Monday, August 04, 2008

Humans are tougher than mice

Animal models continue to influence our understanding of immunity to infection, but how accurately do they predict how our own immune systems respond to different pathogens? Von Bernuth et al. (p. 691) continue a series of studies in which they use rare human immune deficiencies to help unpick the roles played by distinct innate immune pathways. The study focuses on MyD88, a signaling adaptor that is crucial in mice for protection against a wide range of pathogens by connecting key Toll-like receptor (TLR) and interleukin-1 (IL-1) pathways to the activation of immune response genes. In contrast to findings in mice, deficiency of the same protein in the human patients caused susceptibility to only a handful of pyogenic bacteria, despite leaving the subjects with broad deficits in their TLR and IL-1 responses.


Abstract follows:

Pyogenic Bacterial Infections in Humans with MyD88 Deficiency

By Horst von Bernuth et al.

MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

Science 1 August 2008: Vol. 321. no. 5889, pp. 691 - 696

Hormone hope in schizophrenia fight

The "female" hormone estrogen promises new hope to both men and women who suffer from the debilitating symptoms of schizophrenia. Sydney researchers are about to begin a trial of the hormone on people with the mental illness, following a discovery of a genetic glitch that impedes estrogen from doing its job in the brain. The finding comes from an international team led by neurobiologist Cyndi Shannon Weickert, head of a project initiated by the University of NSW, the Prince of Wales Medical Research Institute and the Schizophrenia Research Institute.

Professor Shannon Weickert's team discovered that mutations in the estrogen receptor alpha (ESR1) gene disrupt a cascade of biochemical events in the brains of people with schizophrenia. The result is that estrogen is less able to moderate emotions and thinking. The report -- published recently in the journal Human Molecular Genetics -- "confirms" that estrogen is an important target for drug therapy, said Melbourne University psychiatrist Michael Berk, also with Barwon Health, The Geelong Clinic and the Orygen Research Centre.

Just over 1 per cent of people worldwide suffer the hallucinations, delusions and disordered thinking of the developmental brain disorder. They also may experience "negative" symptoms such as depression, loss of motivation and social avoidance. While anti-psychotic drugs such as chlorpromazine manage "positive" symptoms such as hallucination, they do little for the negative ones.

Monash University psychiatrist Jayashri Kulkarni who is currently heading a three-centre trial of the hormone, involving Professor Berk, said: "The evidence is very clear that estrogen protects the brain from symptoms of psychosis."


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