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N. meningitidis and TLR Polymorphisms: A Fascinating Immunomodulatory Network.

ABSTRACT: N. meningitidis infections represent a global health problem that can lead to the development of serious permanent sequelae. Although the use of antibiotics and prevention via vaccination have reduced the incidence of meningococcal disease, our understanding regarding N. meningitidis pathogenesis is still limited, especially of those mechanisms responsible for IMD and fulminant or deadly septic shock. These severe clinical presentations occur in a limited number of subjects, whereas about 10% of healthy individuals are estimated to carry the bacteria as a commensal. Since TLR activation is involved in the defense against N. meningitidis, several studies have highlighted the association between host TLR SNPs and a higher susceptibility and severity of N. meningitidis infections. Moreover, TLR SNPs induced variations in immunological responses and in their persistence upon vaccination against meningococcal disease. In the absence of mass vaccination programs, the early identification of risk factors for meningococcal disease would be recommended in order to start immunization strategies and antibiotic treatment in those subjects carrying the risk variants. In addition, it could allow us to identify individuals with a higher risk for severe disease and sequelae in order to develop a personalized healthcare of high-risk subjects based on their genomic profile. In this review, we have illustrated important preliminary correlations between TLR variants and meningococcal susceptibility/severity and with vaccine-induced immune responses.

SUBMITTER: Gianchecchi E

PROVIDER: S-EPMC4931637 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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N. meningitidis and TLR Polymorphisms: A Fascinating Immunomodulatory Network.

Gianchecchi Elena E Torelli Alessandro A Piccini Giulia G Piccirella Simona S Montomoli Emanuele E

Vaccines 20160527 2

N. meningitidis infections represent a global health problem that can lead to the development of serious permanent sequelae. Although the use of antibiotics and prevention via vaccination have reduced the incidence of meningococcal disease, our understanding regarding N. meningitidis pathogenesis is still limited, especially of those mechanisms responsible for IMD and fulminant or deadly septic shock. These severe clinical presentations occur in a limited number of subjects, whereas about 10% of ...[more]

PMID: 27240411

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Project description:ObjectiveChronic periaortitis (CP) is a rare disease that is characterised by fibro-inflammatory tissue surrounding the abdominal aorta and has both non-aneurysmal (idiopathic retroperitoneal fibrosis [IRF]) and aneurysmal forms (inflammatory abdominal aortic aneurysm [IAAA]). We investigated whether toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) polymorphisms were associated with susceptibility to, and the clinical features of CP.MethodsOne hundred and two CP patients and 200 healthy controls were molecularly genotyped for TLR-4 gene polymorphism (+896 A/G) (rs4986790), VEGF mutations +936 C/T (rs3025039) and -634 C/G (rs2010963), and an 18 base pair (bp) insertion/deletion (I/D) polymorphism at -2549 of the VEGF promoter region. The patients were grouped on the basis of the type of CP (IRF or IAAA), and the presence or absence of established atherosclerotic disease (ischemic heart disease, cerebrovascular disease, and peripheral arterial disease).ResultsThere were no significant differences in the distribution of the studied polymorphisms between the patients and controls. However, carriage of the +936 T allele was significantly more frequent in the patients with IRF than in those with IAAA (26.5% vs 5.3%; p = 0.046; OR 6.49 [95% CI 0.82-51.54]). There were significantly more carriers of the I allele among the patients with ureteral obstruction (83.8% vs 58.8%; p = 0.006; OR 3.63 [95% CI 1.42-9.28]) and those who received conservative treatment (48.5% vs 23.5%; p = 0.015; OR 3.06 [95% CI 1.22-7.721]) than among those without, and II homozygosity was significantly more frequent in the patients with deep vein thrombosis than in those without (30.4% vs 11.7%, p = 0.031; OR 3.31 [95% CI 1.07-10.21]).ConclusionThe VEGF +936 C/T polymorphism may be associated with an increased risk of developing the non-aneurysmal IRF form of CP. Carriers of the I allele and II homozygosity are respectively at increased risk of developing ureteral obstruction and deep vein thrombosis.

Project description:Recently, it has been observed that mesenchymal stem cells (MSCs) can modulate their immunoregulatory properties depending on the specific in-vitro activation of different Toll-like receptors (TLR), such as TLR3 and TLR4. In the present study, we evaluated the effect of polyinosinic:polycytidylic acid (poly(I:C)) and lipopolysaccharide (LPS) pretreatment on the immunological capacity of MSCs in vitro and in vivo.C57BL/6 bone marrow-derived MSCs were pretreated with poly(I:C) and LPS for 1 hour and their immunomodulatory capacity was evaluated. T-cell proliferation and their effect on Th1, Th17, and Treg differentiation/activation were measured. Next, we evaluated the therapeutic effect of MSCs in an experimental autoimmune encephalomyelitis (EAE) model, which was induced for 27 days with MOG35-55 peptide following the standard protocol. Mice were subjected to a single intraperitoneal injection (2?×?106 MSCs/100 ?l) on day 4. Clinical score and body weight were monitored daily by blinded analysis. At day 27, mice were euthanized and draining lymph nodes were extracted for Th1, Th17, and Treg detection by flow cytometry.Pretreatment of MSCs with poly(I:C) significantly reduced the proliferation of CD3+ T cells as well as nitric oxide secretion, an important immunosuppressive factor. Furthermore, MSCs treated with poly(I:C) reduced the differentiation/activation of proinflammatory lymphocytes, Th1 and Th17. In contrast, MSCs pretreated with LPS increased CD3+ T-cell proliferation, and induced Th1 and Th17 cells, as well as the levels of proinflammatory cytokine IL-6. Finally, we observed that intraperitoneal administration of MSCs pretreated with poly(I:C) significantly reduced the severity of EAE as well as the percentages of Th1 and Th17 proinflammatory subsets, while the pretreatment of MSCs with LPS completely reversed the therapeutic immunosuppressive effect of MSCs.Taken together, these data show that pretreatment of MSCs with poly(I:C) improved their immunosuppressive abilities. This may provide an opportunity to better define strategies for cell-based therapies to autoimmune diseases.

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N. meningitidis and TLR Polymorphisms: A Fascinating Immunomodulatory Network.

Publications

N. meningitidis and TLR Polymorphisms: A Fascinating Immunomodulatory Network.

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