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1.
Pediatr Int ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31465608

RESUMO

BACKGROUND: Interferon-γ (IFN-γ) and interleukin-12 (IL-12) play a crucial role in defense against mycobacteria including responses to Bacillus Calmette-Guérin (BCG) vaccinations. We have previously reported clinical and outcome data of 222 BCG osteitis cases diagnosed in 1960-1988 in Finland. The immunological and genetic reports have been based on 132 blood samples obtained in 2007-2008. METHODS: We compared IFNγ rs2430561 and rs35314021, IL12A rs568408 and rs2243115, and IL12B rs3212227 single nucleotide polymorphisms (SNPs) between 132 BCG osteitis patients and 99 population-based controls. In addition, stimulated productions of IFN-γ and IL-12 in cell cultures were evaluated in relation to the presence of IFNγ and IL12 wild versus variant genotypes, respectively. RESULTS: The distributions of IFNγ rs2430561, IFNγ rs35314021, IL12A rs568408, IL12A rs2243115 and IL12B rs3212227 SNPs did not differ between BCG osteitis patients and Finnish population-based controls. For the IFNγ rs2430561, IFNγ rs35314021 and IL12A rs2243115, the negative result was confirmed by comparing the minor allele frequencies (MAFs) in BCG osteitis cases with those in the publicly available genome aggregation database including data of 3472 Finnish persons. Instead, for the IL12A rs568408 and IL12B rs3212227, the comparisons of MAFs in BCG osteitis cases with those in population-based and in aggregation-based controls gave conflicting results. The presence of the wild versus variant genotype had no significant association with IL-12 or IFN-γ production in BCG-stimulated cell cultures. CONCLUSION: IFNγ gene polymorphisms did not show any association with BCG osteitis after newborn vaccination. This article is protected by copyright. All rights reserved.

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(5): 527, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31175480

RESUMO

The original version of this article unfortunately contained mistake in the following sentence in the Abstract.

4.
J Clin Immunol ; 39(4): 376-390, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31123910

RESUMO

Live-attenuated vaccines (LAVs) can protect humans against 12 viral and three bacterial diseases. By definition, any clinical infection caused by a LAV that is sufficiently severe to require medical intervention attests to an inherited or acquired immunodeficiency that must be diagnosed or identified. Self-healing infections can also result from milder forms of immunodeficiency. We review here the inherited forms of immunodeficiency underlying severe infections of LAVs. Inborn errors of immunity (IEIs) underlying bacille Calmette-Guérin (BCG), oral poliovirus (OPV), vaccine measles virus (vMeV), and oral rotavirus vaccine (ORV) disease have been described from 1951, 1963, 1966, and 2009 onward, respectively. For each of these four LAVs, the underlying IEIs show immunological homogeneity despite genetic heterogeneity. Specifically, BCG disease is due to inborn errors of IFN-γ immunity, OPV disease to inborn errors of B cell immunity, vMeV disease to inborn errors of IFN-α/ß and IFN-λ immunity, and ORV disease to adaptive immunity. Severe reactions to the other 11 LAVs have been described yet remain "idiopathic," in the absence of known underlying inherited or acquired immunodeficiencies, and are warranted to be the focus of research efforts. The study of IEIs underlying life-threatening LAV infections is clinically important for the affected patients and their families, as well as immunologically, for the study of the molecular and cellular basis of host defense against both attenuated and parental pathogens.

6.
Sci Rep ; 7(1): 11691, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28916742

RESUMO

Bacillus Calmette-Guerin (BCG) osteitis was more common in Finland than elsewhere at the time when universal BCG vaccinations were given to Finnish newborns. There is evidence that IL-17 plays a role in the defense against tuberculosis. The aim of this study was to evaluate the associations of IL17A rs4711998, IL17A rs8193036 and IL17A rs2275913 single-nucleotide polymorphisms (SNPs) with the risk of BCG osteitis after newborn vaccination. IL17A rs4711998, rs8193036 and rs2275913 SNPs were determined in 131 adults had presented with BCG osteitis after newborn BCG vaccination. We analyzed, using the HaploView and PLINK programs, whether allele or haplotype frequencies of these SNPs differ between the former BCG osteitis patients and Finnish population controls. Of the three IL17A SNPs studied, rs4711998 associated nominally with BCG osteitis; minor allele frequency was 0.215 in 130 BCG osteitis cases and 0.298 in 99 controls (p = 0.034). Frequency of the second common haplotype (GTA) differed significantly between BCG osteitis cases and controls (0.296 vs. 0.184, p = 0.040 after multi-testing correction). The GTA haplotype of the IL17A SNPs rs4711998, rs8193036 and rs2275913 was associated with osteitis after BCG vaccination.

7.
Acta Paediatr ; 106(11): 1837-1841, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28731539

RESUMO

AIM: Interleukin-17 (IL-17) appears to promote the host's defence against mycobacterial infections. This study evaluated the association between IL17A gene polymorphism and the risk of Bacillus Calmette-Guérin (BCG) osteitis after newborn vaccination and between IL17A gene polymorphism and IL-17A concentrations in serum. METHODS: IL17A rs2275913 gene polymorphisms and serum IL-17A concentrations were studied in 132 adults aged 21-49 years from across Finland, who had BCG osteitis in infancy after a newborn BCG vaccination. The subjects were recruited in 2007-2008, and their whole-blood samples were sent to the National Institute for Health and Welfare, Turku, Finland. Their genotypes and minor allele frequencies were compared with 405 population-based unvaccinated controls aged two to three months from a prospective birth cohort study. RESULTS: The genotypes and allele frequencies of IL17A rs2275913 differed significantly between the former BCG osteitis patients and controls. The genotype was variant in 75.8% of cases and 64.0% of controls (p = 0.012), and the minor allele frequency was 50.0% in the cases and 41.6% of the controls (p = 0.009). Serum IL-17 concentrations did not differ significantly between the cases with wild or variant genotypes. CONCLUSION: IL17A rs2275913 gene polymorphism was associated with a risk of BCG osteitis after vaccination.


Assuntos
Vacina BCG/efeitos adversos , Interleucina-17/genética , Osteíte/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Interleucina-17/sangue , Masculino , Pessoa de Meia-Idade , Osteíte/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Adulto Jovem
8.
Pediatr Infect Dis J ; 36(2): 135-139, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27755461

RESUMO

BACKGROUND: Interferon-gamma (IFN-γ) is a key cytokine in defense against mycobacteria, including Bacillus Calmette-Guérin (BCG). Mannose-binding lectin (MBL) and toll-like receptors (TLRs) are pattern-recognizing molecules of innate immunity. The aim of the present study was to investigate the relationship between polymorphisms in MBL, TLR1, TLR2 and TLR6 encoding genes and stimulated IFN-γ and interleukin-12 (IL-12) ex vivo production in BCG osteitis survivors. METHODS: Data on single nucleotide polymorphisms in the MBL2 gene and TLR1, TLR2 and TLR6 genes were available from 132 former BCG osteitis patients, and data on ex vivo IFN-γ and IL-12 production were available from 115 and 118 patients, respectively. The present study is a secondary analysis of these available data. In an earlier study, we were able to characterize low IFN-γ and low IL-12 producers after BCG+IL-12 or BCG+IFN-γ stimulations, respectively. RESULTS: Three patients had the homozygous variant MBL2 genotype, and one of them was a low IFN-γ producer (both concentration and response <5th percentile). The heterozygous variant MBL2 genotype showed no association with IFN-γ or IL-12 production. The TLR2 variant genotype was present in 14 subjects; 28.6% of them were low IFN-γ producers versus 7.8% of those 103 with the TLR2 wild genotype (P = 0.037). TLR1 or TLR6 polymorphisms had no significant associations with stimulated ex vivo IFN-γ or IL-12 production. CONCLUSIONS: Preliminary evidence was found that variant genotypes of the MBL2 gene (if homozygous) and variant genotypes of the TLR2 gene (only heterozygotes present) are associated with low IFN-γ production.


Assuntos
Vacina BCG/efeitos adversos , Doenças Ósseas Infecciosas/genética , Interferon gama/sangue , Interleucina-12/sangue , Lectina de Ligação a Manose/genética , Osteíte/genética , Receptores Toll-Like/genética , Adulto , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium bovis , Polimorfismo de Nucleotídeo Único/genética , Tuberculose/genética , Adulto Jovem
9.
Pediatr Infect Dis J ; 35(6): 690-4, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26954602

RESUMO

BACKGROUND: Inborn errors of interferon-gamma (IFN-γ)-mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-γ immunity. Our aim was to investigate interleukin (IL)-12 and IFN-γ ex vivo production stimulated with BCG and BCG + IFN-γ or BCG + IL-12, respectively, in BCG osteitis survivors. METHODS: Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-γ were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-γ or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-γ immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole exome sequencing. RESULTS: By the limit of <5th percentile, ex vivo IL-12 concentration and increase in concentration was low in 5 and ex vivo IFN-γ concentration and increase in concentration was low in 6 patients (including 2 samples with both IL-12 and IFN-γ findings). By the limit of <10th percentile, an additional 6 and 4 patients were, respectively, detected (including 2 samples with both findings). With 2 exceptions, low concentrations and low increases in concentrations picked-up the same cases. Mutations in known disease-causing IFN-γ-related genes were not found in any of these patients. CONCLUSION: These findings call for searching of mutations in new genes governing IFN-γ-dependent immunity to live BCG vaccine.


Assuntos
Vacina BCG/efeitos adversos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Leucócitos Mononucleares/imunologia , Mycobacterium bovis/imunologia , Osteíte/induzido quimicamente , Osteíte/imunologia , Adulto , Vacina BCG/administração & dosagem , Feminino , Finlândia , Humanos , Fatores Imunológicos/genética , Masculino , Pessoa de Meia-Idade , Sobreviventes , Adulto Jovem
11.
Acta Paediatr ; 104(5): 485-90, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25605403

RESUMO

AIM: Toll-like receptor (TLR) 1, 2, 6 and 10, the TLR2 subfamily, are known to be associated with immunity against tuberculosis. We evaluated whether polymorphisms in genes encoding TLR1, TLR2 and TLR6 were associated with osteitis in infants who received the Bacillus Calmette-Guérin (BCG) vaccination soon after birth. METHODS: Blood samples from 132 adults aged 21-49 who had BCG osteitis in early childhood were analysed in a controlled study for TLR1 T1805G (rs5743618), TLR2 G2258A (rs5743708) and TLR6 C745T (rs5743810) gene single nucleotide polymorphisms. RESULTS: The frequencies of the variant genotypes differed between the cases and controls: 11.4% versus 5.7% for TLR2 G2258A (p = 0.033) and 77.3% versus 61.6% for TLR6 C745T (p = 0.001). The TLR2 and TLR6 variant genotypes were associated with a higher risk of BCG osteitis, with adjusted odds ratios (aOR) of 2.154 (95%CI 1.026-4.521) and 1.907 (95%CI 1.183-3.075), respectively. The frequency of the TLR1 T1805G variant genotype was 19.7% in the cases and 33.6% in the controls (p = 0.003). The TLR1 variant genotype was associated with a lower risk of BCG osteitis (aOR 0.554, 95%CI 0.336-0.911). CONCLUSION: Gene polymorphisms that regulate the function of the TLR2 subfamily play a role in the development of BCG osteitis in vaccinated infants.


Assuntos
Vacina BCG/efeitos adversos , Osteíte/etiologia , Receptor 1 Toll-Like/genética , Receptor 2 Toll-Like/genética , Receptor 6 Toll-Like/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
12.
Acta Paediatr ; 102(11): 1095-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23865867

RESUMO

AIM: The aim of this study was to evaluate whether mannose-binding lectin (MBL) plays a role in the development of osteitis after Bacillus Calmette-Guerin (BCG) vaccination as a newborn. METHODS: Blood samples were obtained from 132 former BCG osteitis patients, now aged 21-49 years, and analysed for MBL concentration and MBL2 genotype in a controlled setting. RESULTS: Variant genotypes in the MBL2 gene were more common in the former BCG osteitis patients (42.4%) than in the population controls (32.3%, p = 0.033). However, MBL concentrations at the age of 21-49 years were not lower in these patients than in the controls in the same age group. The variant MBL2 genotypes were associated with low serum MBL concentrations, and moreover, MBL concentration was not measurable in two of those three patients who were homozygous for the variant MBL2 genotype. Low serum MBL concentrations were not associated with any illnesses in the medical history of the BCG patients, their siblings or children. CONCLUSION: Preliminary evidence was found that variant, low-MBL-producing genotypes may be associated with the increased risk of BCG osteitis in vaccinated newborns.


Assuntos
Vacina BCG/efeitos adversos , Lectina de Ligação a Manose/genética , Osteíte/etiologia , Adulto , Estudos de Casos e Controles , Seguimentos , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Recém-Nascido , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Adulto Jovem
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