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(Anatomy) (Health) Fever: Immune System “Thermostat”

 
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adedios
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PostPosted: Fri Aug 18, 2006 7:35 am    Post subject: (Anatomy) (Health) Fever: Immune System “Thermostat” Reply with quote






Research Reveals Inner Workings of Immune System “Thermostat”

Brown University
16 August 2006

The immune system runs hot, sending out inflammatory infection-fighting proteins, then cools down by releasing anti-inflammatory soothers. A Brown University-led research team explains how this “thermostat” works in the Journal of Immunology.

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PROVIDENCE, R.I. — When bacteria, viruses or parasites attack, immune system cells unleash the soldiers. These “hot” protein compounds kill invaders – but also trigger inflammation, which, if unchecked, can destroy tissue, induce shock and kill the host. So immune system cells let loose another protein compound to cool down the immune response.

Precisely how this immune system “thermostat” operates is unclear. The leading hypothesis is that these compounds – which act as furnace and air conditioner – battle it out over control of the system’s inflammatory response.

But new research, led by George Yap of Brown University, shows that these cytokines don’t operate independently and in opposition. They operate in harmony and are controlled by the same master. In work published in the Journal of Immunology, Yap and his team show that the “cool” anti-inflammatory protein compound known as Interleukin 10 is activated by Interferon-γ, a class of proteins secreted by a class of white blood cells known as T helper 1 cells. The team then traced secretion of Interferon-γ indirectly to tyrosine kinase 2, or tyk2, the same protein that signals “hot” inflammatory cytokines Interleukin 12 and Interferon-α and Interferon-β.

“Under the prevailing paradigm, scientists believe that the pro- and anti-inflammatory arms of the immune system just antagonize each other,” Yap said. “Here we show that they actually induce each other. ‘Hot’ cytokines don’t inhibit ‘cool’ ones – they trigger their production. Wounding, in effect, triggers a healing process.”

In previous research, Yap discovered that mutant mice with a naturally defective tyk2 gene were immune to arthritis, a condition caused by inflammation. But these mutants were much more susceptible to opportunistic infections. Why? Without tyk2, Yap found, mice didn’t make enough of the pro-inflammatory warriors that destroy harmful bugs and cause inflammation. This finding established the notion that tyk2 signaling controlled Interleukin 12, the furnace side of the system. But what controlled Interleukin 10, the air conditioner?

To find out, Yap and his team conducted a series of experiments in mutant mice infected with the parasite Toxoplasma gondii. They found that Interleukin 10 production by T helper 1 cells is triggered by Interferon-γbut not directly. Another cell, an antigen presenting cell or APC, sends a stimulatory signal back to the T helper 1 cell, ordering it to make Interleukin 10.

“What we see is that the ‘hot’ and ‘cool’ arms of the immune system aren’t independently regulated,” Yap said. “They talk to each other and respond in a dynamic and coordinated fashion.”

Yap said the findings should send a message to drug companies designing and testing tyk2-inhibiting medicines for arthritis and other autoimmune diseases. Block tyk2 function, Yap said, and patients will be more prone to infection – and their arthritis may not be relieved. “There could be a downside to these drugs,” he said.

Brown graduate student Michael Shaw and Brown Medical School student Mark Scott contributed to the research. Gordon Freeman of the Dana-Farber Cancer Institute, Barbara Fox and David Bzik of Dartmouth Medical School and Yasmine Belkaid of the National Institute of Allergy and Infectious Disease served as collaborators.

The National Institute of Allergy and Infectious Diseases funded the research.

*************************************************************

Questions to explore further this topic:

The Immune System

http://www.paete.org/forums/viewtopic.php?t=1121

What is the normal body temperature?


http://www.webmd.com/hw/health.....198785.asp
http://hypertextbook.com/facts/LenaWong.shtml

How is the body temperature measured?

http://www.nlm.nih.gov/medline.....003400.htm

What is thermoregulation?

http://en.wikipedia.org/wiki/Thermoregulation
http://www.rwc.uc.edu/koehler/biophys/8d.html

What is fever?

http://www.kidshealth.org/pare.....fever.html
http://www.cancerhelp.org.uk/h.....page=12850
http://www.nlm.nih.gov/medline.....003090.htm
http://www.bbc.co.uk/health/co.....ver1.shtml
http://hcd2.bupa.co.uk/fact_sheets/html/fever.html

How does the body cool?

http://hyperphysics.phy-astr.g.....oobod.html

What is inflammation?

http://www.clevelandclinic.org.....index=4857
http://en.wikipedia.org/wiki/Inflammation

What is Wilson's Temperature Syndrome?

http://www.wilsonssyndrome.com.....ndrome.htm

What is hypothermia?

http://www.mayoclinic.com/heal.....ia/DS00333

What is hyperthermia?

http://en.wikipedia.org/wiki/Hyperthermia

What are analgesics?

http://en.wikipedia.org/wiki/Analgesic

What are antipyretics?

http://en.wikipedia.org/wiki/Antipyretic
http://en.wikipedia.org/wiki/Analgesic

GAMES

http://faculty.washington.edu/chudler/experi.html


Last edited by adedios on Sat Jan 27, 2007 4:34 pm; edited 2 times in total
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PostPosted: Thu Nov 02, 2006 9:10 pm    Post subject: Reduced body temperature extends lifespan Reply with quote

Scripps Research Institute
2 November 2006

Reduced body temperature extends lifespan in study from the Scripps Research Institute

Lifespan lengthened without dietary restriction
"Our study shows it is possible to increase lifespan in mice by modest but prolonged lowering of core body temperature," said Bruno Conti, an associate professor at Scripps Research who led the study. "This longer lifespan was attained independent of calorie restriction."

Prior to this study, researchers had known that core body temperature and aging were related in cold-blooded animals. Scientists had also known that lifespan could be extended in warm-blooded animals by reducing the number of calories they consumed, which also lowered core body temperature. But the degree of calorie restriction needed to extend lifespan is not easy to achieve, even in mice.

Prior to the current study, critical questions about the relation between calorie restriction, core body temperature, and lifespan remained unanswered. Was calorie restriction itself responsible for longer lifespan, with reduced body temperature simply a consequence? Or was the reduction of core body temperature a key contributor to the beneficial effects of calorie restriction? Conti and colleagues wanted to find out.

To tackle the problem, the scientists decided to try to lower core body temperature directly, without restricting food intake. In cold-blooded animals, such as roundworms (C. elegans) and fruitflies (Drosophila), this task is straight-forward--core body temperature can be lowered simply by changing the temperature of the environment. But for warm-blooded animals, the task is much more challenging.

Conti and colleagues decided to focus their efforts on the preoptic area of the hypothalamus, a structure in the brain that acts as the body's thermostat and is crucial to temperature regulation. Just as holding something warm near the thermostat in a room can fool it into thinking that the entire room is hotter so that the air conditioning turns on, the Scripps Research team reasoned that they could reset the brain's thermostat by producing heat nearby.

To do so, they created a mouse model that produced large quantities of uncoupling protein 2 in hypocretin neurons in the lateral hypothalamus, which is near the preoptic area. The action of uncoupling protein 2 produced heat, which diffused to other brain structures, including the preoptic area. And, indeed, the extra heat worked to induce a continuous reduction of the core body temperature of the mice, lowering it from 0.3 to 0.5 degrees Celsius.

The scientists were then able to measure the effect of lowered core body temperature on lifespan, finding that the mice with lowered core body temperature had significantly longer median lifespan than those that didn't. While this effect was observed in both males and females, in this study the change was more pronounced in females-median lifespan was extended about 20 percent in females and about 12 percent in males.

The researchers performed several experiments to make sure that other factors were not contributing to the lowered core body temperature. They confirmed that the experimental mice were normal in their ability to generate fever, and that these mice moved around about the same amount as normal mice. In addition, the researchers verified that the hypocretin neurons producing uncoupling protein 2 were not involved in temperature regulation.

Importantly, the mice in this study were allowed to eat as much food as they wished, and the experimental and control mice ate the same amount. The weight of the female experimental and control mice did not differ significantly. However, experimental male mice weighed about 10 percent more than the control group, most likely reflecting the reduced energy required to maintain a lower core body temperature, according to the paper.

"Our model addresses something more basic than the amount of food," said Tamas Bartfai, who is chair of the Molecular and Integrative Neurosciences Department, director of the Harold L. Dorris Neurological Research Center at Scripps Research, and an author of the paper. "It works at the level of the thermoregulatory set point that is governed by intra-brain temperature and neurotransmitters. This mechanism, we believe, will be a good target for pharmacological manipulation or heating."

The idea to manipulate the temperature set-point came when Conti and Bartfai joined Scripps Research in the year 2000. Both scientists share common interests in neuroimmunology and the mechanisms of fever. It took over five years of work to conclude this study.

The researchers are now working to identify the precise mechanisms that are responsible for the beneficial effects of reduced core body temperature. They are also investigating whether their findings can be applied to research on obesity.

###
The findings appear in a paper in the journal Science on November 3.

Other authors on the study include Manuel Sanchez-Alavez, Raphaelle Winsky-Sommerer, Maria Concetta Morale, Jacinta Lucero, Sara Brownell, Veronique Fabre, Salvador Huitron-Resendiz, Steven Henriksen, Eric P. Zorilla, and Luis de Lecea, all of Scripps Research.

The study was supported by The Harold Dorris Neurological Research Institute, The Ellison Medical Foundation, and the National Institutes of Health.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
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PostPosted: Wed Dec 13, 2006 1:54 pm    Post subject: Worms produce surprise insight into human fever Reply with quote

American Society for Cell Biology
13 December 2006

Worms produce surprise insight into human fever

Patients fighting infections may be taking wrong fever-reducing drugs
Give or take a few dozen trillions, a human adult has about 70 trillion cells. An adult Caenorhabditis elegans roundworm has exactly 959 cells.

Yet we have an awful lot in common, says Alejandro Aballay of Duke University, who has been exploring two “highly conserved” cell-signaling pathways for innate immunity shared by worms and humans. For one, we have a lot of common enemies, particularly soil-borne pathogens. C. elegans, of course, lives in the soil. Human populations merely ingest soil by the ton in our food, on our hands, and suspended in our drinking water.

Some of these basic pathways that set off the worm’s innate immune defenses have homologs—similar proteins in mammal cells, including ours. These conserved pathways are involved in many similar “effector” strategies against hostile bugs peristalsis, low gut pH, lytic enzymes, and antimicrobial peptides to prevent microbial colonization of the intestine.

In dissecting two conserved pathways required for C. elegans immunity to bacteria, Aballay found a wealth of data on innate immunity plus a surprising insight into another classic metazoan response to infection fever.

The first pathway was p38 MAPK/CED-3, which is also required for the activation of programmed cell death under certain stresses. The other was a heat shock transcription factor-1 (HSF-1) pathway, which is elicited by increased temperature independently of p38 MAPK/CED-3. Aballay identified genes in both pathways that encoded immunity effector molecules plus relevant signaling molecules and transcription factors. In fluorescently labeled transgenic worms, he mapped gene expression in the two target pathways as they came into direct contact with a small zoo of pathogenic microbes.

The big surprise was the discovery that the HSF-1 pathway was required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis. It indicated that HSF-1 is part of a broad, multi-pathogen defense pathway. And it also suggested something new about fever, says Aballay.

Fever is an ancient immune mechanism used by metazoans in response to microbial infections. Warm-blooded “homeotherms” like rats (and people) can increase their internal body temperature in response to infection, yet even cold-blooded “poikilotherms” like worms migrate toward warmer environments in response to infections. But the mechanism of fever as a response to infection is still largely unknown. The activation of the HSF-1 pathways by heat shock and its function in C. elegans immunity provides both a molecular explanation for the beneficial role of behavioral fevers in poikilotherms and a mechanism by which fever works in metazoans, says Aballay.

It also raises questions about the HSF-1 pathway in humans and whether drugs currently used to reduce fever in infected patients may make matters worse by preventing activation of the HSF-1 pathway. Aspirin and similar anti-inflammatory drugs, which reduce fever but also activate HSF-1 signaling, could offer the best of both worlds, says Aballay. He also points out that new drugs designed to activate HSF-1 are already in clinical trials for treating neurodegenerative diseases. “Our work opens the possibility of using co-inducers of HSF-1 to boost immunity to treat infectious diseases and immunodeficiencies,” says Aballay.
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PostPosted: Fri Feb 23, 2007 9:00 am    Post subject: Global Warming to Fuel More Childhood Fevers Reply with quote

Global Warming to Fuel More Childhood Fevers

By LiveScience Staff
posted: 22 February 2007
01:12 pm ET

Warmer temperatures promised by climate change researchers could affect children more than adults in the form of more frequent fevers.

An Australian researcher compared emergency room visits for children under age six to climate data. Higher temperatures outside were related to more visits by children with fevers and gastroenteritis.

'We showed that maximum daily temperature is strongly associated with emergency presentations of fever and gastroenteritis among young children, with UV index negatively associated with gastroenteritis," said Lawrence Lam, a pediatrics lecturer at Sydney University

For the full article:

http://www.livescience.com/env.....fever.html
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