Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Among the exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgs in vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such as d-galactosamine (d-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS without d-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4+ and CD8+), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in the d-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with TSS

Vitamin D, Cognitive Dysfunction and Dementia in Older Adults

The physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3, is a fat-soluble steroid hormone with a well established role in skeletal health. A growing body of evidence suggests that low vitamin D levels also play a role in the pathogenesis of a wide range of non-skeletal age-associated diseases such as cancer, heart disease, type 2 diabetes and stroke. Low serum 25-hydroxyvitamin D (25(OH)D) levels, a stable marker of vitamin D status, are also associated with increased odds of prevalent cognitive dysfunction, Alzheimer’s and all-cause dementia in a number of studies, raising the possibility that vitamin D plays a role in the aetiology of cognitive dysfunction and dementia. So far the majority of human studies reporting associations between vitamin D and cognition or dementia have been cross-sectional or case-control designs that are unable to exclude the possibility that such associations are a result of disease progression rather than being causal. Animal and in-vitro experiments have identified a number of neuroprotective mechanisms that might link vitamin D status to cognitive dysfunction and dementia including vasoprotection and amyloid phagocytosis and clearance, but the clinical relevance of these mechanisms in humans is not currently clear. Two recent large prospective studies go some way to establish the temporal relationship with cognitive decline. The relative risk of cognitive decline was 60% higher (relative risk 1.60, 95% CI 1.2-2.0) in elderly Italian adults who are severely deficient (<25 nmol/L) when compared them with those sufficient (>75 nmol/L). Similarly the odds of cognitive decline were 41% higher (odds ratio 1.41, 95% CI 0.9-2.2) when elderly US men in the lowest quartile (<50 nmol/L) were compared with those in the highest quartile (>74 nmol/L). To our knowledge no prospective studies have examined the association between 25(OH)D levels and incident dementia or neuroimaging abnormalities. The possible therapeutic benefits of vitamin D have attracted considerable interest as over 1 billion people worldwide are thought to have insufficient 25(OH)D levels, which can be increased using inexpensive well-tolerated dietary supplements. However, no large randomized controlled trials have yet examined the effect of vitamin D supplements upon cognitive decline or incident dementia. Further studies are urgently needed to establish which mechanisms may have clinical relevance in human populations and whether vitamin D supplements are effective at minimizing cognitive decline or preventing dementia