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Inmunidad Innata , Inmunomodulación , Neumonía Viral/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Animales , Vacuna BCG/inmunología , COVID-19 , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/transmisión , Humanos , Inmunidad Innata/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Linfopenia/patología , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Pandemias , Neumonía Viral/patología , Neumonía Viral/fisiopatología , Neumonía Viral/transmisión , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/patología , Replicación ViralRESUMEN
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.
Asunto(s)
Enfermedades Autoinmunes/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Síndromes de Inmunodeficiencia/genética , Corticoesteroides/uso terapéutico , Adulto , Enfermedades Autoinmunes/complicaciones , Colitis/complicaciones , Colitis/genética , Colitis/patología , Femenino , Fiebre/complicaciones , Fiebre/tratamiento farmacológico , Fiebre/genética , Haploinsuficiencia , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Linfopenia/complicaciones , Linfopenia/genética , Masculino , Persona de Mediana Edad , Mutación , Pancitopenia/complicaciones , Pancitopenia/tratamiento farmacológico , Pancitopenia/genética , Linaje , Polimorfismo de Nucleótido Simple , Recurrencia , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/diagnóstico por imagen , Infecciones del Sistema Respiratorio/genética , Esplenomegalia/complicaciones , Esplenomegalia/genética , Síndrome , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Asunto(s)
Inmunidad Innata , Linfocitos/inmunología , Adolescente , Adulto , Animales , Biomarcadores , Niño , Modelos Animales de Enfermedad , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Janus Quinasa 3/deficiencia , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos/metabolismo , Linfopenia/sangre , Linfopenia/etiología , Ratones , Ratones Noqueados , Fenotipo , Inmunodeficiencia Combinada Grave/sangre , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/metabolismo , Inmunodeficiencia Combinada Grave/terapia , Piel/inmunología , Piel/patologíaRESUMEN
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.
Asunto(s)
Discapacidad Intelectual , Linfopenia , Humanos , Proteína NEDD8/genética , Proteína NEDD8/metabolismo , Transducción de Señal/genética , Discapacidad Intelectual/genética , FN-kappa B/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Linfopenia/genéticaRESUMEN
BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations. METHODS: We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality. RESULTS: After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher. CONCLUSIONS: Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).
Asunto(s)
COVID-19 , Síndromes de Inmunodeficiencia , Linfopenia , Infecciones Oportunistas , Enfermedades de Inmunodeficiencia Primaria , Humanos , COVID-19/complicaciones , Síndromes de Inmunodeficiencia/complicaciones , Linfopenia/etiología , Linfocitos T CD4-Positivos , Recuento de Linfocito CD4 , Enfermedades de Inmunodeficiencia Primaria/complicacionesRESUMEN
Interleukin-7 (IL-7) availability determines the size and proliferative state of the resting T cell pool. However, the mechanisms that regulate steady-state IL-7 amounts are unclear. Using experimental lymphopenic mouse models and IL-7-induced homeostatic proliferation to measure IL-7 availability in vivo, we found that radioresistant cells were the source of IL-7 for both CD4+ and CD8+ T cells. Hematopoietic lineage cells, although irrelevant as a source of IL-7, were primarily responsible for limiting IL-7 availability via their expression of IL-7R. Unexpectedly, innate lymphoid cells were found to have a potent influence on IL-7 amounts in the primary and secondary lymphoid tissues. These results demonstrate that IL-7 homeostasis is achieved through consumption by multiple subsets of innate and adaptive immune cells.
Asunto(s)
Células Madre Hematopoyéticas/fisiología , Interleucina-7/metabolismo , Linfocitos/inmunología , Linfopenia/inmunología , Linfocitos T/fisiología , Inmunidad Adaptativa , Animales , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Homeostasis , Humanos , Inmunidad Innata , Interleucina-7/genética , Interleucina-7/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tolerancia a Radiación , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismoRESUMEN
In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.
Asunto(s)
Betacoronavirus/genética , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno/inmunología , Linfopenia/virología , Neumonía Viral/inmunología , Neumonía Viral/virología , Síndrome de Dificultad Respiratoria/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Animales , Infecciones Asintomáticas/epidemiología , Betacoronavirus/clasificación , Betacoronavirus/aislamiento & purificación , COVID-19 , China/epidemiología , Estudios de Cohortes , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/epidemiología , Enfermedad Crítica/epidemiología , Progresión de la Enfermedad , Evolución Molecular , Femenino , Variación Genética , Genoma Viral/genética , Hospitalización/estadística & datos numéricos , Humanos , Mediadores de Inflamación/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Interleucina-8/sangre , Interleucina-8/inmunología , Recuento de Linfocitos , Linfopenia/complicaciones , Masculino , Persona de Mediana Edad , Pandemias , Filogenia , Neumonía Viral/complicaciones , Neumonía Viral/epidemiología , Síndrome de Dificultad Respiratoria/complicaciones , SARS-CoV-2 , Linfocitos T/citología , Linfocitos T/inmunología , Factores de Tiempo , Resultado del Tratamiento , Virulencia/genética , Esparcimiento de Virus , Adulto Joven , Zoonosis/transmisión , Zoonosis/virologíaRESUMEN
We detected ENU-induced alleles of Mfsd1 (encoding the major facilitator superfamily domain containing 1 protein) that caused lymphopenia, splenomegaly, progressive liver pathology, and extramedullary hematopoiesis (EMH). MFSD1 is a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified association between MFSD1 and both GLMP (glycosylated lysosomal membrane protein) and GIMAP5 (GTPase of immunity-associated protein 5). Germline knockout alleles of Mfsd1, Glmp, and Gimap5 each caused lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver. We found that the interactions of MFSD1 and GLMP with GIMAP5 are essential to maintain normal GIMAP5 expression, which in turn is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings identify the protein complex MFSD1-GLMP-GIMAP5 operating in hematopoietic and extrahematopoietic tissues to regulate immunity and liver homeostasis.
Asunto(s)
Proteínas de Unión al GTP , Linfopenia , Humanos , Proteínas de Unión al GTP/metabolismo , Proteómica , Hígado/metabolismo , Linfocitos/metabolismo , Linfopenia/genética , HomeostasisRESUMEN
Endoplasmic reticulum (ER) calcium (Ca2+ ) stores are critical to proteostasis, intracellular signaling, and cellular bioenergetics. Through forward genetic screening in mice, we identified two members of a new complex, Pacs1 and Wdr37, which are required for normal ER Ca2+ handling in lymphocytes. Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca2+ release from the ER after antigen receptor stimulation. Pacs1-deficient cells showed diminished inositol triphosphate receptor expression together with increased ER and oxidative stress. Mature Pacs1-/- B cells proliferated and died in vivo under lymphocyte replete conditions, indicating spontaneous loss of cellular quiescence. Disruption of Pacs1-Wdr37 did not diminish adaptive immune responses, but potently suppressed lymphoproliferative disease models by forcing loss of quiescence. Thus, Pacs1-Wdr37 plays a critical role in stabilizing lymphocyte populations through ER Ca2+ handling and presents a new target for lymphoproliferative disease therapy.
Asunto(s)
Retículo Endoplásmico/metabolismo , Eliminación de Gen , Linfopenia/genética , Trastornos Linfoproliferativos/genética , Proteínas Nucleares/genética , Proteínas de Transporte Vesicular/genética , Animales , Linfocitos B/metabolismo , Señalización del Calcio , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Linfopenia/metabolismo , Trastornos Linfoproliferativos/metabolismo , Masculino , Ratones , Células 3T3 NIH , Proteínas Nucleares/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Interleukin 7 (IL-7) has a critical role in the development of early CD4(-)CD8(-) double-negative (DN) thymocytes. Although the transcription factor STAT5 is an important component of IL-7 signaling, differences in the phenotypes of mice deficient in STAT5, IL-7, IL-7 receptor alpha (IL-7rα) or the kinase Jak3 suggest the existence of STAT5-independent IL-7 signaling. Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1. This NFAT-activation pathway was critical for the survival and development of DN thymocytes, as deficiency in NFATc1 blocked thymocyte development at the DN1 stage, leading to T cell lymphopenia. In addition, our results demonstrated a cooperative function for NFATc1 and STAT5 in guiding thymocyte development in response to IL-7 signals.
Asunto(s)
Interleucina-7/genética , Factores de Transcripción NFATC/genética , Factor de Transcripción STAT5/genética , Transducción de Señal/inmunología , Timocitos/citología , Animales , Antígenos CD4/genética , Antígenos CD4/inmunología , Antígenos CD8/genética , Antígenos CD8/inmunología , Diferenciación Celular , Regulación de la Expresión Génica , Interleucina-7/inmunología , Janus Quinasa 3/genética , Janus Quinasa 3/inmunología , Linfopenia/inmunología , Linfopenia/patología , Ratones , Ratones Transgénicos , Factores de Transcripción NFATC/deficiencia , Fosforilación , Regiones Promotoras Genéticas , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Factor de Transcripción STAT5/inmunología , Timocitos/inmunología , Transcripción GenéticaRESUMEN
Frequent plateletpheresis is associated with severe lymphopenia of uncertain clinical significance. We assessed the functional impact of frequent platelet donations and associated lymphopenia on the response to neoantigens. We conducted a prospective study of 102 platelet donors (HIV uninfected) who were naive to meningococcal vaccination recruited at Brigham and Women's Hospital. One dose of quadrivalent meningococcal conjugate vaccine was administered. Seroresponse was defined as a fourfold increase of serum bactericidal antibody titers and seroprotection was defined as postvaccination titers of ≥1:8, for each of the 4 vaccine antigens (A, C, W, and Y). Mean age of participants was 61 years, 69% were male, and medial number of platelet donations in prior year was 14 (interquartile range, 4-20). Frequent platelet donors had a low CD4 count (14% with ≤200/µL and 34% with ≤350/µL). Seroresponse rates varied from 68% for serogroup Y to 86% for serogroup A and were higher for participants with baseline titers of <1:8. Postvaccination seroprotection rates varied from 76% for serogroup Y to 96% for serogroup A. After adjustments for age, sex, and frequent donations, lower total lymphocyte or lower CD4 counts were not associated with lower responses. These data suggest no impairment by plateletpheresis-associated lymphopenia on response to these neoantigens. This trial was registered at www.clinicaltrials.gov as #NCT04224311.
Asunto(s)
Linfopenia , Infecciones Meningocócicas , Vacunas Meningococicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Antibacterianos , Infecciones Meningocócicas/prevención & control , Estudios Prospectivos , Vacunas ConjugadasRESUMEN
Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.
Asunto(s)
Leucemia-Linfoma de Células T del Adulto , Linfoma , Linfopenia , Neutropenia , Trombocitopenia , Adulto , Humanos , Anciano , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Recurrencia , Inhibidores Enzimáticos , Enfermedad CrónicaRESUMEN
Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases.
Asunto(s)
Microbioma Gastrointestinal , Tolerancia Inmunológica , Linfopenia , Ratones Transgénicos , Animales , Ratones , Microbioma Gastrointestinal/inmunología , Linfopenia/inmunología , Tolerancia Inmunológica/inmunología , Piel/inmunología , Piel/microbiología , Piel/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Timo/inmunología , Ratones Endogámicos C57BLRESUMEN
Sepsis is a host inflammatory response to severe infection associated with high mortality that is caused by lymphopenia-associated immunodeficiency. However, it is unknown how lymphopenia persists after the accelerated lymphocyte apoptosis subsides. Here we show that sepsis rapidly ablated osteoblasts, which reduced the number of common lymphoid progenitors (CLPs). Osteoblast ablation or inducible deletion of interleukin-7 (IL-7) in osteoblasts recapitulated the lymphopenic phenotype together with a lower CLP number without affecting hematopoietic stem cells (HSCs). Pharmacological activation of osteoblasts improved sepsis-induced lymphopenia. This study demonstrates a reciprocal interaction between the immune and bone systems, in which acute inflammation induces a defect in bone cells resulting in lymphopenia-associated immunodeficiency, indicating that bone cells comprise a therapeutic target in certain life-threatening immune reactions.
Asunto(s)
Linfocitos B/fisiología , Síndromes de Inmunodeficiencia/inmunología , Interleucina-7/metabolismo , Células Progenitoras Linfoides/fisiología , Osteoblastos/fisiología , Sepsis/inmunología , Linfocitos T/fisiología , Animales , Células Cultivadas , Citocinas/metabolismo , Interleucina-7/genética , Depleción Linfocítica , Linfopenia , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Long-lasting sepsis-induced immunoparalysis has been principally studied in primary (1°) memory CD8 T cells; however, the impact of sepsis on memory CD8 T cells with a history of repeated cognate Ag encounters is largely unknown but important in understanding the role of sepsis in shaping the pre-existing memory CD8 T cell compartment. Higher-order memory CD8 T cells are crucial in providing immunity against common pathogens that reinfect the host or are generated by repeated vaccination. In this study, we analyzed peripheral blood from septic patients and show that memory CD8 T cells with defined Ag specificity for recurring CMV infection proliferate less than bulk populations of central memory CD8 T cells. Using TCR-transgenic T cells to generate 1° and higher-order (quaternary [4°]) memory T cells within the same host, we demonstrate that the susceptibility and loss of both memory subsets are similar after sepsis induction, and sepsis diminished Ag-dependent and -independent (bystander) functions of these memory subsets equally. Both the 1° and 4° memory T cell populations proliferated in a sepsis-induced lymphopenic environment; however, due to the intrinsic differences in baseline proliferative capacity, expression of receptors (e.g., CD127/CD122), and responsiveness to homeostatic cytokines, 1° memory T cells become overrepresented over time in sepsis survivors. Finally, IL-7/anti-IL-7 mAb complex treatment early after sepsis induction preferentially rescued the proliferation and accumulation of 1° memory T cells, whereas recovery of 4° memory T cells was less pronounced. Thus, inefficient recovery of repeatedly stimulated memory cells after polymicrobial sepsis induction leads to changes in memory T cell pool composition, a notion with important implications in devising strategies to recover the number and function of pre-existing memory CD8 T cells in sepsis survivors.
Asunto(s)
Linfopenia , Sepsis , Humanos , Animales , Ratones , Células T de Memoria , Linfocitos T CD8-positivos , Citocinas/metabolismo , Linfopenia/metabolismo , Memoria Inmunológica , Ratones Endogámicos C57BLRESUMEN
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an ultra-rare combined primary immunodeficiency disease caused by heterozygous gain-of-function mutations in the chemokine receptor CXCR4. WHIM patients typically present with recurrent acute infections associated with myelokathexis (severe neutropenia due to bone marrow retention of mature neutrophils). Severe lymphopenia is also common, but the only associated chronic opportunistic pathogen is human papillomavirus and mechanisms are not clearly defined. In this study, we show that WHIM mutations cause more severe CD8 than CD4 lymphopenia in WHIM patients and WHIM model mice. Mechanistic studies in mice revealed selective and WHIM allele dose-dependent accumulation of mature CD8 single-positive cells in thymus in a cell-intrinsic manner due to prolonged intrathymic residence, associated with increased CD8 single-positive thymocyte chemotactic responses in vitro toward the CXCR4 ligand CXCL12. In addition, mature WHIM CD8+ T cells preferentially home to and are retained in the bone marrow in mice in a cell-intrinsic manner. Administration of the specific CXCR4 antagonist AMD3100 (plerixafor) in mice rapidly and transiently corrected T cell lymphopenia and the CD4/CD8 ratio. After lymphocytic choriomeningitis virus infection, we found no difference in memory CD8+ T cell differentiation or viral load between wild-type and WHIM model mice. Thus, lymphopenia in WHIM syndrome may involve severe CXCR4-dependent CD8+ T cell deficiency resulting in part from sequestration in the primary lymphoid organs, thymus, and bone marrow.
Asunto(s)
Agammaglobulinemia , Compuestos Heterocíclicos , Síndromes de Inmunodeficiencia , Linfopenia , Neutropenia , Humanos , Animales , Ratones , Síndromes de Inmunodeficiencia/genética , Movilización de Célula Madre Hematopoyética/efectos adversos , Agammaglobulinemia/complicaciones , Agammaglobulinemia/genética , Neutropenia/genética , Linfocitos T CD8-positivos , Receptores CXCR4/genéticaRESUMEN
Rationale: Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. Objectives: To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. Methods: We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release. We explored if decreased concentrations of lymphocyte-derived proteins in patients with lymphopenia were associated with an increase in mortality. We sought to identify host response phenotypes in patients with lymphopenia by cluster analysis of plasma biomarkers. Measurements and Main Results: A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (>1.0 × 109/L; n = 167), mild lymphopenia (>0.5 to ⩽1.0 × 109/L; n = 194), and severe lymphopenia (⩽0.5 × 109/L; n = 78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia (n = 272), decreased concentrations of several lymphocyte-derived proteins (e.g., CCL5, IL-4, IL-13, IL-17A) were associated with an increase in mortality (at P < 0.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: "hyporesponsive" (23.2%), "hypercytokinemic" (36.4%), and "inflammatory-injurious" (40.4%), with substantially differing mortality rates of 9.5%, 5.1%, and 26.4%, respectively. A 10-biomarker model accurately predicted these host response phenotypes in an external cohort with similar mortality distribution. The inflammatory-injurious phenotype showed a remarkable combination of relatively high inflammation and organ damage markers with high antiinflammatory cytokine levels yet low proinflammatory cytokine levels. Conclusions: Lymphopenia in COVID-19 signifies a heterogenous group of patients with distinct host response features. Specific host responses contribute to lymphopenia-associated mortality in COVID-19, including reduced CCL5 levels.
Asunto(s)
Anemia , COVID-19 , Linfopenia , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Linfopenia/complicaciones , Citocinas , Inflamación/complicaciones , Biomarcadores , Anemia/complicacionesRESUMEN
BACKGROUND: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. OBJECTIVES: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. METHODS: MYSM1-deficient pre- and non-B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. RESULTS: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient's peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. CONCLUSIONS: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair.
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Daño del ADN , Reparación del ADN , Linfopenia , Humanos , Recién Nacido , Roturas del ADN de Doble Cadena , Daño del ADN/genética , Histonas/genética , Histonas/metabolismo , Linfopenia/genética , Transactivadores/genética , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismoRESUMEN
BACKGROUND: The immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL). OBJECTIVE: We sought to determine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts. METHODS: Samples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti-spike and anti-receptor binding domain antibodies were measured. T-cell receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T-cell responses. RESULTS: The median age of ICL participants was 51 years, and their median CD4 count was 150 cells/µL; 11 participants had CD4 counts ≤100 cells/µL. Anti-spike IgG antibody levels were greater in HVs than in patients with ICL after 2 and 3 doses of mRNA vaccine. There was no detectable significant difference, however, in anti-S IgG between HVs and participants with ICL and CD4 counts >100 cells/µL. The depth of spike-specific T-cell responses by T-cell receptor sequencing was lower in individuals with ICL. Activation-induced markers and cytokine production of spike-specific CD4 T cells in participants with ICL did not differ significantly compared with HVs after 2 or 3 vaccine doses. CONCLUSIONS: Patients with ICL and CD4 counts >100 cells/µL can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination; however, patients with more severe CD4 lymphopenia have blunted vaccine-induced immunity and may require additional vaccine doses and other risk mitigation strategies.
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COVID-19 , Linfopenia , Humanos , Persona de Mediana Edad , Vacunas contra la COVID-19 , Vacunas de ARNm , SARS-CoV-2 , COVID-19/prevención & control , Vacunación , Receptores de Antígenos de Linfocitos T , Inmunidad , ARN Mensajero , Anticuerpos AntiviralesRESUMEN
BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.