RESUMEN
Age-associated changes in the T cell compartment are well described. However, limitations of current single-modal or bimodal single-cell assays, including flow cytometry, RNA-seq (RNA sequencing) and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile >300,000 single T cells from healthy children (aged 11-13 years) and older adults (aged 55-65 years) by using the trimodal assay TEA-seq (single-cell analysis of mRNA transcripts, surface protein epitopes and chromatin accessibility), which revealed that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4+ T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8αα+ T cell subset lost with age that is epigenetically poised for rapid effector responses and has distinct inhibitory, costimulatory and tissue-homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.
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Subgrupos de Linfocitos T , Transcriptoma , Niño , Humanos , Anciano , Envejecimiento/genética , Epítopos/metabolismo , Análisis de la Célula IndividualRESUMEN
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
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Linfocitos B , Proteínas de Unión al ADN , Proteínas de Homeodominio , Proteínas Nucleares , Diferenciación Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Humanos , Tolerancia Inmunológica , Recuento de Linfocitos , Proteínas Nucleares/deficienciaRESUMEN
A defining feature of vertebrate immunity is the acquisition of immunological memory, which confers enhanced protection against pathogens by mechanisms that are incompletely understood. Here, we compared responses by virus-specific naive T cells (T(N)) and central memory T cells (T(CM)) to viral antigen challenge in lymph nodes (LNs). In steady-state LNs, both T cell subsets localized in the deep T cell area and interacted similarly with antigen-presenting dendritic cells. However, upon entry of lymph-borne virus, only T(CM) relocalized rapidly and efficiently toward the outermost LN regions in the medullary, interfollicular, and subcapsular areas where viral infection was initially confined. This rapid peripheralization was coordinated by a cascade of cytokines and chemokines, particularly ligands for T(CM)-expressed CXCR3. Consequently, in vivo recall responses to viral infection by CXCR3-deficient T(CM) were markedly compromised, indicating that early antigen detection afforded by intranodal chemokine guidance of T(CM) is essential for efficient antiviral memory.
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Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Ganglios Linfáticos/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Quimiocina CXCL9/inmunología , Células Dendríticas/inmunología , Interferón gamma/inmunología , Ganglios Linfáticos/citología , Virus de la Coriomeningitis Linfocítica , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CXCR3/inmunología , Células del Estroma/inmunología , Virus de la Estomatitis Vesicular IndianaRESUMEN
BACKGROUND: The invariant TCR ζ/CD247 homodimer is crucial for TCR/CD3 expression and signaling through its 3 immunoreceptor tyrosine-based activation motifs (ITAMs). Homozygous null mutations in CD247 lead to immunodeficiency, while carriers exhibit 50% reduced surface CD3. It is unclear whether carriers of other CD247 variants show dominant-negative effects. OBJECTIVE: We sought to analyze and model the potential impact on T-cell receptor (TCR) expression and function of heterozygous nonsense CD247 mutations found in patients with signs of immunodeficiency or autoimmunity. METHODS: Jurkat T cells, either wild-type (WT) or CRISPR/Cas9-edited CD247-deficient (ZKO), were lentivirally transduced with WT CD247 or mutations ablating 1 (Q142X), 2 (Q101X), or 3 (Q70X) ITAMs. RESULTS: Three patients from unrelated families were studied. Two heterozygous nonsense CD247 mutations were identified (p.Y152X and p.Q101X), which affected ITAM-3 and ITAM-2 and ITAM-3, respectively. Both mutations were associated with low surface CD3 expression and normal intracellular CD247 levels using a transmembrane-specific antibody, but very low intracellular CD247 levels using an ITAM-3-specific one, suggesting the presence of truncated variants in T cells. Transduction of the mutations lacking 1, 2, or 3 ITAMs into ZKO cells could not restore normal surface CD3 expression (only 60%, 22%, and 10%, respectively), whereas in WT cells, normal surface CD3 expression was reduced (to 39%, 19%, and 9% of normal levels), and both effects were dependent on ITAM number. All 6 transfectants showed reduced CD69 induction (25% to 50%), indicating that they were unable to signal downstream properly, neither isolated nor associated with WT CD247. CONCLUSIONS: Our results suggest that CD247 variants lacking ITAMs due to nonsense, but not null, mutations are defective for normal TCR assembly and exert a dominant-negative effect on TCR expression and signaling in vitro. This, in turn, may correlate with clinical features in vivo.
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Cryptosporidium is a ubiquitous protozoan parasite that infects gut epithelial cells and causes self-limited diarrhea in immunocompetent individuals. However, in immunocompromised hosts with global defects in T cell function, this infection can result in chronic, life-threatening disease. In addition, there is a subset of individuals with primary immunodeficiencies associated with increased risk for life-threatening cryptosporidiosis. These patients highlight MHC class II expression, CD40-CD40L interactions, NF-κB signaling, and IL-21 as key host factors required for resistance to this enteric pathogen. Understanding which immune deficiencies do (or do not) lead to increased risk for severe Cryptosporidium may reveal mechanisms of parasite restriction and aid in the identification of novel strategies to manage this common pathogen in immunocompetent and deficient hosts.
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Criptosporidiosis , Cryptosporidium , Síndromes de Inmunodeficiencia , Humanos , Diarrea/complicaciones , Diarrea/parasitología , Huésped InmunocomprometidoRESUMEN
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.
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Agammaglobulinemia , Síndromes de Inmunodeficiencia , Linfopenia , Neutropenia , Verrugas , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/genética , Verrugas/diagnóstico , Verrugas/epidemiología , Verrugas/genética , Agammaglobulinemia/genética , Receptores CXCR4/genética , Neutropenia/genética , Linfopenia/complicaciones , Progresión de la EnfermedadRESUMEN
T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8⺠T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics.
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Presentación de Antígeno , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Memoria Inmunológica/inmunología , Traslado Adoptivo , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD8-positivos/metabolismo , Comunicación Celular , Diferenciación Celular , Células Dendríticas/metabolismo , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transcriptoma/inmunologíaRESUMEN
After homing to lymph nodes, CD8+ T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell-DC interactions. We show here that the duration of phase one and T cell activation kinetics correlated inversely with the number of complexes of cognate peptide and major histocompatibility complex (pMHC) per DC and with the density of antigen-presenting DCs per lymph node. Very few pMHC complexes were necessary for the induction of full-fledged T cell activation and effector differentiation. However, neither T cell activation nor transition to phase two occurred below a threshold antigen dose determined in part by pMHC stability. Thus, phase one permits T cells to make integrated 'measurements' of antigen dose that determine subsequent T cell participation in immune responses.
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Antígenos de Superficie/metabolismo , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos de Superficie/genética , Células Cultivadas , Células Dendríticas/metabolismo , Relación Dosis-Respuesta Inmunológica , Cinética , Complejo Mayor de Histocompatibilidad/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Fragmentos de Péptidos/genética , Linfocitos T/metabolismoRESUMEN
PURPOSE OF REVIEW: Childhood obesity, with persistent chronic inflammation, is a worldwide epidemic. Obesity causes dysregulation throughout the immune system, affecting the balance and levels of cytokines, adipokines, and innate and adaptive immune cells. The present review focuses on the impact of obesity on immune function in children: altering the baseline activation state of immune cells and affecting the ability of the host to combat pathogens and malignancy and respond appropriately to vaccination. RECENT FINDINGS: Obesity causes dysregulation of the immune system. Single-cell RNA-sequencing of adipose tissue and resident immune cells is quantifying the impact of obesity on the frequency of immune cell subsets and their states. The system-wide alterations in immune function in obesity are most evident upon perturbation, including the response to infection (e.g. increased risk of severe COVID-19 in the ongoing pandemic), vaccination, and malignancy. However, mechanistic research in pediatric obesity is limited and this impacts our ability to care for these children. SUMMARY: We must better understand baseline and perturbed immune health in obese children to determine how to account for altered frequency and function of humoral and cellular immune components in acute infection, during vaccine design and when considering therapeutic options for this complex, medically vulnerable group.
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Sistema Inmunológico/fisiología , Obesidad Infantil/inmunología , Adipoquinas/inmunología , Tejido Adiposo/inmunología , Niño , Citocinas/inmunología , Humanos , Inmunidad Celular , Inmunidad Humoral , Infecciones/inmunología , VacunaciónRESUMEN
There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.
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COVID-19/terapia , Síndrome de Dificultad Respiratoria/terapia , Adolescente , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/uso terapéutico , COVID-19/complicaciones , Humanos , Inmunización Pasiva/métodos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Síndrome de Dificultad Respiratoria/etiología , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Sueroterapia para COVID-19RESUMEN
OBJECTIVE: The aim of the study was to compare presenting clinical and laboratory features among children meeting the surveillance definition for multisystem inflammatory syndrome in children (MIS-C) across a range of illness severities. METHODS: This is a retrospective single-center study of patients younger than 21 years presenting between March 1 and May 15, 2020. Included patients met the Centers for Disease Control and Prevention criteria for MIS-C (inflammation, fever, involvement of 2 organ systems, lack of alternative diagnoses). We defined 3 subgroups by clinical outcomes: (1) critical illness requiring intensive care interventions; (2) patients meeting Kawasaki disease (KD) criteria but not requiring critical care; and (3) mild illness not meeting either criteria. A comparator cohort included patients with KD at our institution during the same time frame in 2019. RESULTS: Thirty-three patients were included (5, critical; 8, 2020 KD; 20, mild). The median age for the critical group was 10.9 years (2.7 for 2020 KD; 6.0 for mild, P = 0.033). The critical group had lower median absolute lymphocyte count (850 vs 3005 vs 2940/uL, P = 0.005), platelets (150 vs 361 vs 252 k/uL, P = 0.005), and sodium (129 vs 136 vs 136 mmol/L, P = 0.002), and higher creatinine (0.7 vs 0.2 vs 0.3 mg/dL, P = 0.002). In the critical group, 60% required vasoactive medications, and 40% required mechanical ventilation. Clinical and laboratories features were similar between the 2020 and 2019 KD groups. CONCLUSIONS: We describe 3 groups with inflammatory syndromes during the SARS-CoV-2 pandemic. The initial profile of lymphopenia, thrombocytopenia, hyponatremia, and abnormal creatinine may help distinguish critically ill MIS-C patients from classic/atypical KD or more benign acute inflammation.
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Betacoronavirus , Infecciones por Coronavirus/diagnóstico , Cuidados Críticos/métodos , Manejo de la Enfermedad , Síndrome Mucocutáneo Linfonodular/diagnóstico , Pandemias , Neumonía Viral/diagnóstico , Adolescente , COVID-19 , Niño , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Estudios Retrospectivos , SARS-CoV-2RESUMEN
BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
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Linfocitos B/inmunología , Diferenciación Celular/inmunología , Inmunodeficiencia Variable Común/inmunología , Endotoxemia/inmunología , Deficiencia de IgA/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Linfocitos B/patología , Niño , Preescolar , Inmunodeficiencia Variable Común/patología , Endotoxemia/patología , Femenino , Humanos , Deficiencia de IgA/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/patologíaRESUMEN
Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS's recommendations for the use of genetic testing in light of these issues.
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Pruebas Genéticas , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Biomarcadores , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes de Inmunodeficiencia/terapia , Diagnóstico Prenatal , Análisis de Secuencia de ADNRESUMEN
The original version of this article unfortunately contained mistakes in some of the author names and affiliations. The correct list of author names and affiliations is below, with the corrections in bold.
RESUMEN
BACKGROUND: Pediatric asthma is a major contributor to emergency room utilization and hospital readmission rates. OBJECTIVE: To develop an allergy departmentâbased intervention to improve follow-up appointment scheduling processes for pediatric asthma patients after discharge for asthma exacerbation. METHODS: This quality improvement study was conducted in the allergy clinic of an urban, tertiary children's hospital. Children receiving subspecialty allergy care for asthma were included into the intervention group during the intervention period. The quality improvement intervention consisted of 3 attempts by telephone to reach the family to schedule the follow-up appointment. If this was unsuccessful or if the appointment was not kept, then a reminder letter was sent to the family. The primary outcome of interest in this study was the percent of postdischarge follow-up appointments scheduled within 30 days of discharge. Secondary outcomes measured were the percent of allergy appointments attended within 30 days of discharge and the 30-day hospital readmission rate. RESULTS: Demographics did not differ significantly between the intervention and baseline preintervention year. The initial baseline scheduled allergy follow-up visit rate was 48.8 ± 13.3% of patients discharged per month. This increased to an overall rate of 75.7 ± 20.1% patients scheduling allergy follow-up within 30 days of discharge during the intervention year. We also observed a significant increase in attended allergy visits 30 days postdischarge from 35.5 ± 15.6% in year 1 to 53.9 ± 25.5% during the intervention year and a significant decrease in the 30-day readmission rate on the allergy service. CONCLUSION: These data suggests that minor changes in allergy practice organization can significantly affect posthospitalization follow-up rates and decrease asthma readmission rates.
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Citas y Horarios , Asma/terapia , Servicio de Urgencia en Hospital , Hospitales Pediátricos , Readmisión del Paciente/estadística & datos numéricos , Adolescente , Niño , Preescolar , Continuidad de la Atención al Paciente/normas , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Evaluación de Resultado en la Atención de Salud , Alta del Paciente , Atención Primaria de Salud , Modelos de Riesgos Proporcionales , Mejoramiento de la Calidad/organización & administraciónRESUMEN
Verrucae vulgaris in patients with severe combined immunodeficiency (SCID) after hematopoietic stem cell transplantation (HCST) can be challenging to manage. We describe two brothers with X-linked SCID who had severe, persistent verrucae that did not respond to traditional topical therapies, including liquid nitrogen, imiquimod, salicylic acid, sinecatechins, 40% urea, and 5-fluorourcil. Both brothers had full response to topical 3% cidofovir, which should be considered in recalcitrant warts in individuals with SCID after HSCT.
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Antivirales/uso terapéutico , Citosina/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Organofosfonatos/uso terapéutico , Inmunodeficiencia Combinada Grave/etiología , Verrugas/tratamiento farmacológico , Niño , Cidofovir , Citosina/uso terapéutico , Humanos , Masculino , Resultado del Tratamiento , Verrugas/etiologíaRESUMEN
BACKGROUND: Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint. OBJECTIVE: We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders. METHODS: A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines. RESULTS: Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID. CONCLUSION: A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.
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Proteínas Portadoras/genética , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Predisposición Genética a la Enfermedad , Mutación , Proteínas Nucleares/genética , Adolescente , Adulto , Anciano , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Biomarcadores , Proteínas Portadoras/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Inmunodeficiencia Variable Común/diagnóstico , Proteínas de Unión al ADN , Exoma , Familia , Femenino , Estudios de Asociación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Isotipos de Inmunoglobulinas/sangre , Isotipos de Inmunoglobulinas/inmunología , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Linaje , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Factores de Transcripción , Adulto JovenRESUMEN
Recent advances in the understanding of immune dysregulation in autoimmune diseases have enabled the development of new monoclonal antibody-based drugs called biologics. Biologics have been used to target aberrant immune responses in many diseases, but patients with rheumatologic and other autoimmune diseases have benefited the most and improvements in outcomes have been significant. The use of biologics is not without hazard, however, as these agents block immune pathways adapted to protect the host. This has been borne out by increased rates of infections as well as induction of new autoimmune and hematologic adverse effects. As new drugs for the treatment of autoimmune conditions are entering the pipeline, it is incumbent on the practicing immunologist to understand the mechanism of these biologics and the implications of clinical use.