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1.
J Clin Immunol ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953710

RESUMO

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 416 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

2.
Allergy Asthma Proc ; 41(1): 66-69, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888785

RESUMO

Mycobacterium avium complex (MAC) infections, generally viewed as opportunistic infections, often trigger an evaluation for an underlying immunodeficiency disorder. However, MAC infections can occur in patients who presumably are immunocompetent, particularly in those with an underlying structural lung disease. T-cell immunity plays a critical role in controlling MAC infection. We presented a case of lymphopenia, which complicated the clinical course of a pulmonary MAC infection in a patient who was negative for human immunodeficiency virus.

3.
Front Immunol ; 10: 2742, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849949

RESUMO

Almost 70 years after establishing the concept of primary immunodeficiency disorders (PIDs), more than 320 monogenic inborn errors of immunity have been identified thanks to the remarkable contribution of high-throughput genetic screening in the last decade. Approximately 40 of these PIDs present with autoimmune or auto-inflammatory symptoms as the primary clinical manifestation instead of infections. These PIDs are now recognized as diseases of immune dysregulation. Loss-of function mutations in genes such as FOXP3, CD25, LRBA, IL-10, IL10RA, and IL10RB, as well as heterozygous gain-of-function mutations in JAK1 and STAT3 have been reported as causative of these disorders. Identifying these syndromes has considerably contributed to expanding our knowledge on the mechanisms of immune regulation and tolerance. Although whole exome and whole genome sequencing have been extremely useful in identifying novel causative genes underlying new phenotypes, these approaches are time-consuming and expensive. Patients with monogenic syndromes associated with autoimmunity require faster diagnostic tools to delineate therapeutic strategies and avoid organ damage. Since these PIDs present with severe life-threatening phenotypes, the need for a precise diagnosis in order to initiate appropriate patient management is necessary. More traditional approaches such as flow cytometry are therefore a valid option. Here, we review the application of flow cytometry and discuss the relevance of this powerful technique in diagnosing patients with PIDs presenting with immune dysregulation. In addition, flow cytometry represents a fast, robust, and sensitive approach that efficiently uncovers new immunopathological mechanisms underlying monogenic PIDs.

4.
J Clin Immunol ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31768891
5.
Front Pediatr ; 7: 55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024866

RESUMO

In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene-based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5'and 3' untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy.

6.
Expert Rev Clin Immunol ; 15(5): 529-540, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30681380

RESUMO

INTRODUCTION: CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients' susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.

7.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607663

RESUMO

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Assuntos
Reparo do DNA/genética , Granuloma/complicações , Granuloma/virologia , Síndromes de Imunodeficiência/complicações , Vírus da Rubéola/patogenicidade , Dermatopatias/etiologia , Dermatopatias/virologia , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Criança , Pré-Escolar , Feminino , Granuloma/genética , Cabelo/anormalidades , Cabelo/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hirschsprung/genética , Doença de Hirschsprung/virologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/virologia , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virologia , Rubéola (Sarampo Alemão)/genética , Rubéola (Sarampo Alemão)/virologia , Pele/virologia , Dermatopatias/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
8.
Immunol Cell Biol ; 97(4): 368-379, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30264496

RESUMO

Hyper IgE syndromes comprise a group of rare primary immunodeficiency disorders characterized by a triad of atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels. Job syndrome or autosomal dominant hyper IgE syndrome because of heterozygous loss-of-function mutations with dominant negative effect in signal transducer and activator of transcription-3 is the prototype of these disorders. However, several other genetically characterized immunodeficiency disorders have been identified over the past decade and joined the umbrella of hyper IgE syndromes including autosomal recessive mutations in the DOCK8, ZNF431 and PGM3 genes and heterozygous mutations with dominant negative effect in the CARD11 gene. Moreover, a number of phenotypically distinct immunodeficiency disorders can mimic hyper IgE syndromes, adding to the diagnostic challenge. Herein, we will concisely review these disorders, their molecular bases, highlighting key distinguishing clinical and laboratory findings and therapeutic options.

9.
Front Immunol ; 9: 2756, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564228

RESUMO

Background: Primary immunodeficiency disorders (PIDD) comprise a group of life-threatening congenital diseases characterized by absent or impaired immune responses. Despite the fact that effective, curative treatments are available with optimal clinical outcomes when diagnosed early, newborn screening does not exist for the majority of these diseases due to the lack of detectable, specific biomarkers or validated methods for population-based screening. Peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno-SRM) is a sensitive proteomic assay, involving antibody-mediated peptide capture, that allows for concurrent quantification of multiple analytes. This assay has promise for use in potential newborn screening of PIDDs that lead to diminished or absent target proteins in the majority of cases. Objective: To determine and evaluate if a multiplex assay based on immuno-SRM is able to reliably and precisely distinguish affected patients with X-linked agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), and CD3ϵ-associated severe combined immunodeficiency (SCID) from one another and from unaffected normal control dried blood spot (DBS) samples. Methods: We performed a blinded, multiplexed analysis of proteolytically-generated peptides from WASp, BTK, and CD3ϵ (for WAS, XLA, and SCID, respectively) in DBS samples from 42 PIDD patients, 40 normal adult controls, and 62 normal newborns. The peptide ATPase copper transporting protein (ATP7B) 1056 was simultaneously monitored for quality assurance purposes. Results: The immuno-SRM assays reliably quantified the target peptides in DBS and accurately distinguished affected patients from normal controls. Analysis of signature peptides found statistically significant reduction or absence of peptide levels in affected patients compared to control groups in each case (WASp and BTK: p = 0.0001, SCID: p = 0.05). Intra and inter-assay precision ranged from 11 to 22% and 11 to 43% respectively; linearity (1.39-2000 fmol peptide), and stability (≤ 0.09% difference in 72 h) showed high precision for the multiplexed assay. Inter-laboratory assay comparison showed high concordance for measured peptide concentrations, with R2 linearity ≥ 0.97 for the WASp 274, CD3ϵ 197, BTK 407, and ATP7B 1056 peptides. Conclusion: Immuno-SRM-based quantification of proteotypic peptides from WASp, BTK, and CD3ϵ in DBS distinguishes relevant PIDD cases from one another and from controls, raising the possibility of employing this approach for large-scale multiplexed newborn screening of selective PIDDs.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/metabolismo , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/metabolismo , Anticorpos/metabolismo , Bioensaio/métodos , Biomarcadores/metabolismo , Cromatografia Líquida/métodos , Estudos de Coortes , ATPases Transportadoras de Cobre/metabolismo , Teste em Amostras de Sangue Seco/métodos , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Recém-Nascido , Espectrometria de Massas/métodos , Triagem Neonatal/métodos , Peptídeos/metabolismo , Proteômica/métodos
10.
Nat Commun ; 9(1): 5224, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30523250

RESUMO

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.


Assuntos
Doença de Alzheimer/imunologia , Autoanticorpos/imunologia , Homeostase/imunologia , Neoplasias Ovarianas/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Escleroderma Sistêmico/imunologia , Idoso , Sequência de Aminoácidos , Animais , Autoanticorpos/sangue , Autoanticorpos/metabolismo , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mapas de Interação de Proteínas/imunologia , Receptor de Endotelina A/genética , Receptor de Endotelina A/imunologia , Receptor de Endotelina A/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Homologia de Sequência de Aminoácidos
12.
Front Immunol ; 9: 2411, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443250

RESUMO

Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.


Assuntos
Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Predisposição Genética para Doença , Enteropatias/diagnóstico , Enteropatias/genética , Fenótipo , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/etiologia , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Biomarcadores , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Heterogeneidade Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoglobulina E/imunologia , Estimativa de Kaplan-Meier , Masculino , Mutação , Poliendocrinopatias Autoimunes/mortalidade , Poliendocrinopatias Autoimunes/terapia , Síndrome , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
13.
Front Pediatr ; 6: 230, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30177960

RESUMO

We report a novel homozygous JAK3 mutation in two female Brazilian SCID infants from two unrelated kindreds. Patient 1 was referred at 2 months of age due to a family history of immunodeficiency and the appearance of a facial rash. The infant was screened for TRECs (T-cell receptor excision circles) and KRECs (kappa-deleting recombination excision circles) for the assessment of newly formed naïve T and B cells respectively, which showed undetectable TRECs and normal numbers of KRECs. Lymphocyte immunophenotyping by flow cytometry confirmed the screening results, revealing a T-B+NK- SCID. The patient underwent successful HSCT. Patient 2 was admitted to an intensive care unit at 8 months of age with severe pneumonia, BCGosis, and oral moniliasis; she also had a positive family history for SCID but newborn screening was not performed at birth. At 10 months of age she was diagnosed as a T-B+NK- SCID and underwent successful HSCT. JAK3 sequencing revealed the same homozygous missense mutation (c.2350G>A) in both patients. This mutation affects the last nucleotide of exon 17 and it is predicted to disrupt the donor splice site. cDNA sequencing revealed skipping of exon 17 missing in both patients, confirming the predicted effect on mRNA splicing. Skipping of exon 17 leads to an out of frame deletion of 151 nucleotides, frameshift and creation of a new stop codon 60 amino acids downstream of the mutation resulting in a truncated protein which is likely nonfunctional.

14.
Immunotherapy ; 10(14): 1193-1202, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30088423

RESUMO

AIM: To assess the safety and efficacy of an intravenous immunoglobulin (IVIG) 10% preparation (Panzyga®; Octapharma AG, Lachen, Switzerland) in predominantly antibody-deficient children with primary immunodeficiency disease. METHODS: Data from two prospective, open-label and noncontrolled multicenter Phase III studies of IVIG 10% that included 25 patients <16 years of age were analyzed for efficacy, pharmacokinetics and safety. RESULTS: The rate of serious bacterial infections was 0.04/patient-year. A maximal infusion rate of 0.14 ml/kg/min was achieved in 82% of pediatric patients (n = 9). Infusions of immunoglobulin G trough levels between infusions remained ≥5-6 g/l; median half-life was 32.79-36.62 days. Abdominal pain, headache and chills were the most common treatment-related adverse events. CONCLUSION: IVIG 10% is safe and effective for the treatment of predominantly antibody-deficient children.


Assuntos
Agamaglobulinemia/terapia , Infecções Bacterianas/epidemiologia , Imunodeficiência de Variável Comum/terapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Adolescente , Adulto , Agamaglobulinemia/epidemiologia , Idoso , Infecções Bacterianas/etiologia , Criança , Imunodeficiência de Variável Comum/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
16.
Front Immunol ; 9: 289, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29503650

RESUMO

Background: New sequencing techniques have revolutionized the identification of the molecular basis of primary immunodeficiency disorders (PID) not only by establishing a gene-based diagnosis but also by facilitating defect-specific treatment strategies, improving quality of life and survival, and allowing factual genetic counseling. Because these techniques are generally not available for physicians and their patients residing in developing countries, collaboration with overseas laboratories has been explored as a possible, albeit cumbersome, strategy. To reduce the cost of time and temperature-sensitive shipping, we selected Guthrie cards, developed for newborn screening, to collect dried blood spots (DBS), as a source of DNA that can be shipped by regular mail at minimal cost. Method: Blood was collected and blotted onto the filter paper of Guthrie cards by completely filling three circles. We enrolled 20 male patients with presumptive X-linked agammaglobulinemia (XLA) cared for at the Vietnam National Children's Hospital, their mothers, and several sisters for carrier analysis. DBS were stored at room temperature until ready to be shipped together, using an appropriately sized envelope, to a CLIA-certified laboratory in the US for sequencing. The protocol for Sanger sequencing was modified to account for the reduced quantity of gDNA extracted from DBS. Result: High-quality gDNA could be extracted from every specimen. Bruton tyrosine kinase (BTK) mutations were identified in 17 of 20 patients studied, confirming the diagnosis of XLA in 85% of the study cohort. Type and location of the mutations were similar to those reported in previous reviews. The mean age when XLA was suspected clinically was 4.6 years, similar to that reported by Western countries. Two of 15 mothers, each with an affected boy, had a normal BTK sequence, suggesting gonadal mosaicism. Conclusion: DBS collected on Guthrie cards can be shipped inexpensively by airmail across continents, providing sufficient high-quality gDNA for Sanger sequencing overseas. By using this method of collecting gDNA, we were able to confirm the diagnosis of XLA in 17 of 20 Vietnamese patients with the clinical diagnosis of agammaglobulinemia.


Assuntos
Agamaglobulinemia/diagnóstico , Coleta de Amostras Sanguíneas/métodos , DNA/análise , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Triagem Neonatal/métodos , Manejo de Espécimes/métodos , Adulto , Agamaglobulinemia/genética , Coleta de Amostras Sanguíneas/instrumentação , Criança , Pré-Escolar , Análise Mutacional de DNA/instrumentação , Análise Mutacional de DNA/métodos , Países em Desenvolvimento , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/instrumentação , Fenótipo , Vietnã
17.
Eur J Pharm Sci ; 118: 80-86, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29522908

RESUMO

Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2-75 years with common variable immunodeficiency (n = 43) or X-linked agammaglobulinaemia (n = 8). Patients were treated with IVIG 10% every 3 (n = 21) or 4 weeks (n = 30) at a dose of 200-800 mg/kg for 12 months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15 min post-infusion. The maximum concentration of total IgG (mean ±â€¯SD) was 21.82 ±â€¯5.83 g/L in patients treated 3-weekly and 17.42 ±â€¯3.34 g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2 g/L for patients on the 3-week schedule and between 8.10 and 8.65 g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5-65.9) days, with generally similar values for the IgG subclasses (26.7-38.0 days). Median half-lives for specific antibodies ranged between 21.3 and 51.2 days for anti-cytomegalovirus, anti-Haemophilus influenzae, anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti-Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections.


Assuntos
Agamaglobulinemia/metabolismo , Imunodeficiência de Variável Comum/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Imunoglobulinas Intravenosas/farmacocinética , Adolescente , Adulto , Agamaglobulinemia/sangue , Idoso , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/sangue , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Allergy Clin Immunol ; 142(5): 1571-1588.e9, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29518426

RESUMO

BACKGROUND: Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. OBJECTIVES: We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function. METHODS: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. RESULTS: Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. CONCLUSION: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.


Assuntos
Ligante de CD40/deficiência , Interferon gama/farmacologia , Neutrófilos/efeitos dos fármacos , Animais , Ligante de CD40/imunologia , Feminino , Células HL-60 , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/fisiologia , Paracoccidioides , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia , Explosão Respiratória/efeitos dos fármacos , Staphylococcus aureus , Acetato de Tetradecanoilforbol/farmacologia , Transcriptoma/efeitos dos fármacos
19.
J Allergy Clin Immunol ; 142(1): 219-234, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29248492

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. OBJECTIVE: We sought to define how dysfunctional gene transcription is causally linked to the degree of TH cell deficiency and genomic instability in the XLT/WAS clinical spectrum. METHODS: In human TH1- or TH2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp. RESULTS: WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative to TH2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (TH1 genes) in TH1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (TH2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores. CONCLUSION: Transcriptional R-loop imbalance is a novel molecular defect causative in TH1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically.


Assuntos
Instabilidade Genômica/genética , Células Th1/patologia , Síndrome de Wiskott-Aldrich/genética , Células Cultivadas , Dano ao DNA/genética , Humanos , Transcrição Genética , Síndrome de Wiskott-Aldrich/patologia
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