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1.
J Clin Immunol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31705452

RESUMO

BACKGROUND: The correlation between different methods for the detection of pneumococcal polysaccharide vaccine (PPV) responses to diagnose specific polysaccharide antibody deficiency (SAD) is poor and the criteria for defining a normal response lack consensus. We previously proposed fifth percentile (p5) values of PPV responses as a new cutoff for SAD. OBJECTIVE: To analyze the association of SAD (determined by either World Health Organization (WHO)-standardized ELISA or multiplex bead-based assay) with abnormal response to Salmonella (S.) typhi Vi vaccination in a cohort of patients with recurrent infections. METHODS: Ninety-four patients with a clinical history suggestive of antibody deficiency received PPV and S. typhi Vi vaccines. Polysaccharide responses to either 3 or 18 pneumococcal serotypes were measured by either the WHO ELISA or a multiplex in-house bead-based assay. Anti-S. typhi Vi IgG were measured by a commercial ELISA kit. Allohemagglutinins (AHA) were measured by agglutination method. RESULTS: Based on the American Academy of Allergy, Asthma and Immunology (AAAAI) criteria for WHO ELISA, 18/94 patients were diagnosed with SAD and 22/93 based on serotype-specific p5 cutoffs for bead-based assay. The association between the two methods was significant, with 10 subjects showing abnormal response according to both techniques. Abnormal response to S. typhi Vi vaccination was found in 7 patients, 6 of which had SAD. No correlation was found between polysaccharide response and AHA, age, or clinical phenotype. CONCLUSION: The lack of evidence-based gold standards for the diagnosis of SAD represents a challenge in clinical practice. In our cohort, we confirmed the insufficient correlation between different methods of specific PPV response measurement, and showed that the S. typhi Vi response was not contributive. Caution in the interpretation of results is warranted until more reliable diagnostic methods can be validated.

2.
J Exp Med ; 216(9): 2057-2070, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270247

RESUMO

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

3.
J Clin Immunol ; 39(3): 298-308, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30838481

RESUMO

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.

5.
Immunol Cell Biol ; 97(4): 389-402, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30779216

RESUMO

Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology.

6.
Immunol Rev ; 287(1): 62-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565235

RESUMO

Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small- and medium-size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro-inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti-TNF therapy with etanercept and that is the first-line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients' refractory to anti-cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine-tune and steer future therapeutic strategies.


Assuntos
Adenosina Desaminase/genética , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Macrófagos/imunologia , Animais , Diferenciação Celular , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Poliarterite Nodosa , Acidente Vascular Cerebral Lacunar
7.
J Allergy Clin Immunol ; 143(2): 507-527, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30075154

RESUMO

Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αß T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors.

9.
J Clin Immunol ; 38(8): 938-939, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30430354

RESUMO

The original version of this article unfortunately did not display the appropriate captions in the figure. The correct version is displayed below.

11.
Hum Vaccin Immunother ; 14(5): 1234-1242, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29400602

RESUMO

Serotype-independent protein-based pneumococcal vaccines represent attractive alternatives to capsular polysaccharide-based vaccines. The aim of this study was to identify novel immunogenic proteins from Streptococcus pneumoniae that may be used in protein-based pneumococcal vaccine. An immunoproteomics approach and a humanized severe combined immunodeficient mouse model were used to identify S. pneumoniae proteins that are immunogenic for the human immune system. Among the several proteins identified, SP1683 was selected, recombinantly produced, and infection and colonization murine models were used to evaluate the capacity of SP1683 to elicit protective responses, in comparison to known pneumococcal immunogenic proteins (PhtD and detoxified pneumolysin, dPly). Immunisation with SP1683 elicited a weaker antibody response than immunisation with PhtD and did not provide protection in the model of invasive disease. However, similar to PhtD, it was able to significantly reduce colonization in the mouse model of nasopharyngeal carriage. Treatment with anti-IL17A and anti-IL17F antibodies abolished the protection against colonization elicited by SP1683 or PhtD + dPly, which indicated that the protection afforded in this model was Th17-dependent. In conclusion, intranasal immunization with the pneumococcal protein SP1683 conferred IL17-dependent protection against nasopharyngeal carriage in mice, but systemic immunization did not protect against invasive disease. These results do not support the use of SP1683 as an isolated pneumococcal vaccine antigen. Nevertheless, SP1683 could be used as a first line of defence in formulations combining several proteins.


Assuntos
Proteínas de Bactérias/imunologia , Nasofaringe/microbiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Administração Intranasal , Adulto , Animais , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/administração & dosagem , Buffy Coat/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunogenicidade da Vacina , Leucócitos Mononucleares , Camundongos , Camundongos SCID , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/administração & dosagem , Proteômica/métodos , Sorogrupo , Streptococcus pneumoniae/genética , Vacinação/métodos
13.
Blood ; 130(24): 2682-2688, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-28974505

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1 DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency and bone marrow failure. Tumor necrosis factor-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9) and reduced intensity (5). Donors were HLA-matched sibling (n = 1), HLA-matched unrelated (n = 9), HLA-mismatched unrelated (n = 3), and HLA haploidentical sibling (n = 1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18 months (range, 5 months to 13 years). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as day +14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft-versus-host disease grade 1 in 2, grade 2 in 3, and grade 3-4 in 1, and moderate chronic graft-versus-host disease in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment of DADA2.


Assuntos
Adenosina Desaminase/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Adenosina Desaminase/sangue , Adenosina Desaminase/metabolismo , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Síndromes de Imunodeficiência/enzimologia , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Fenótipo , Condicionamento Pré-Transplante/métodos
15.
J Clin Immunol ; 37(8): 801-810, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28993958

RESUMO

Hypomorphic IKBKG mutations in males are typically associated with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Some mutations cause immunodeficiency without EDA (NEMO-ID). The immunological profile associated with these NEMO-ID variants is not fully documented. We present a 2-year-old patient with suspected immunodeficiency in which a hemizygous p.Glu57Lys IKBKG variant was identified. At the age of 1 year, he had an episode of otitis media that evolved into a bilateral mastoiditis (Pseudomonas spp). Hypogammaglobulinemia, specific (polysaccharide) antibody deficiency, and low switched memory B cell subsets were noticed. The mother was heterozygous for the variant but had no signs of incontinentia pigmenti. Patient peripheral blood mononuclear cells produced low amounts of IL-6 after stimulation with IL-1ß, Pam3CSK4, and FSL-1. In patient fibroblasts, IκB-α was degraded normally upon stimulation with IL-1ß or TNF-α. Transduction of wild-type and variant NEMO in NEMO-/- deficient SV40 fibroblasts revealed a slight but significant reduction of IL-6 production upon stimulation with IL-1ß and TNF-α. In conclusion, we demonstrated that p.Glu57Lys leads to specific immunological defects in vitro. No other pathogenic PID variants were identified through whole exome sequencing. As rare polymorphisms have been described in IKBKG and polygenic inheritance remains an option in the presented case, this study emphasizes the need for thorough functional and genetic evaluation when encountering and interpreting suspected disease-causing NEMO-ID variants.


Assuntos
Imunodeficiência de Variável Comum/genética , Displasia Ectodérmica/genética , Fibroblastos/fisiologia , Quinase I-kappa B/genética , Mutação/genética , Infecções por Pseudomonas/diagnóstico , Pseudomonas/fisiologia , Agamaglobulinemia , Células Cultivadas , Pré-Escolar , Imunodeficiência de Variável Comum/diagnóstico , Displasia Ectodérmica/diagnóstico , Hemizigoto , Humanos , Quinase I-kappa B/metabolismo , Interleucina-6/metabolismo , Masculino , Mastoidite , Otite , Polimorfismo Genético
16.
Curr Opin Allergy Clin Immunol ; 17(6): 421-430, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28938278

RESUMO

PURPOSE OF REVIEW: Next-generation sequencing, especially whole exome sequencing (WES), has revolutionized the molecular diagnosis of inborn errors of immunity. This review summarizes the generation and analysis of next-generation sequencing data. RECENT FINDINGS: The focus is on prioritizing strategies for unveiling the potential disease-causing variant. We also highlighted oversights and imperfections of WES and targeted panel sequencing, as well as the need for functional validation. SUMMARY: The information is crucial for a judicious use of WES by researchers, but even more so by the clinical immunologist.


Assuntos
Análise Mutacional de DNA/métodos , Exoma/genética , Imunidade/genética , Sequenciamento Completo do Exoma/métodos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Triagem Neonatal , Polimorfismo de Nucleotídeo Único
17.
Front Immunol ; 8: 546, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28553290

RESUMO

BACKGROUND: Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking. OBJECTIVE: To establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA. METHODS: One hundred healthy subjects (10-55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3-4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method. RESULTS: Applying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (≥11.2 U/ml) and fold increase (≥2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were ½ for anti-B and » for anti-A. CONCLUSION: We establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort.

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