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The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.
Asunto(s)
Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Anergia Clonal/inmunología , Histocompatibilidad Materno-Fetal/inmunología , Tolerancia Periférica/inmunología , Células Precursoras de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Artritis Experimental/inmunología , Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T , Immunoblotting , Masculino , Ratones , Ratones Noqueados , Neuropilina-1/metabolismo , Embarazo , Receptores de Antígenos de Linfocitos T/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Autotolerancia , Timocitos/inmunologíaRESUMEN
BACKGROUND: Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS). MATERIAL AND METHODS: We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient. RESULTS: Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient's circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient's neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay. CONCLUSION: PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.
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Enfermedad Granulomatosa Crónica , Niño , Preescolar , Femenino , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/metabolismo , Humanos , NADPH Oxidasas/genética , Sitios de Empalme de ARN , Especies Reactivas de Oxígeno , Estallido RespiratorioRESUMEN
Rheumatoid arthritis develops in association with a defect in peripheral CD4(+) T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4(+) T cell clonal anergy induction. We therefore explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4(+) T cells in the setting of selective T cell lymphopenia. CD4(+) T cell recognition of self-GPI peptide/MHC class II complexes in normal murine hosts did not lead to arthritis and instead caused those T cells to develop a Folate receptor 4(hi)CD73(hi) anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3(+)CD4(+) regulatory T cells could not make GPI-specific CD4(+) T cells anergic and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3(+)CD4(+) regulatory T cells are insufficient to functionally inactivate all autoreactive CD4(+) T cells that encounter self-Ag.
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Antígenos CD/inmunología , Antígenos de Neoplasias/inmunología , Artritis Reumatoide/inmunología , Anergia Clonal/inmunología , Receptores de Superficie Celular/inmunología , Linfocitos T Reguladores/inmunología , Tetraspaninas/inmunología , Animales , Antígenos CD/genética , Antígenos de Neoplasias/genética , Artritis Reumatoide/genética , Anergia Clonal/genética , Glucosa-6-Fosfato Isomerasa/genética , Glucosa-6-Fosfato Isomerasa/inmunología , Linfopenia/genética , Linfopenia/inmunología , Ratones , Ratones Transgénicos , Receptores de Superficie Celular/genética , Linfocitos T Reguladores/patología , Tetraspaninas/genéticaRESUMEN
B cells are a key component of the humoral (antibody-mediated) immune response which is responsible for defense against a variety of pathogens. Here we provide an overview of the current understanding of B cell development and function and briefly describe inborn errors of immunity associated with B cell development defects which can manifest as immune deficiency, malignancy, autoimmunity, or allergy. The knowledge and application of B cell biology are essential for laboratory evaluation and clinical assessment of these B cell disorders.
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Centro Germinal , Inmunidad Humoral , Humanos , Linfocitos T Colaboradores-Inductores , Linfocitos B , Activación de LinfocitosRESUMEN
It is indeed a privilege to be an immunologist in what is arguably the golden age of immunology. From astounding advances in fundamental knowledge to groundbreaking immunotherapeutic offerings, immunology has carved out an enviable niche for itself in basic science and clinical medicine. The need and the vital importance of appropriate education, training, and certification in clinical immunology was recognized by the World Health Organization as far back as 1972. In the United States, Ph.D. scientists with board certification in medical laboratory immunology have served as directors of high-complexity Clinical Laboratory Improvement Amendments- and College of American Pathologists-certified clinical immunology laboratories since 1977. From 1977 to 2017, board certification for medical laboratory immunology was administered by the American Society for Microbiology through the American Board of Medical Laboratory Immunology examination. The American Board of Medical Laboratory Immunology examination was phased out in 2017, and in the fall of 2019, the American Society for Clinical Pathology (ASCP) Board of Certification (BOC) examination committee took on the responsibility of developing a new doctoral-level certification examination for medical laboratory immunology. This transition to the ASCP BOC represents a well-deserved and much-needed recognition of the rapid advances in and the highly specialized nature of medical laboratory immunology and its ever-increasing relevance to patient care. This new ASCP BOC certification is called the Diplomate in Medical Laboratory Immunology, and, as of April 1, 2023, it is now available to potential examinees. In this report, we describe the examination, eligibility routes, and potential career pathways for successful diplomates.
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Certificación , Laboratorios , HumanosRESUMEN
A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of approximately 355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-alpha, or histone deacetylase inhibitors. Thus, IL-12 and IFN-alpha/beta enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.
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Linfocitos T CD8-positivos/inmunología , Ensamble y Desensamble de Cromatina/inmunología , Regulación de la Expresión Génica/inmunología , Memoria Inmunológica/genética , Interferón Tipo I/fisiología , Interleucina-12/fisiología , Acetilación , Animales , Presentación de Antígeno , Diferenciación Celular , Histonas/metabolismo , Ratones , Proteínas de Dominio T Box/genéticaRESUMEN
The annual meeting of the Association of Medical Laboratory Immunologists (AMLI) was convened virtually over the month of August. Prior to the emergence of the COVID-19 pandemic, AMLI's scientific committee had chosen the following topics as the focus of its 2020 meeting: Histocompatibility Testing and Transplant Immunology; Secondary Immunodeficiency and Immunotherapy Monitoring; ANA Update; and Emerging Infectious Diseases and New Algorithms for Testing. Given the central role of the discipline in the evaluation of the host response to infection, it was apt to add a separate session on antibody testing for SARS-CoV-2 infections to the original program. The current report provides an overview of the subjects discussed in the course of this meeting.
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Alergia e Inmunología , COVID-19/inmunología , Inmunoterapia/métodos , SARS-CoV-2/fisiología , Sociedades Médicas , Algoritmos , Animales , Procesos de Grupo , Prueba de Histocompatibilidad , Interacciones Huésped-Patógeno , Humanos , Laboratorios , Pandemias , SARS-CoV-2/química , Inmunología del Trasplante , Realidad VirtualRESUMEN
Knowledge related to the biology of inborn errors of immunity and associated laboratory testing methods continues to expand at a tremendous rate. Despite this, many patients with inborn errors of immunity suffer for prolonged periods of time before identification of their underlying condition, thereby delaying appropriate care. Understanding that test selection and optimal evaluation for patients with recurrent infections or unusual patterns of inflammation can be unclear, we present a document that distills relevant clinical features of immunologic disease due to inborn errors of immunity and related appropriate and available test options. This document is intended to serve the practicing clinical immunologist and, in turn, patients by describing best available test options for initial and expanded immunologic evaluations across the disease spectrum. Our goal is to demystify the process of evaluating patients with suspected immune dysfunction and to enable more rapid and accurate diagnosis of such individuals.
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Laboratorios , Enfermedades de Inmunodeficiencia Primaria , Humanos , Inflamación , Motivación , ReinfecciónRESUMEN
X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. The only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCT on an asymptomatic patient remains debatable. This uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later.
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Fanconi anemia (FA) is an inherited bone marrow failure and cancer predisposition disorder due to mutations in DNA repair pathways proteins (FANC). The dysfunctional proteins are unable to repair DNA breaks and cause genomic instability. Mutations in many of the 19 FANC genes are well characterized biochemically and clinically. Little is known about the FANCD2 gene which acts downstream of the FA-core proteins. Here we report a 11-year-old female previously diagnosed with FA and bone marrow failure. Gene sequencing demonstrated deletion of exons 2-18 and a pathologic missense mutation (c. 2444G>A, p. Arg815Gln) in FANCD2 (Chr3). Her medical history is significant for an episode of pneumococcal sepsis despite adequate vaccination. Repeated blood samples and immunophenotyping demonstrated severe lymphopenia. There were markedly low CD4+ T-cell counts with a low CD4:CD8 ratio. Changes in the composition of the B-cell population included significantly diminished absolute total B-cells, and decreased mature cells. There was no immunogenic response to vaccination against S. pneumoniae. The NK-cell count was unaffected and demonstrated normal spontaneous and stimulated cytotoxic response. Bone marrow analysis demonstrated hypocellularity without dysplasia. The clinical and laboratory features are suggestive of combined immune deficiency. FANCD2 may be involved in the transition of immature B and T cells to mature cells, a process that requires substantial DNA recombination not observed in NK cells. Additional genetic and biochemical evaluation is needed to further characterize the novel genetic and clinical findings.
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OBJECTIVE: To determine the autoantibody repertoire and clinical associations in a multiethnic cohort of American patients with systemic sclerosis (SSc). METHODS: There were 1000 patients with SSc (196 Hispanic, 228 African American, 555 white, and 21 other) who were screened for antinuclear antibodies (ANA), including anticentromere antibodies (ACA) by indirect immunofluorescence assay, antitopoisomerase-1 (topo-1/Scl-70) by immunodiffusion, and anti-RNA polymerase III (RNAP III) by ELISA. Sera from 160 patients with mainly nucleolar and/or speckled ANA pattern, but negative for ACA, Scl-70, and RNAP III, were further characterized by immunoprecipitation for SSc-specific antibodies. RESULTS: The prevalence of antibodies against RNAP III, Th/To, and PM/Scl did not differ significantly among the ethnic groups. The frequency of anti-Scl-70 was lowest in whites (18.0%) compared with 24.0% and 26.8% in Hispanics and African Americans (p = 0.01), respectively. Compared with African American patients, Hispanic and white subjects had a higher frequency of ACA (p < 0.0001) and lower frequency of U3-RNP (p < 0.0001). U3-RNP antibodies were uniquely higher in African American patients, independent of clinical subset, while Th/To autoantibodies were associated with limited cutaneous SSc in white subjects. Overall, Hispanic and African American patients had an earlier age of onset and a predominance of diffuse cutaneous SSc compared with their white counterparts. CONCLUSION: SSc-specific antibodies may predict disease subset; however, the hierarchy of their prevalence differs across ethnic groups. This study provides the most extensive analysis to date on the relevance of autoantibodies in the diagnosis and clinical manifestations of SSc in Hispanic American patients.
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Autoanticuerpos/sangre , Esclerodermia Sistémica/inmunología , Adulto , Negro o Afroamericano , Femenino , Hispánicos o Latinos , Humanos , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/etnología , Estudios Seroepidemiológicos , Estados Unidos , Población BlancaRESUMEN
Celiac disease (CD) is an autoimmune disorder that occurs in genetically susceptible individuals of all ages and is triggered by immune response to gluten and related proteins. The disease is characterized by the presence of HLA-DQ2 and/or -DQ8 haplotypes, diverse clinical manifestations, gluten-sensitive enteropathy, and production of several autoantibodies of which endomysial, tissue transglutaminase, and deamidated gliadin peptide antibodies are considered specific. Although antireticulin antibodies (ARA) have historically been used in the evaluation of CD, these assays lack optimal sensitivities and specificities for routine diagnostic use. This minireview highlights the advances in CD-specific serologic testing and the rationale for eliminating ARA from CD evaluation consistent with recommendations for diagnosis.
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Autoanticuerpos/sangre , Enfermedad Celíaca/diagnóstico , Tamizaje Masivo/métodos , Reticulina/inmunología , Proteínas de Unión al GTP/inmunología , Gliadina/inmunología , Humanos , Proteína Glutamina Gamma Glutamiltransferasa 2 , Pruebas Serológicas/métodos , Transglutaminasas/inmunologíaRESUMEN
During Ag stimulation of T cells, the recognition of B7 molecules by the CD28 costimulatory receptor increases the level of c-Fos, a component of the AP-1 transactivator known to bind the 5' Il2 gene enhancer. In this study, we show that the costimulation of Fos transcription by CD28 is associated with increased binding of p300/CREB-binding protein (CBP) molecules at the Fos promoter, and is blocked by an adenoviral E1A molecular antagonist of p300/CBP. Furthermore, transcriptional activation by a C-terminal domain of CBP is strengthened when CD28 molecules are actively signaling. This increased amount and activity of p300/CBP molecules at the Fos gene correlated with higher histone H4 acetylation and RNA polymerase II association with the promoter. These data suggest a global mechanism whereby CD28 signaling influences the rate and intensity of new gene expression during Ag recognition via direct control over the coactivator function of p300/CBP.
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Antígenos CD28/metabolismo , Proteína de Unión a CREB/fisiología , Activación Transcripcional/inmunología , Factores de Transcripción p300-CBP/fisiología , Acetilación , Animales , Antígenos CD28/fisiología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proteína de Unión a CREB/metabolismo , Células Cultivadas , Histonas/metabolismo , Humanos , Células Jurkat , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Fosforilación , Regiones Promotoras Genéticas , Transporte de Proteínas/genética , Transporte de Proteínas/inmunología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Proteínas Proto-Oncogénicas c-fos/genética , ARN Polimerasa II/metabolismo , Serina/metabolismo , Transducción de Señal/inmunología , Proteína Elk-1 con Dominio ets/metabolismo , Factores de Transcripción p300-CBP/metabolismoRESUMEN
T cell clonal anergy induction in lymphopenic nu/nu mice was found to be ineffective. Exposure to a tolerizing peptide Ag regimen instead induced aggressive CD4(+) cell cycle progression and increased Ag responsiveness (priming). Reconstitution of T cell-deficient mice by an adoptive transfer of mature peripheral lymphocytes was accompanied by the development of a CD25(+)Foxp3(+)CTLA-4(+)CD4(+) regulatory T cell population that acted to dampen Ag-driven cell cycle progression and facilitate the induction of clonal anergy in nearby responder CD25(-)CD4(+) T cells. Thus, an early recovery of CD25(+) regulatory T cells following a lymphopenic event can prevent exuberant Ag-stimulated CD4(+) cell cycle progression and promote the development of clonal anergy.