Lung ultrasound features and relationships with respiratory mechanics of evolving BPD in preterm rabbits and human neonates

Evolving bronchopulmonary dysplasia (BPD) is characterized by impaired alveolarization leading to lung aeration inhomogeneities. Hyperoxia-exposed preterm rabbits have been proposed to mimic evolving BPD; therefore, we aimed to verify if this model has the same lung ultrasound and mechanical features of evolving BPD in human neonates. Semiquantitative lung ultrasound and lung mechanics measurement was performed in 25 preterm rabbits (28days of gestation) and 25 neonates (mean gestational age approximate to 26wk) with evolving BPD. A modified rabbit lung ultrasound score (rLUS) and a validated neonatal lung ultrasound score (WS) were used. Lung ultrasound images were recorded and evaluated by two independent observers blinded to each other's evaluation. Lung ultrasound findings were equally heterogeneous both in rabbits as in human neonates and encompassed all the classical lung ultrasound semiology. Lung ultrasound and histology examination were also performed in 13 term rabbits kept under normoxia as further control and showed the absence of ultrasound and histology abnormalities compared with hyperoxia-exposed preterm rabbits. The interrater absolute agreement for the evaluation of lung ultrasound images in rabbits was very high [ICC: 0.989 (95%Cl: 0.975-0.995); P < 0.0001], and there was no difference between the two observers. Lung mechanics parameters were similarly altered in both rabbits and human neonates. There were moderately significant correlations between airway resistances and lung ultrasound scores in rabbits (rho = 0.519; P = 0.008) and in neonates (rho = 0.409; P = 0.042). In conclusion, the preterm rabbit model fairly reproduces the lung ultrasound and mechanical characteristics of preterm neonates with evolving BPD.NEW & NOTEWORTHY We have reported that hyperoxia-exposed preterm rabbits and human preterm neonates with evolving BPD have the same lung ultrasound appearance, and that lung ultrasound can be fruitfully applied on this model with a brief training. The animal model and human neonates also presented the same relationship between semiquantitative ultrasound-assessed lung aeration and airway resistances. In conclusion, this animal model fairly reproduce evolving BPD as it is seen in clinical practice

Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases

The role of gammaherpesviruses in the development of autoimmunity

The development of autoimmune diseases is thought to involve both genetic and environmental factors. Epstein-Barr virus (EBV) has been associated with the development of both multiple sclerosis (MS) and systemic lupus erythematosus (SLE). My research projects aimed at identifying the mechanism that this virus is exploiting to cause autoimmunity. In the first project, the role of EBV infection of the blood brain barrier (BBB) as a trigger of MS was investigated. EBV was found to be able to infect human primary endothelial cells isolated from the BBB. EBV infected brain endothelial cells upregulated pro-inflammatory mediators and supported increased immune cell adhesion. These results suggest that EBV has the ability of increasing the BBB permeability. EBV latency and reactivation in endothelial cells could lead to initial inflammation and infiltration of the first wave of autoreactive immune cells during MS initiation. The second and third research project were aimed at developing a mouse model to study the interactions between latent gammaherpesvirus infection and the host’s immune system that may lead to autoimmunity. The role of murine gamma herpesvirus 68 (γHV-68), the murine equivalent to EBV, was analyzed in the experimental autoimmune encephalomyelitis (EAE) model, an experimentally induced model to study MS, and in the New Zealand Black and White (NZBW) model, a spontaneous SLE mouse model. Mice latently infected with γHV-68 developed more severe EAE that mirrored human MS more closely than EAE in uninfected mice. γHV-68 EAE mice developed lesions composed of CD4 and CD8 T cells, loss of myelin in the brain parenchyma and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression and decreased regulatory T cells frequencies. γHV-68 NZBW mice exhibited a similar Th1 skewed response and they produced different types of autoantibodies, if compared to uninfected NZBW mice. Clearly, gammaherpesvirus latency polarizes the adaptive immune response in both mouse models, directs a heightened brain pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat

Chapter 4 - Epstein-Barr Virus and Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that leads to myelin loss and progressive disability. The causes of MS are still unknown but the disease process is likely triggered by an environmental factor(s) in genetically susceptible individuals. Several different viruses have been identified as possible MS triggers but increasing evidence strongly associates Epstein-Barr virus (EBV) to MS. Epidemiological findings show that EBV infection, especially if accompanied by mononucleosis, greatly increases MS risk. Other relevant findings include the correlation between disease onset and the titer of anti-EBV antibodies in the serum. Dysregulated EBV specific T cells responses have been detected in MS, suggesting that MS patients might have a decreased ability to control EBV replication and there is also evidence of cross-reactivity between EBV antigens and myelin. The main site of EBV latency is the B cell compartment and B cell depletion therapies have been recently shown to strongly reduce disease activity in relapsing-remitting MS. Intriguingly EBV positive B cell follicles have been found in the brain of MS patients. Further, EBV has been shown to infect cell types other than B cells and these could play a role in MS pathogenesis. Despite all these findings, it is still unclear how EBV triggers MS. In this review we will summarize past literature and discuss possible mechanisms that EBV is exploiting to trigge

Epstein\u2013Barr virus and autoimmunity: the role of a latent viral infection in multiple sclerosis and systemic lupus erythematosus pathogenesis

Multiple sclerosis (MS) and systemic lupus erythematosus (SLE) are both chronic autoimmune diseases with unknown etiology. To date, EBV is the most closely implicated infectious agent to be associated with both MS and SLE. Epidemiological findings show a strong correlation between EBV infection and the risk of developing these diseases. The type and magnitude of both EBV-specific antibodies and T-cell responses produced by MS or SLE patients are dysregulated when compared with healthy cohorts. Despite all these findings, it is still not clear if and how EBV triggers autoimmunity. EBV infects and establishes latency mainly in B cells, but it can also infect other cell types and indirectly influence the activation status of the immune system by stimulating the production of proinflammatory mediators. This could play a role in both MS and SLE pathogenesis. In this review we will summarize recent literature that links EBV infection to SLE and MS, and discuss possible new mechanisms that explain how EBV drives autoimmunit

\u3b1v\u3b23 Integrin boosts the innate immune response elicited in epithelial cells through plasma membrane and endosomal Toll-like receptors

We report that \u3b1v\u3b23 integrin strongly affects the innate immune response in epithelial cells. \u3b1v\u3b23 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by \u3b1v\u3b23 integrin. The boosting was exerted specifically by \u3b1v\u3b23 integrin but not by \u3b1v\u3b26 or \u3b1v\u3b28 integrin. Current and previous work indicates that integrin- TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response

Epstein-Barr virus infection of human brain microvessel endothelial cells: A novel role in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory neurological disease that is widely regarded as the outcome of complex interactions between a genetic predisposition and an environmental trigger. Epstein-Barr virus (EBV) has recently been associated with the onset of MS, yet understanding how it elicits autoimmunity remains elusive. Neuroinflammation, including the entry of autoreactive T cells, likely follows a breach of the blood-brain barrier (BBB) leading to CNS lesions in MS. We show that EBV can infect human BBB cells leading to increased production of pro-inflammatory mediators that result in immune cell adherence thus modeling a key step in MS pathogenesi