RESUMO
PURPOSE: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. METHODS: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. RESULTS: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. CONCLUSION: DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.
Assuntos
Eczema , Hipersensibilidade , Síndrome de Job , Criança , Humanos , Lactente , Pré-Escolar , Estudos Retrospectivos , Síndrome de Job/genética , Eczema/epidemiologia , Eczema/genética , Mutação , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.
Assuntos
Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Mutação/imunologia , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Adolescente , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente , Linfócitos/imunologia , Masculino , México , FenótipoRESUMO
Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.
Assuntos
Guias de Prática Clínica como Assunto , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Consenso , Humanos , América LatinaRESUMO
BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated. OBJECTIVE: We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. METHODS: We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4+ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. RESULTS: DOCK8-deficient memory CD4+ T cells were biased toward a TH2 type, and this was at the expense of TH1 and TH17 cells. In vitro polarization of DOCK8-deficient naive CD4+ T cells revealed the TH2 bias and TH17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. CONCLUSION: Investigations into the DOCK8-deficient CD4+ T cells provided an explanation for some of the clinical features of this disorder: the TH2 bias is likely to contribute to atopic disease, whereas defects in TH1 and TH17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Alérgenos/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Leucócitos Mononucleares/imunologia , Masculino , Adulto JovemRESUMO
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.
Assuntos
Doença Granulomatosa Crônica/complicações , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Vacina BCG/administração & dosagem , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/mortalidade , Micoses/diagnóstico , Micoses/epidemiologia , Micoses/etiologia , Micoses/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Tuberculose/diagnóstico , Tuberculose/etiologiaRESUMO
PURPOSE: The hallmark of Primary immunodeficiencies (PID) is unusual infection, although other immunological non-infectious manifestations such as autoimmunity, allergy and cancer are often present. Most published reports focus on one disease or defect groups, so that a global prevalence of non-infectious manifestations of PID is hard to find. We aimed to describe the clinical features of our pediatric patients with PID, as well as the frequency and evolution of allergy, cancer and autoimmunity. METHODS: We reviewed all the available charts of patients being followed for PID from 1991 to the spring of 2012 at the National Institute of Pediatrics, Mexico City, to describe their demographic, clinical and laboratory features. Their diagnoses were established by pediatric immunologists in accordance to ESID criteria, including routine immunological workup and specialized diagnostic assays. We divided patients by decade of diagnosis to analyze their survival curves. RESULTS: There were 168 charts available, from which we excluded one duplicate and six equivocal diagnoses. We studied the charts of 161 PID patients (68% male, 86% alive), mostly from the center of the country, with a positive family history in 27% and known consanguinity in 11%. Eighty percent of the patients were diagnosed during the last decade. Current median age was 124 months; median age at onset of infections, 12 months; median age at diagnosis, 52 months; median age at death, 67.5 months. Severe infection and bleeding were the cause of 22 deaths. Eighty-six percent of all patients had at least one infection, while non-infectious manifestations had a global prevalence of 36%, namely: autoimmunity 19%, allergies 17%, and cancer 2.4%. Survival curves were not significantly different when compared by decade of diagnosis. CONCLUSIONS: Compared to other registry reports, we found a lower prevalence of antibody defects, and of associated allergy and cancer. We could only locate two isolated IgA deficiencies and four cases of cancer among our PID patients. Although antibody defects are the most prevalent group (30%), the distribution we found is similar to that reported in Iran, Kuwait, Egypt and Taiwan, with a close 27% share for phagocyte defects, and 26% for the formerly called "well-defined" syndromes. Of note, autoimmune and inflammatory complications are high among our patients with chronic granulomatous disease, as has been reported in both the United States and Japan, but not in Europe.
Assuntos
Doenças Autoimunes/epidemiologia , Hipersensibilidade/epidemiologia , Síndromes de Imunodeficiência/epidemiologia , Infecções/epidemiologia , Neoplasias/epidemiologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/mortalidade , Criança , Consanguinidade , Feminino , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/mortalidade , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/mortalidade , Infecções/diagnóstico , Infecções/mortalidade , Masculino , México , Neoplasias/diagnóstico , Neoplasias/mortalidade , Fenótipo , Prevalência , Análise de SobrevidaRESUMO
Signal transducer and activator of transcription 3 (STAT3) deficiency is a primary immunodeficiency characterized by eczema, complicated recurrent infections, elevated serum immunoglobulin E (IgE), osteopenia, and minimal trauma fractures. Zoledronic acid (ZA) is a long-acting bisphosphonate that has been successfully used in children with secondary osteoporosis and osteogenesis imperfecta. We describe the case of a 7-year-old male with STAT3 deficiency and minimal trauma fractures, who also developed osteonecrosis of the hip. He responded well to intravenous ZA every 6 months for 18 months. Three years later, he walks independently and unaided, and has not suffered any other fractures. Although more studies are needed, ZA might help reduce minimal trauma fractures in patients with STAT3 deficiency.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Fraturas Ósseas/tratamento farmacológico , Quadril/patologia , Imidazóis/uso terapêutico , Osteonecrose/tratamento farmacológico , Fator de Transcrição STAT3/deficiência , Criança , Fraturas Ósseas/etiologia , Humanos , Masculino , Ácido ZoledrônicoRESUMO
The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages.
Assuntos
Adenocarcinoma/complicações , Agamaglobulinemia/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Neoplasias Gástricas/complicações , Adenocarcinoma/diagnóstico , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/terapia , Biópsia , Consanguinidade , Análise Mutacional de DNA , Evolução Fatal , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Lactente , Masculino , Linhagem , Neoplasias Gástricas/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Analyze feelings about allergen-specific immunotherapy on Twitter using the VADER model VADER (Valence Aware Dictionary and sEntiment Reasoner) model. METHODS: tweets related to specific allergen immunotherapy were obtained through the Twitter Application Programming Interface (API). The keywords "allergy shot" were used between January 1, 2012, and December 31, 2022. The data was processed by removing URLs, usernames, hashtags, multiple spaces, and duplicate tweets. Subsequently, a sentiment analysis was performed using the VADER model. RESULTS: A total of 34,711 tweets were retrieved, of which 1928 were eliminated. Of the remaining 32,783 tweets, 32.41% expressed a negative sentiment, 31.11% expressed a neutral sentiment, and 36.47% expressed a positive sentiment, with an average polarity of 0.02751 (neutral) over the 11-year period. CONCLUSIONS: The average polarity of tweets about allergen-specific immunotherapy is neutral over the 11 years analyzed. There was an annual increase in the average polarity over the years, with 2017, 2018, and 2022 having positive polarity averages. Additionally, the number of tweets decreased over time.
OBJETIVO: Analizar los sentimientos acerca de la inmunoterapia alérgeno-específica en Twitter mediante el modelo VADER (Valence Aware Dictionary and sEntiment Reasoner). MÉTODOS: Se utilizaron tweets relacionados con la inmunoterapia alérgeno-específica obtenidos a través del API (Application Programming Interface) de Twitter. Se incorporaron las palabras clave "allergy shot" en el período comprendido entre el 1 de enero de 2012 y el 31 de diciembre de 2022. Los datos obtenidos fueron procesados, eliminando las URL, nombres de usuarios, hashtags, espacios múltiples y tweets duplicados. Posteriormente, se realizó un análisis de sentimientos utilizando el modelo VADER. RESULTADOS: Se recolectaron 34,711 tweets, de los que se eliminaron 1928. De los 32,783 tweets restantes, se encontró que el 32.41% de los usuarios expresó un sentimiento negativo, el 31.11% un sentimiento neutral y el 36.47% un sentimiento positivo, con una media de polaridad de 0.02751 (neutral) a lo largo de los 11 años. CONCLUSIONES: La polaridad media de los tweets acerca de la inmunoterapia alérgeno-específica es neutral a lo largo de los 11 años analizados. Existe un aumento anual en la polaridad media positiva a lo largo de los años, sobre todo entre 2017, 2018 y 2022. La cantidad de tweets disminuyó con el tiempo.
Assuntos
Dessensibilização Imunológica , Mídias Sociais , Aprendizado de Máquina não Supervisionado , Humanos , Dessensibilização Imunológica/métodos , EmoçõesRESUMO
Epstein-Barr virus (EBV) is an gamma of herpes virus affecting exclusively humans, was the first oncogenic virus described and is associated with over seven different cancers. Curiously, the exchange of genes during viral infections has enabled the evolution of other cellular organisms, favoring new functions and the survival of the host. EBV has been co-evolving with mammals for hundreds of millions of years, and more than 95% of adults have been infected in one moment of their life. The infection is acquired primarily during childhood, in most cases as an asymptomatic infection. However, during adolescence or young adulthood, around 10 to 30% develop infectious mononucleosis. The NK and CD8+ T cells are the cytotoxic cells of the immune system that focus on antiviral responses. Importantly, an essential role of NK and CD8+ T cells has been demonstrated during the control and elimination of EBV-infected cells. Nonetheless, when the cytotoxic function of these cells is compromised, the infection increases the risk of developing lymphoproliferative diseases and cancer, often fatal. In this review, we delineate EBV infection and the importance of cytotoxic responses by NK and CD8+ T cells during the control and elimination of EBV-infected cells. Furthermore, we briefly discuss the main inborn errors of immunity that compromise cytotoxic responses by NK and CD8+ T cells, and how this scenario affects the antiviral response during EBV infection. Finally, we conclude the review by underlying the need for an effective EBV vaccine capable of preventing infection and the consequent development of malignancies and autoimmune diseases.
El virus Epstein-Barr es una variante del herpes virus que afecta exclusivamente a humanos; fue el primer virus oncogénico descrito y se ha relacionado con más de siete diferentes tipos de cáncer. Curiosamente, el intercambio de genes debido a infecciones virales ha permitido la evolución de los organismos celulares, favoreciendo el desarrollo de nuevas funciones y supervivencia del hospedero. El virus Epstein-Barr comparte cientos de millones de años de coevolución con la especie humana y más del 95% de la población adulta mundial se ha infectado en algún momento de su vida. La infección se adquiere principalmente durante la infancia, y en la mayoría de los casos aparece sin ninguna manifestación grave aparente. Sin embargo, en los adolescentes y la población joven-adulta, alrededor de un 10 a 30% evolucionan a mononucleosis infecciosa. Las células NK y T CD8+ son células citotóxicas cruciales durante las respuestas antivirales y se ha demostrado que que controlan y eliminan la infección por el virus Epstein-Barr. No obstante, cuando se afecta su función efectora, el desenlace puede ser fatal. El objetivo de esta revisión es describir la infección por el virus Epstein-Barr y el papel decisivo de las células NK y T CD8+ durante el control y eliminación de la infección. Además, se discuten brevemente los principales defectos genéticos que afectan a estas células y conllevan a la incapacidad para eliminar el virus. Finalmente, se resalta la necesidad de elaborar una vacuna efectiva contra el virus Epstein-Barr y cómo podrían evitarse los procesos neoplásicos y enfermedades autoinmunes.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Células Matadoras Naturais , Humanos , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T CD8-Positivos/imunologiaRESUMO
Background: G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Objective: The G6PC3 c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it. Methods: Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date. Results: Based on the length of haplotypes shared amongst ten carriers of the G6PC3 c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency. Conclusion: The G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.
RESUMO
G6PC3 deficiency is a monogenic immunometabolic disorder that causes syndromic congenital neutropenia. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican origin. Based on the shared haplotypes amongst carriers of the c.210delC mutation, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it originated in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived cells. G6PC3 pathology is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the variant c.210delC impacts glycolysis by performing extracellular flux assays on patient-derived cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3 deficient patients reported in the literature to date, and we found that c.210delC carriers display all prominent clinical features observed in prior G6PC3 deficient patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.
RESUMO
BACKGROUND: Hereditary actin-related protein 2/3 complex subunit 1B deficiency is characterized clinically by ear, skin, and lung infections, bleeding, eczema, food allergy, asthma, skin vasculitis, colitis, arthritis, short stature, and lymphadenopathy. OBJECTIVE: We aimed to describe the clinical, laboratory, and genetic features of six patients from four Mexican families. METHODS: We performed exome sequencing in patients of four families with suspected actinopathy, collected their data from medical records, and reviewed the literature for reports of other patients with actin-related protein 2/3 complex subunit 1B deficiency. RESULTS: Six patients from four families were included. All had recurrent infections, mainly bacterial pneumonia, and cellulitis. A total of 67% had eczema whereas 50% had food allergies, failure to thrive, hepatomegaly, and bleeding. Eosinophilia was found in all; 84% had thrombocytopenia, 67% had abnormal-size platelets and anemia. Serum levels of IgG, IgA, and IgE were highly increased in most; IgM was normal or low. T cells were decreased in 67% of patients, whereas B and NK cells were increased in half of patients. Two of the four probands had compound heterozygous variants. One patient was successfully transplanted. We identified 28 other patients whose most prevalent features were eczema, recurrent infections, failure to thrive, bleeding, diarrhea, allergies, vasculitis, eosinophilia, platelet abnormalities, high IgE/IgA, low T cells, and high B cells. CONCLUSION: Actin-related protein 2/3 complex subunit 1B deficiency has a variable and heterogeneous clinical spectrum, expanded by these cases to include keloid scars and Epstein-Barr virus chronic hepatitis. A novel deletion in exon 8 was shared by three unrelated families and might be the result of a founder effect.
Assuntos
Eczema , Eosinofilia , Infecções por Vírus Epstein-Barr , Vasculite , Humanos , Proteína 2 Relacionada a Actina , Actinas , Insuficiência de Crescimento , Herpesvirus Humano 4 , Imunoglobulina A , Imunoglobulina E , Reinfecção , Proteína 3 Relacionada a Actina/metabolismoRESUMO
Combinedimmunodeficiency (CID) due to DOCK8 deficiency is an inborn error of immunity (IBD) characterized by dysfunctional T and B lymphocytes; The spectrum of manifestations includes allergy, autoimmunity, inflammation, predisposition to cancer, and recurrent infections. DOCK8 deficiency can be distinguished from other CIDs or within the spectrum of hyper-IgE syndromes by exhibiting profound susceptibility to viral skin infections, associated skin cancers, and severe food allergies. The 9p24.3 subtelomeric locus where DOCK8 is located includes numerous repetitive sequence elements that predispose to the generation of large germline deletions and recombination-mediated somatic DNA repair. Residual production DOCK8 protein contributes to the variable phenotype of the disease. Severe viral skin infections and varicella-zoster virus (VZV)-associated vasculopathy, reflect an essential role of the DOCK8 protein, which is required to maintain lymphocyte integrity as cells migrate through the tissues. Loss of DOCK8 causes immune deficiencies through other mechanisms, including a cell survival defect. In addition, there are alterations in the response of dendritic cells, which explains susceptibility to virus infection and regulatory T lymphocytes that could help explain autoimmunity in patients. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment; it improves eczema, allergies, and susceptibility to infections.
Lainmunodeficiencia combinada (IDC) por deficiencia de DOCK8 es un error innato de la inmunidad, caracterizado por alteración en linfocitos T y B; el espectro de manifestaciones incluye alergia, autoinmunidad, inflamación, predisposición a cáncer e infecciones recurrentes. La deficiencia de DOCK8 se puede distinguir de otras IDC o dentro del espectro de síndromes de hiper-IgE porque presenta una profunda susceptibilidad a las infecciones virales de la piel, con cánceres de piel asociados y alergias alimentarias graves. El locus subtelomérico 9p24.3, donde se ubica DOCK8, incluye numerosos elementos repetitivos de secuencia que predisponen a la generación de grandes deleciones de la línea germinal, así como a la reparación del ADN somático, mediada por recombinación. La producción residual de la proteína DOCK8 contribuye al fenotipo variable de la enfermedad. Las infecciones virales graves de la piel y la vasculopatía asociada a virus de la varicela zóster (VVZ) reflejan una función importante de la proteína DOCK8, que normalmente se requiere para mantener la integridad de los linfocitos a medida que las células migran a través de tejidos. La pérdida de DOCK8 provoca deficiencias inmunitarias a través de otros mecanismos, incluido un defecto de supervivencia celular. Existen alteraciones en la respuesta de las células dendríticas, lo que explica la susceptibilidad a infección por virus, así como en los linfocitos T reguladores que podrían ayudar a explicar la autoinmunidad en los pacientes. El trasplante de células hematopoyéticas pluripotenciales es por el momento el único tratamiento curativo, mejora el eccema, la alergia y la susceptibilidad a infecciones.
Assuntos
Hipersensibilidade , Síndromes de Imunodeficiência , Síndrome de Job , Humanos , Síndrome de Job/complicações , Síndrome de Job/terapia , Síndrome de Job/genética , Inflamação , Linfócitos B , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
The autoimmune lymphoproliferative syndrome (ALPS) is an inborn immunity error, which is the result of a heterogeneous group of mutations in the genes that regulate the apoptosis phenomenon. It typically appears in the first years of life. The most common clinical signs are lymphoid expansion with lymphadenopathy, splenomegaly, and hepatomegaly; immune disease with different types of cytopenia, including thrombocytopenia, hemolytic anemia, and lymphoma. The lab abnormalities that facilitate the diagnosis of ALPS include the presence of double negative alpha/beta T cells, high interleukin levels, vitamin B12 in the blood, and FAS-mediated defective apoptosis in the in vitro assay. The treatment of ALPS is focused on three aspects: The treatment of the manifestations of the disease, the prevention/treatment of complications, and the curative treatment (hematopoietic progenitor cell transplantation [HPCT]). The use of immunosuppressive therapy is suggested only for severe complications of lymphoproliferation or concomitant autoimmune manifestations. Splenectomy is not recommended for autoimmune manifestations in patients with ALPS. HPCT is reserved for selected patients. The survival rate to 50 years is estimated at 85% for patients with FAS deficiency.
El síndrome linfoproliferativo autoinmune (ALPS, autoimmune lymphoproliferative syndrome) es un error innato de la inmunidad, resultado de un grupo heterogéneo de alteraciones en los genes que regulan el fenómeno de apoptosis. Se manifiesta típicamente en los primeros años de vida. Las manifestaciones clínicas más comunes son la expansión linfoide con linfadenopatía, esplenomegalia y hepatomegalia, enfermedad autoinmune con citopenias, incluyendo trombocitopenia y anemia hemolítica, así como linfoma. Las anomalías de laboratorio que facilitan el diagnóstico de ALPS incluyen presencia de células alfa-beta T doble negativas, niveles elevados de interleucina 10, vitamina B12 en sangre y apoptosis defectuosa mediada por FAS en ensayo in vitro. El tratamiento de ALPS se centra en tres aspectos: el tratamiento de las manifestaciones de la enfermedad, la prevención y tratamiento de las complicaciones y el tratamiento curativo (trasplante de células progenitoras hematopoyéticas [TCPH]). Se sugiere el uso de tratamiento inmunosupresor solo para las complicaciones graves de la linfoproliferación o manifestaciones autoinmunes concomitantes. La esplenectomía no se recomienda para las manifestaciones autoinmunes en pacientes con ALPS. El TCPH se reserva para pacientes seleccionados. La tasa de supervivencia a 50 años se estima en 85 % para los pacientes con deficiencia de FAS.
Assuntos
Síndrome Linfoproliferativa Autoimune , Algoritmos , Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/terapia , HumanosRESUMO
DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.
RESUMO
Mutations in the genes coding for cytokines, receptors, second messengers, and transcription factors of interferon gamma (IFN-γ) immunity cause Mendelian susceptibility to mycobacterial disease (MSMD). We report the case of a 7-year-old male patient with partial dominant (PD) IFN-γ receptor 1 deficiency who had suffered from multifocal osteomyelitis attributable to bacille Calmette-Guérin vaccination since the age of 18 months. He developed hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory complication, and died with multiorgan dysfunction, despite having been diagnosed and treated relatively early. Patients with PD IFN-γR1 deficiency usually have good prognosis and might respond to human recombinant subcutaneous IFN-γ. Several monogenic congenital defects have been linked to HLH, a catastrophic "cytokine storm" that is usually ascribed to lymphocyte dysfunction and thought to be triggered by interferon gamma. This is the sixth patient with both MSMD and HLH of whom we are aware. The fact that patients with macrophages that cannot respond to IFN-γ still develop HLH, bring these assumptions into question.
RESUMO
BACKGROUND: The features in a clinical history from a patient with suspected primary immunodeficiency (PID) direct the differential diagnosis through pattern recognition. PIDs are a heterogeneous group of more than 250 congenital diseases with increased susceptibility to infection, inflammation, autoimmunity, allergy and malignancy. Linear discriminant analysis (LDA) is a multivariate supervised classification method to sort objects of study into groups by finding linear combinations of a number of variables. OBJECTIVE: To identify the features that best explain membership of pediatric PID patients to a group of defect or disease. MATERIAL AND METHOD: An analytic cross-sectional study was done with a pre-existing database with clinical and laboratory records from 168 patients with PID, followed at the National Institute of Pediatrics during 1991-2012, it was used to build linear discriminant models that would explain membership of each patient to the different group defects and to the most prevalent PIDs in our registry. After a preliminary run only 30 features were included (4 demographic, 10 clinical, 10 laboratory, 6 germs), with which the training models were developed through a stepwise regression algorithm. We compared the automatic feature selection with a selection made by a human expert, and then assessed the diagnostic usefulness of the resulting models (sensitivity, specificity, prediction accuracy and kappa coefficient), with 95% confidence intervals. RESULTS: The models incorporated 6 to 14 features to explain membership of PID patients to the five most abundant defect groups (combined, antibody, well-defined, dysregulation and phagocytosis), and to the four most prevalent PID diseases (X-linked agammaglobulinemia, chronic granulomatous disease, common variable immunodeficiency and ataxiatelangiectasia). In practically all cases of feature selection the machine outperformed the human expert. Diagnosis prediction using the equations created had a global accuracy of 83 to 94%, with sensitivity of 60 to 100%, specificity of 83 to 95% and kappa coefficient of 0.37 to 0.76. CONCLUSIONS: In general, the selection of features has clinical plausibility, and the practical advantage of utilizing only clinical attributes, infecting germs and routine lab results (blood cell counts and serum immunoglobulins). The performance of the model as a diagnostic tool was acceptable. The study's main limitations are a limited sample size and a lack of cross validation. This is only the first step in the construction of a machine learning system, with a wider approach that includes a larger database and different methodologies, to assist the clinical diagnosis of primary immunodeficiencies.
Antecedentes: las características clínicas de un paciente con sospecha de inmunodeficiencia primaria orientan el diagnóstico diferencial por medio del reconocimiento de patrones. Las inmunodeficiencias primarias son un grupo heterogéneo de más de 250 enfermedades congénitas con mayor susceptibilidad a padecer infecciones, autoinflamación, autoinmunidad, alergia y cáncer. El análisis discriminante lineal es un método multivariante de clasificación supervisada para agrupar a los sujetos a partir de encontrar combinaciones lineales de un número de variables. Objetivo: identificar las características que mejor explican la pertenencia de pacientes pediátricos con inmunodeficiencias primarias a un grupo de defectos o a una enfermedad. Material y método: estudio analítico transversal en el que a partir de una base de datos preexistente, con registros clínicos y de laboratorio de 168 pacientes con inmunodeficiencia primaria, seguidos en el Instituto Nacional de Pediatría de 1991 a 2012, construimos modelos discriminantes lineales para explicar la pertenencia de cada paciente a los diferentes grupos de defectos y a las inmunodeficiencias primarias más prevalentes en nuestro registro. Luego de una corrida preliminar se incluyeron únicamente las 30 variables (4 demográficas, 10 clínicas, 10 de laboratorio y 6 gérmenes) de mayor peso, a partir de las que se construyeron los modelos de entrenamiento con el algoritmo paso-a-paso (stepwise) hacia atrás, utilizando selección automatizada de variables e incorporación manual "teórica" por un experto humano. Se evaluó la utilidad clínica de los modelos resultantes (sensibilidad, especificidad, exactitud y coeficiente kappa), con intervalos de confianza de 95%. Resultados: los modelos incluyeron 6 a 14 variables para explicar la pertenencia de 168 pacientes con inmunodeficiencias primarias a los cinco grupos más numerosos (combinados, anticuerpos, bien definidos, desregulación y fagocitosis) y las cuatro enfermedades más prevalentes (agammaglobulinemia ligada al cromosoma X, enfermedad granulomatosa crónica, inmunodeficiencia común variable y ataxia-telangiectasia). Prácticamente en todos los casos el desempeño de la máquina fue superior al del experto humano en lo que respecta a la selección de los atributos más pertinentes para incorporar en los modelos. La predicción del diagnóstico con base en las ecuaciones construidas tuvo exactitud global de 83 a 94%, con sensibilidad de 60 a 100%, especificidad de 83 a 95% y coeficiente kappa de 0.37 a 0.76. Conclusiones: la selección de variables, en general, tiene plausibilidad clínica y tiene la ventaja práctica de utilizar solamente atributos clínicos, gérmenes encontrados y estudios de laboratorio de rutina (biometría hemática e inmunoglobulinas séricas). El desempeño del modelo como herramienta de predicción fue aceptable. Las principales limitaciones del estudio incluyen un tamaño de muestra limitado, lo que no permitió que realizáramos validación cruzada en la evaluación. Éste es solamente un primer paso en la construcción de un sistema de aprendizaje automático, con un abordaje más amplio que incluya una base de datos más grande y diferentes metodologías, para asistir el diagnóstico clínico de las inmunodeficiencias primarias.