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1.
Clin Perinatol ; 47(1): 41-52, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32000928

RESUMO

Autoinflammatory disorders are rare genetic defects that result in inflammation in the absence of an infectious or autoimmune disease. Although very rare, these disorders can occur in the perinatal period, and recognizing their presentation is important because there are often long-term complications and effective targeted therapies for these disorders. Most of these disorders present with rash, fevers, and laboratory evidence of inflammation. Importantly, these disorders can now be separated into their pathophysiologic mechanisms of action, which can also guide therapies. The article reviews the different mechanisms of autoinflammatory disorders and highlights those disorders that can present in the newborn period.

2.
Nat Commun ; 10(1): 3931, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477722

RESUMO

Natural killer (NK) cells are critical to both innate and adaptive immunity. However, the development and heterogeneity of human NK cells are yet to be fully defined. Using single-cell RNA-sequencing technology, here we identify distinct NK populations in human bone marrow and blood, including one population expressing higher levels of immediate early genes indicative of a homeostatic activation. Functionally matured NK cells with high expression of CX3CR1, HAVCR2 (TIM-3), and ZEB2 represents terminally differentiated status with the unique transcriptional profile. Transcriptomic and pseudotime analyses identify a transitional population between CD56bright and CD56dim NK cells. Finally, a donor with GATA2T354M mutation exhibits reduced percentage of CD56bright NK cells with altered transcriptome and elevated cell death. These data expand our understanding of the heterogeneity and development of human NK cells.


Assuntos
Medula Óssea/metabolismo , Células Matadoras Naturais/metabolismo , Análise de Célula Única/métodos , Transcriptoma/genética , Células da Medula Óssea/metabolismo , Antígeno CD56/genética , Antígeno CD56/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Heterogeneidade Genética , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
3.
Arthritis Rheumatol ; 71(3): 451-459, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30225949

RESUMO

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Calgranulina A/sangue , Calgranulina B/sangue , Proteína S100A12/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Quimioterapia de Manutenção/métodos , Masculino , Exacerbação dos Sintomas , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Suspensão de Tratamento
4.
J Clin Invest ; 128(7): 3071-3087, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889099

RESUMO

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.


Assuntos
Mutação em Linhagem Germinativa , Fator de Transcrição Ikaros/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Mutação com Perda de Função , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Genes Dominantes , Heterozigoto , Humanos , Fator de Transcrição Ikaros/química , Fator de Transcrição Ikaros/imunologia , Lactente , Masculino , Células Mieloides/imunologia , Linhagem , Fenótipo , Domínios Proteicos/genética , Homologia de Sequência de Aminoácidos , Linfócitos T/imunologia , Adulto Jovem
5.
J Clin Immunol ; 38(4): 540-541, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29781065

RESUMO

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.

6.
Arthritis Rheumatol ; 70(9): 1508-1518, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29604189

RESUMO

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/patologia , Quimioterapia de Indução/estatística & dados numéricos , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Lactente , Tábuas de Vida , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Exacerbação dos Sintomas , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
7.
J Clin Immunol ; 38(3): 320-329, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29675737

RESUMO

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.


Assuntos
Testes Genéticos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Biomarcadores , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/normas , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/terapia , Diagnóstico Pré-Natal , Análise de Sequência de DNA
8.
J Clin Immunol ; 38(3): 225-233, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29453744

RESUMO

Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n = 354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (< 2 IU/ml) occurs in only 3.3% (95% CI, 1.9-5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6-85.7%) of patients with CVID. Conversely, a high IgE (> 180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is > 2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.


Assuntos
Biomarcadores , Imunodeficiência de Variável Comum/diagnóstico , Imunoglobulina E/sangue , Adolescente , Adulto , Alérgenos/imunologia , Criança , Estudos de Coortes , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Feminino , Humanos , Imunização , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Masculino , Sensibilidade e Especificidade , Adulto Jovem
9.
Front Immunol ; 8: 1470, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29167668

RESUMO

Severe combined immunodeficiency (SCID) is a life-threatening condition of newborns and infants caused by defects in genes involved in T cell development. Newborn screening (NBS) for SCID using the T cell receptor excision circle (TREC) assay began in Wisconsin in 2008 and has been adopted or is being implemented by all states in 2017. It has been established that NBS using the TREC assay is extremely sensitive to detect SCID in the newborn period. Some controversies remain regarding how screening positives are handled by individual states, including when to perform confirmatory flow cytometry, what is the necessary diagnostic workup of patients, what infection prophylaxis measures should be taken, and when hematopoietic stem cell transplantation should occur. In addition, the TREC can also assay detect infants with T cell lymphopenia who are not severe enough to be considered SCID; management of these infants is also evolving.

10.
J Clin Immunol ; 37(5): 427-433, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28589420

RESUMO

PURPOSE: The specific antibody response to the unconjugated 23-valent pneumococcal polysaccharide vaccine is one of the most common tests used to assess for possible humoral immunodeficiency. The results can be difficult to interpret because most people have been immunized with one or more of the pneumococcal vaccines and there is controversy regarding what constitutes a normal response. To circumvent this problem, we developed an ELISA to measure IgG-specific antibodies to the Salmonella Vi Typhim (S. Typhim) vaccine, a pure polysaccharide vaccine, which is a neoantigen for the vast majority of people in the USA. METHODS: We compared the pre- and post-vaccination serum titers to the Vi Typhim vaccine in healthy controls (n = 22), patients previously diagnosed with a primary immunodeficiency (n = 30), and patients referred for possible humoral immune deficiency (n = 29). We also determined if the S. Typhim vaccine could be used to assess specific antibody responses in people on antibody replacement therapy. RESULTS: Following immunization with the S. Typhim vaccine, we found that a 2-fold increase in titers is 100% sensitive and specific in detecting known humoral immune deficiencies as determined by ROC curve analysis. This cut-off value was successfully applied to possible immune deficiency patients (n = 29), resulting in the diagnosis of seven subjects with humoral immunodeficiency. The use of immunoglobulin replacement therapy did not affect the median response ratios compared to subjects not receiving gammaglobulin. CONCLUSION: This study suggests that measurement of the specific antibody response to the S. Typhim vaccine may have advantages over pneumococcal vaccination in the evaluation of the humoral immune response.


Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Anticorpos Antibacterianos/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Adolescente , Adulto , Agamaglobulinemia/sangue , Idoso , Anticorpos Antibacterianos/sangue , Área Sob a Curva , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/imunologia , Curva ROC , Vacinas Tíficas-Paratíficas/administração & dosagem , Vacinação , Adulto Jovem
11.
Stem Cell Reports ; 8(3): 491-499, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28238794

RESUMO

Genome editing in induced pluripotent stem cells is currently hampered by the laborious and expensive nature of identifying homology-directed repair (HDR)-modified cells. We present an approach where isolation of cells bearing a selectable, HDR-mediated editing event at one locus enriches for HDR-mediated edits at additional loci. This strategy, called co-targeting with selection, improves the probability of isolating cells bearing HDR-mediated variants and accelerates the production of disease models.


Assuntos
Edição de Genes , Marcação de Genes , Genoma Humano , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Reparo do DNA por Junção de Extremidades , Técnicas de Introdução de Genes , Vetores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Reparo de DNA por Recombinação
12.
Pediatr Clin North Am ; 64(1): 111-125, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27894439

RESUMO

Autoinflammatory disorders are disorders characterized by rash, arthritis, fever, and systemic inflammation. These disorders are caused by mutations in genes important in innate immune system sensors. This review highlights the workup of an individual with recurrent episodes of inflammation, features of these disorders, the genetic defects that cause these disorders, and the specific treatments available.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/imunologia , Criança , Diagnóstico Tardio , Diagnóstico Diferencial , Erros de Diagnóstico , Febre , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Imunidade Inata , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/imunologia , Doenças Raras/terapia , Recidiva , Síndrome
13.
Pediatr Clin North Am ; 64(1): 27-37, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27894450

RESUMO

Although primary immunodeficiencies typically present with recurrent, chronic, or severe infections, autoimmune manifestations frequently accompany these disorders and may be the initial clinical manifestations. The presence of 2 or more autoimmune disorders, unusual severe atopic disease, or a combination of these disorders should lead a clinician to consider primary immunodeficiency disorders.


Assuntos
Doenças Autoimunes/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Doenças Raras/diagnóstico , Doenças Autoimunes/imunologia , Criança , Diagnóstico Tardio , Diagnóstico Diferencial , Erros de Diagnóstico , Humanos , Síndromes de Imunodeficiência/imunologia , Doenças Raras/imunologia
14.
Expert Rev Hematol ; 9(6): 579-84, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27139719

RESUMO

INTRODUCTION: Newborn screening (NBS) for Severe combined immunodeficiency (SCID)/severe T cell lymphopenia (sTCL) is being increasingly used worldwide. AREAS COVERED: In this manuscript we will discuss the following: 1) The rationale for screening newborns for SCID/sTCL; 2) The scientific basis for the use of the T cell receptor excision circle (TREC) assay in screening newborns for SCID/sTCL; 3) The published outcomes of current NBS programs. Expert commentary: 4) Some of the ethical dilemmas that occur when screening newborns for SCID. Finally, we will discuss the future directions for expanding NBS to include other primary immunodeficiencies.


Assuntos
Triagem Neonatal , Imunodeficiência Combinada Severa/diagnóstico , Testes Genéticos/ética , Testes Genéticos/métodos , Humanos , Recém-Nascido , Programas de Rastreamento , Triagem Neonatal/ética , Triagem Neonatal/métodos , Receptores de Antígenos de Linfócitos T/genética , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/etiologia
15.
J Pediatr Gastroenterol Nutr ; 63(2): 218-25, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26825770

RESUMO

OBJECTIVE: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-ß signaling. METHODS AND RESULTS: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4 T cells from xIAP mice compared with colitis induced by naïve CD4 T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP or WT Treg cells with naïve WT CD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL-17A-producing CD4 T cells in mice receiving Tregs from xIAP mice. CONCLUSIONS: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4 T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.


Assuntos
Colite/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Proteínas Inibidoras de Apoptose/deficiência , Interleucina-17/imunologia , Transtornos Linfoproliferativos/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Doença Crônica , Colite/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Proteínas Inibidoras de Apoptose/imunologia , Transtornos Linfoproliferativos/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Fator de Crescimento Transformador beta/imunologia
16.
J Allergy Clin Immunol ; 136(5): 1186-205.e1-78, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26371839

RESUMO

The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Comitês Consultivos , Animais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Medicina Baseada em Evidências , Humanos
17.
J Clin Immunol ; 35(6): 573-82, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26275445

RESUMO

PURPOSE: To develop an assay to quantify serum immunoglobulin (IgG, IgM, IgA) levels using dried blood spots (DBS) obtained on collection cards to be used as a tool for targeted screening for hypogammaglobulinemia. METHODS: DBS samples, along with simultaneous serum samples, were collected from 107 healthy individuals (11 months to 57 years of age). After eluting proteins from DBS, IgG, IgM, and IgA were quantified by an enzyme-linked immunosorbent assay (ELISA). The Ig-DBS assay was validated through calibration curve performance, intra- and inter-assay precision, accuracy, specificity, selectivity, and linearity. The ELISA measurements were compared with serum Ig levels obtained using a standard nephelometry assay on serum samples collected simultaneously with the DBS samples and the results of the two assays were correlated. The stability of IgG, IgM, and IgA in the DBS was tested at room temperature, 36° to 38 °C, 2 to 8 °C, and -25 to -40 °C, from 4 to 14 days. RESULTS: The Ig-DBS assay demonstrated precision, accuracy, specificity, selectivity, and linearity. Using the identified correlation coefficients of 0.834 for IgG, 0.789 for IgM, and 0.918 for IgA, the standard nephelometry-based normal reference ranges for all 3 serum Ig isotypes could be used with the Ig-DBS assay in individuals ≥16 years of age. The DBS samples were stable for 14 days at room temperature in a closed polyethylene bag. CONCLUSIONS: The Ig-DBS assay is both sensitive and accurate for quantification of serum immunoglobulins. Samples are sufficiently stable at ambient temperature to allow for convenient shipping and analysis at a centralized laboratory. This assay therefore presents a new option for screening patients ≥16 years of age for hypogammaglobulinemia in any setting.


Assuntos
Agamaglobulinemia/diagnóstico , Teste em Amostras de Sangue Seco/métodos , Programas de Rastreamento/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lactente , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
18.
Blood ; 125(4): 591-9, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25359994

RESUMO

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.


Assuntos
Doenças Autoimunes/genética , Doenças Genéticas Inatas/genética , Transtornos Linfoproliferativos/genética , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Humanos , Lactente , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Masculino , Mutação , Fosforilação/genética , Fosforilação/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
19.
J Clin Immunol ; 35(1): 11-4, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25352054

RESUMO

Gain of function (GOF) mutation in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) is the cause of a primary immunodeficiency (PID) characterized by recurrent sinopulmonary infections and lymphoproliferation. We describe a family of two adults and three children with GOF mutation in PIK3CD, all with recurrent sinopulmonary infections and varied infectious and non-infectious complications. The two adults have Primary Sclerosing Cholangitis (PSC) without evidence of Cryptosporidium parvum infection and have required liver transplantation. PSC is a novel phenotype of GOF mutation in PIK3CD.


Assuntos
Colangite Esclerosante/enzimologia , Colangite Esclerosante/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação de Sentido Incorreto , Adulto , Substituição de Aminoácidos , Criança , Colangite Esclerosante/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Heterozigoto , Humanos , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Fígado/patologia , Masculino , Linhagem
20.
Clin Epidemiol ; 6: 379-93, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25368531

RESUMO

Juvenile idiopathic arthritis (JIA) is a group of disorders characterized by arthritis persisting for at least 6 weeks with onset before the age of 16 years. Within this cluster of conditions, the polyarticular form (involving more than four joints within the first 6 months) is further divided based on the presence of rheumatoid factor. Children with polyarticular JIA pose unique diagnostic and therapeutic challenges compared to children with involvement of fewer joints. Polyarticular JIA patients tend to have a more refractory course and therefore are at increased risk for joint damage, resulting in poorer functional outcomes and decreased quality of life. Although the ability to treat this disorder continues to improve, especially with the advent of biologic agents, there is still much about the epidemiology and pathogenesis of polyarticular JIA that is unknown. The epidemiology of polyarticular JIA varies worldwide with a vast difference in reported cases between different global regions as well as within individual countries. Several genetic risk loci have been identified conferring increased susceptibility to JIA, many within the human leukocyte antigen region. Beyond the genome, environmental factors also seem to contribute to the etiology of polyarticular JIA. This review article will focus on the epidemiology and current treatments of polyarticular JIA and briefly discuss genetic and environmental influences on the pathogenesis of JIA as well as new and emerging therapies.

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