RESUMEN
Granulomatous lymphocytic interstitial lung disease (GLILD) represents a fatal immune dysregulatory complication in common variable immunodeficiency (CVID). Evidence-based diagnostic guidelines are lacking, and GLILD treatment consists in immunosuppressive drugs; nonetheless, therapeutical strategies are heterogeneous and essentially based on experts' opinions and data from small case series or case reports.We aimed to evaluate the efficacy and safety of first-line Rituximab monotherapy for CVID-related GLILD, by assessing symptoms and quality of life alterations, immunological parameters, pulmonary function tests, and lung computed tomography.All six GLILD patients received Rituximab infusions as a first-line treatment. Rituximab was administered at 375 mg/m2 monthly for six infusions followed by maintenance every 3 months; none of the patients experienced severe adverse events. Symptom burden and quality of life significantly improved in treated patients compared to a control group of CVID patients without GLILD. Rituximab treatment indirectly caused a trend toward reduced T-cell activation and exhaustion markers sCD25 and sTIM-3. Lung function improved in treated patients, with statistically significant increases in TLC and DLCO. Lung CT scan findings expressed by means of Baumann scoring system displayed a reduction in the entire cohort.In conclusion, first-line monotherapy with Rituximab displayed high efficacy in disease remission in all treated patients, with improvement of symptoms and amelioration of quality of life, as well as restoration of PFTs and lung CT scan findings.
Asunto(s)
Inmunodeficiencia Variable Común , Enfermedades Pulmonares Intersticiales , Humanos , Rituximab/uso terapéutico , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Calidad de Vida , PulmónRESUMEN
INTRODUCTION: Autoimmunity is a common feature in CVID patients. To date the mechanisms leading to the development of such complications are not fully elucidated. MATERIALS AND METHODS: Data from 122 CVID patients subdivided in three groups based on the absence of autoimmunity (n-AI) or the presence of hematologic autoimmune phenomena (Cy-AI) or non-hematologic autoimmune phenomena (n-Cy-AI) were evaluated. RESULTS: We identified a total of 128 autoimmune manifestations in 55/122 patients (45.1%). 30/122 (24.6%) patients presented hematologic autoimmune phenomena while 29/122 (23.8%) presented gastrointestinal autoimmune involvement. Immune thrombocytopenia was the most common manifestation (27/122; 22.1%), followed by autoimmune hemolytic anemia (18/122; 14.8%) and autoimmune enteropathy (17/122; 13.9%). Cy-AI patients displayed higher CD4+ effector memory and terminally differentiated CD8+ cells with lower percentages of naïve and recent thymic emigrants (RTEs) CD4+ cells and a significant expansion of the CD19hiCD21low population. CONCLUSIONS: CVID patients developing autoimmune cytopenias display characteristic immune phenotypic features.
Asunto(s)
Inmunodeficiencia Variable Común , Púrpura Trombocitopénica Idiopática , Autoinmunidad , Linfocitos T CD4-Positivos , Humanos , InmunofenotipificaciónRESUMEN
Dedicator of Cytokinesis 8 (DOCK8) deficiency is a rare form of autosomal recessive combined immunodeficiency. The effect of DOCK8 deficiency on Natural Killer cell biology has not been fully elucidated yet. Thus, we undertook a detailed phenotypic and functional evaluation of NK cells from seven patients with DOCK8 deficiency. Patients' immature CD56bright NK cells were defective in IFN-γ secretion, while their mature CD56dim NK cells showed impaired cytotoxicity, partially rescued upon rIL-2 addition. Cross-linking of NK cell receptors revealed a specific defect in the CD3 zeta chain-dependent activation pathway in DOCK8 deficiency. Lack of DOCK8, but not of WASP, impaired CCR7 expression on human CD56bright NK cells, a critical receptor for their migration to secondary lymph nodes. Evaluation of a patient's lymph node showed a severe reduction in NK cells that showed increased intracellular expression of CCR7. Our data suggest that DOCK8 deficiency variably affects NK cell homeostasis in humans.
Asunto(s)
Citocinesis , Factores de Intercambio de Guanina Nucleótido , Células Asesinas Naturales , Receptores CCR7 , Antígeno CD56/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Receptores CCR7/genética , Receptores CCR7/metabolismo , Proteína del Síndrome de Wiskott-AldrichRESUMEN
PURPOSE: Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. METHODS: Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. RESULTS: Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naïve CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/- cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients' age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. CONCLUSIONS: Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.
Asunto(s)
Síndrome de Deleción Distal 11q de Jacobsen , Linfocitos B , Niño , Citometría de Flujo , Humanos , Células Asesinas Naturales , Recuento de LinfocitosRESUMEN
BACKGROUND: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. OBJECTIVE: Our aim was to describe the natural history of XLA. METHODS: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base. RESULTS: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease. CONCLUSIONS: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.
Asunto(s)
Agammaglobulinemia/epidemiología , Enfermedades Genéticas Ligadas al Cromosoma X/epidemiología , Infecciones/epidemiología , Enfermedades Pulmonares/epidemiología , Sinusitis/epidemiología , Adolescente , Adulto , Agammaglobulinemia/mortalidad , Niño , Preescolar , Estudios de Seguimiento , Enfermedades Genéticas Ligadas al Cromosoma X/mortalidad , Humanos , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Adulto JovenRESUMEN
Mutations affecting the non-canonical pathway of NF-κB were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5+, and CXCR5- Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFNγ, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Centro Germinal/inmunología , Subunidad p52 de NF-kappa B/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Autoinmunidad , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Niño , Inmunodeficiencia Variable Común/genética , Citocinas/metabolismo , Femenino , Humanos , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Eliminación de Secuencia/genética , Transducción de Señal , Adulto JovenRESUMEN
This study provides evidence for the first time for APDS-1 presenting as MAS/HLH, with evident clinical implications in patient's management and prognosis.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Linfohistiocitosis Hemofagocítica/diagnóstico , Síndrome de Activación Macrofágica/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Niño , Humanos , Linfohistiocitosis Hemofagocítica/genética , Síndrome de Activación Macrofágica/genética , Masculino , Mutación , Enfermedades de Inmunodeficiencia Primaria/genéticaRESUMEN
Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
Asunto(s)
Enfermedades de Inmunodeficiencia Primaria/epidemiología , Adolescente , Adulto , Niño , Preescolar , Bases de Datos Factuales , Femenino , Geografía Médica , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Vigilancia de la Población , Prevalencia , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/historia , Enfermedades de Inmunodeficiencia Primaria/terapia , Pronóstico , Sistema de Registros , Adulto JovenRESUMEN
This study provides evidence for a novel role for NFKB2 in human B cell development in the bone marrow and in the periphery, leading to progressive peripheral B cell deficiency not always combined with autoimmune phenomena, broadening thus the clinical spectrum of NFKB2 mutated CVID disease and implying an essential role for NFKB2 in early human B cell development.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Linfopoyesis/genética , Subunidad p52 de NF-kappa B/genética , Células Precursoras de Linfocitos B/inmunología , Adulto , Linfocitos B/inmunología , Inmunodeficiencia Variable Común/inmunología , Mutación del Sistema de Lectura , Humanos , MasculinoRESUMEN
This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.
Asunto(s)
Agammaglobulinemia/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Linfopenia/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Adulto , Agammaglobulinemia/inmunología , Linfocitos B/citología , Linfocitos B/inmunología , Fosfatidilinositol 3-Quinasa Clase I/inmunología , Femenino , Mutación con Ganancia de Función , Humanos , Linfopenia/inmunología , Linfopoyesis , Enfermedades de Inmunodeficiencia Primaria/inmunologíaRESUMEN
CCRL2 is a 7-transmembrane domain receptor that shares structural and functional similarities with the family of atypical chemokine receptors (ACKRs). CCRL2 is upregulated by inflammatory signals and, unlike other ACKRs, it is not a chemoattractant-scavenging receptor, does not activate ß-arrestins, and is widely expressed by many leukocyte subsets. Therefore, the biological role of CCRL2 in immunity is still unclear. We report that CCRL2-deficient mice have a defect in neutrophil recruitment and are protected in 2 models of inflammatory arthritis. In vitro, CCRL2 was found to constitutively form homodimers and heterodimers with CXCR2, a main neutrophil chemotactic receptor. By heterodimerization, CCRL2 could regulate membrane expression and promote CXCR2 functions, including the activation of ß2-integrins. Therefore, upregulation of CCRL2 observed under inflammatory conditions is functional to finely tune CXCR2-mediated neutrophil recruitment at sites of inflammation.
Asunto(s)
Artritis/metabolismo , Artritis/patología , Neutrófilos/patología , Receptores de Quimiocina/metabolismo , Receptores de Interleucina-8B/metabolismo , Animales , Artritis/complicaciones , Antígenos CD18/metabolismo , Supervivencia Celular , Modelos Animales de Enfermedad , Inflamación/complicaciones , Inflamación/patología , Ratones Noqueados , Infiltración Neutrófila , Conformación Proteica , Multimerización de Proteína , Receptores CCR , Receptores de Quimiocina/química , Receptores de Quimiocina/deficiencia , Receptores de Interleucina-8B/química , Transducción de SeñalAsunto(s)
Agammaglobulinemia/diagnóstico , Linfocitos B/inmunología , COVID-19/diagnóstico , Síndromes de Inmunodeficiencia/diagnóstico , Pulmón/diagnóstico por imagen , Miastenia Gravis/diagnóstico , SARS-CoV-2/fisiología , Linfocitos T/inmunología , Timoma/diagnóstico , Neoplasias del Timo/diagnóstico , Presión de las Vías Aéreas Positiva Contínua , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XAsunto(s)
Síndrome Linfoproliferativo Autoinmune/etiología , Mutación de Línea Germinal , Homocigoto , Receptor fas/deficiencia , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/metabolismo , Síndrome Linfoproliferativo Autoinmune/terapia , Biomarcadores , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Trasplante de Células Madre Hematopoyéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfocitos T/inmunología , Linfocitos T/metabolismoAsunto(s)
Antígeno CTLA-4/genética , Deleción Cromosómica , Cromosomas Humanos Par 2 , Inmunodeficiencia Variable Común/terapia , Haploinsuficiencia , Trasplante de Células Madre Hematopoyéticas , Adulto , Alelos , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Femenino , Humanos , Adulto JovenAsunto(s)
Citotoxicidad Inmunológica/inmunología , Síndromes de Inmunodeficiencia/inmunología , Células Asesinas Naturales/inmunología , Proteínas de Unión al GTP rac/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Humanos , Síndromes de Inmunodeficiencia/genética , Activación de Linfocitos/inmunología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/inmunología , Transducción de Señal/inmunología , Proteínas de Unión al GTP rac/genética , Proteína RCA2 de Unión a GTPRESUMEN
Plasmacytoid dendritic cells (pDCs) are multifaceted immune cells executing various innate immunological functions. Their first line of defence consists in type I interferons (I-IFN) production upon nucleic acids sensing through endosomal Toll-like receptor (TLR) 7- and 9-dependent signalling pathways. Type I IFNs are a class of proinflammatory cytokines that have context-dependent functions on cancer immunosurveillance and immunoediting. In the last few years, different studies have reported that pDCs are also able to sense cytosolic DNA through cGAS-STING (stimulator of interferon genes) pathway eliciting a potent I-IFN production independently of TLR7/9. Human pDCs are also endowed with direct effector functions via the upregulation of TRAIL and production of granzyme B, the latter modulated by cytokines abundant in cancer tissues. pDCs have been detected in a wide variety of human malignant neoplasms, including virus-associated cancers, recruited by chemotactic stimuli. Although the role of pDCs in cancer immune surveillance is still uncompletely understood, their spontaneous activation has been rarely documented; moreover, their presence in the tumor microenvironment (TME) has been associated with a tolerogenic phenotype induced by immunosuppressive cytokines or oncometabolites. Currently tested treatment options can lead to pDCs activation and disruption of the immunosuppressive TME, providing a relevant clinical benefit. On the contrary, the antibody-drug conjugates targeting BDCA-2 on immunosuppressive tumor-associated pDCs (TA-pDCs) could be proposed as novel immunomodulatory therapies to achieve disease control in patients with advance stage hematologic malignancies or solid tumors. This Review integrate recent evidence on the biology of pDCs and their pharmacological modulation, suggesting their relevant role at the forefront of cancer immunity.