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    • There remains scope for immune and genetic hypotheses to

    2018-11-07

    There remains scope for immune and genetic hypotheses to inform our understanding of GWI and similar syndromes. One order salvinorin a has been that a stress-induced modulation of circulating pro-inflammatory factors may have primed soldiers to have an exaggerated response to insults, be they chemical exposure, vaccination post-deployment or other medication, thus precipitating GWI. Recent reports include that of greater cytokine variability in veterans with GWI compared to controls (), and of a mouse model of increased corticosterone (consistent with a physiological stress state) priming a pro-inflammatory response to a substance analogous to some of the postulated exposures in GWI (). Such findings are not specific to GWI, but if replicated they do at least offer the possibility of new hope and treatments. We note that recruitment is underway in Minnesota for a trial of prednisone, a steroid with anti-inflammatory properties, in GWI. To date, large-scale replication of immunological mechanisms in the etiology of GWI has remained elusive and the heterogeneity of exposures (e.g. vaccinations) across different armies remains a challenge to rigorously testing this hypothesis.
    Rubella virus (RV) is responsible for benign postnatal and deadly antenatal infections. Its involvement in developmental defects in children following congenital transmission was first made by Sir Norman McAlister Gregg in 1941. Indeed, the maternal primary infection results in an RV viremia and placental transfer. If it occurs before 12weeks of gestation, during organogenesis, it can result in severe fetal damage causing miscarriage or malformations primarily affecting the cardiovascular system, eyes, ears and the central nervous system; it is fatal in nearly one third of cases during the first year of life (). This severe RV infection acquired in utero early in pregnancy is named as Congenital Rubella Syndrome or CRS. In 2014, 141 CRS cases were reported from 114 countries mostly from South-East Asia (n=86/141), although reporting is probably inconsistent according to the authors themselves (). This number had been estimated as closer to 100,000 cases each year in developing countries alone (). To better understand the pathogenesis of CRS in the absence of an animal model, the first histopathological explorations were conducted in some of the 20,000 fetuses infected during the 1964–1965 epidemics in the US when about 12.5 M Rubella cases were reported (). Although these studies identified histological lesions in the heart, blood vessels, crystalline lens, ears, brain, teeth and liver consistent with clinical features and sequelae of CRS, they did not solved the mechanisms of virus teratogenicity (). In particular, until recently, the exact nature of the cell types infected with RV remained unknown. The objective of the study by Lazar and colleagues was therefore to identify, through immunohistochemical staining of viral antigens, infected cells in tissues from CRS cases to better understand the molecular details of the CRS pathogenesis (). The authors relied on the exploration of three fatal cases of CRS in term and close to term babies diagnosed during the outbreak in Romania in 2011–2012. This report provided at least two principle findings, which contribute significantly to our understanding of the CRS pathophysiology. The first was the detection of RV antigens in fibroblasts in the myocardium of 2 patients without detection of histological signs of myocarditis or viral antigens in cardiac myocytes. Infection restricted to cardiac fibroblasts, associated with the detection of viral antigens in adventitial fibroblasts of large blood vessels, raises the question of the mechanism by which congenital cardiovascular malformations (patent ductus arteriosus and branch pulmonary artery stenosis) arise in CRS patients. This suggests that RV positive myocardial cells assessed in two previous studies could be transiently infected cells during the acute phase of the disease and not persistently infected cells linked with congenital malformations observed in the CRS (). This also excludes a priori cytolytic injury of cardiac myocytes and more likely suggests a disturbance of the normal development of the cardiovascular system through cardiac fibroblasts infection, which form structural scaffolding for the attachment of cardiac cell types during development, express growth factors and cytokines and regulate proliferation of embryonic cardiomyocytes (). The second main finding identified viral antigens in the progenitor cell of granular layer in the brain. If lesions of the granular layer had already been reported, the description of RV progenitor cells infection is a novelty that could connect mental retardation and microcephaly observed in the CRS to the involvement of multipotent neural stem cells that give rise to precursors of many neuronal or glial lineages involved in the normal CNS development. These results shed new light on the possible pathophysiology of neurological impairment observed in the CRS since the only mechanism described so far was the in vitro infection of astrocytes that can lead in vivo to an alteration of the normal brain functioning resulting in neurological deficit ().