Laura Pöyhönen

Toll-like receptor 2 subfamily gene polymorphisms are associated with Bacillus Calmette-Guerin osteitis following newborn vaccination

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.

Interferon-gamma-dependent Immunity in Bacillus Calmette-Guerin Vaccine Osteitis Survivors

Background: Inborn errors of interferon-gamma (IFN-&ggr;)-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-&ggr; immunity. Our aim was to investigate interleukin (IL)-12 and IFN-&ggr; ex vivo production stimulated with BCG and BCG + IFN-&ggr; 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-&ggr; were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-&ggr; or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-&ggr; 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-&ggr; concentration and increase in concentration was low in 6 patients (including 2 samples with both IL-12 and IFN-&ggr; 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-&ggr;-related genes were not found in any of these patients. Conclusion: These findings call for searching of mutations in new genes governing IFN-&ggr;-dependent immunity to live BCG vaccine.

Interleukin-10 gene promoter region polymorphisms are not associated with BCG osteitis in vaccinated infants.

SETTING Complications arising from bacille Calmette-Guérin (BCG) vaccination were recorded in a national register in Finland until 1988. In the period 1960-1988, 222 patients suffered from BCG osteitis. OBJECTIVE To evaluate whether single nucleotide polymorphisms (SNPs) in the promoter region of the gene encoding interleukin 10 (IL-10) are associated with BCG osteitis after vaccination in neonates. DESIGN Blood samples of 132 former BCG osteitis patients now aged 21-49 years were analysed in a controlled study for IL10 rs1800896 (-1082G/A), rs1800871 (-819C/T), rs1800872 (-592C/A) and rs1800890 (-3575T/A) polymorphisms. RESULTS The frequencies of genotypes of IL10 rs1800896, rs1800871, rs1800872 and rs1800890, the frequencies of variant genotypes and the frequencies of major or minor alleles did not differ between patients and controls. Furthermore, the frequencies of the eight possible combinations of the three IL10 alleles located close to each other (IL10 rs1800896, IL10 rs1800871 and IL10 rs1800872) were surprisingly similar. CONCLUSION Our results suggest that polymorphisms of the IL-10 encoding gene do not play a central role in the development of complications due to BCG vaccination, although the IL10 gene, especially IL10 rs1800896 (-1082G/A) polymorphism, is known to be associated with tuberculosis risk in Europeans and North Americans.

Variant MBL2 genotypes producing low mannose-binding lectin may increase risk of Bacillus Calmette–Guerin osteitis in vaccinated newborns

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.

Haplotype of the Interleukin 17A gene is associated with osteitis after Bacillus Calmette-Guerin vaccination

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.

Association of mbl2 , tlr1 , tlr2 and tlr6 Polymorphisms With Production of Ifn-γ and Il-12 in Bcg Osteitis Survivors R1

Background: Interferon-gamma (IFN-&ggr;) 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-&ggr; 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-&ggr; 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-&ggr; and low IL-12 producers after BCG+IL-12 or BCG+IFN-&ggr; stimulations, respectively. Results: Three patients had the homozygous variant MBL2 genotype, and one of them was a low IFN-&ggr; producer (both concentration and response <5th percentile). The heterozygous variant MBL2 genotype showed no association with IFN-&ggr; or IL-12 production. The TLR2 variant genotype was present in 14 subjects; 28.6% of them were low IFN-&ggr; 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-&ggr; 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-&ggr; production.

Interleukin 17A gene polymorphism rs2275913 is associated with osteitis after the Bacillus Calmette-Guérin vaccination

Interleukin‐17 (IL‐17) appears to promote the hosts 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.

Orthopedic Complications in Former Bacillus Calmette-Guérin Osteitis Patients.

In 160 Finnish former Bacillus Calmette-Guérin osteitis patients, a questionnaire revealed that later in life, 22 (13.8%) had mild orthopedic complications as a consequence of the infection.

Toll-like receptor 1, 2 and 6 polymorphisms: no association with 11 serum cytokine concentrations

Finnish newborns were vaccinated with Bacillus Callmette-Guerin (BCG) vaccine from 1940s until 2006. The diagnostics of severe complications after vaccination was centralised until 1988, and 222 children presented with BCG osteitis from 1960 to 1988 (1). Pattern-recognition receptors (PRR), such as toll-like receptors (TLR), recognise surface structures of pathogens and initiate inflammatory and immune responses in the host (2) Cytokines, such as tumor necrosis factor (TNF), interferons (IFN) and interleukins (IL) are important mediators in these responses. TLR1 and TLR6 work as co-receptors to TLR2, and the group is called the TLR2 subfamily (2). This article is protected by copyright. All rights reserved.