7 replies to this topic

[Lazarus Long]

How does an organism select its enemies and know its friends?

Too metaphorical for a biological discussion? Not an evolutionary biologist.

I want to start this off by suggesting that issue of the cumulative damage to cells is addresed in the body in a number of ways but one very significant one is through prevention, ie the Immune response.

The immune response is very significant for any discussion about aging because clearly the more effective an organism is at preventing damage to cells the longer it can thrive.

What is ironic about it however is that we have some examples of the immune system itself going haywire and causing the damage to the organism, or geting confused by benign substances that are mistaken for hazardous ones. All of this is an aside to the serious issue of an AIDS epidemic that is a viral infection which compromises the immune system completely and may do so by targeting the genes for that system directly and interfering with their normal operations.

To conclude this introduction of topic I am includinding an article from January's Nature Magazine section on Immunology. It may be found here:

http://www.nature.co...s/ni888_fs.html

Nature Immunology 4, 269 - 273 (2003)
doi:10.1038/ni888
Published online: 27 January 2003
© Nature America, Inc.

Angiogenins: a new class of microbicidal proteins involved in innate immunity

Lora V. Hooper, Thaddeus S. Stappenbeck, Chieu V. Hong & Jeffrey I. Gordon

Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Although angiogenins have been implicated in tumor-associated angiogenesis, their normal physiologic function remains unclear. We show that a previously uncharacterized angiogenin, Ang4, is produced by mouse Paneth cells, is secreted into the gut lumen and has bactericidal activity against intestinal microbes. Ang4 expression is induced by Bacteroides thetaiotaomicron, a predominant member of the gut microflora, revealing a mechanism whereby intestinal commensal bacteria influence gut microbial ecology and shape innate immunity. Furthermore, mouse Ang1 and human angiogenin, circulating proteins induced during inflammation, exhibit microbicidal activity against systemic bacterial and fungal pathogens, suggesting that they contribute to systemic responses to infection. These results establish angiogenins as a family of endogenous antimicrobial proteins.

Full Text

PDF

[Lazarus Long]

Here, add these all to the discussion as current, but I would appreciate some help posting classic theory and contrasting ones from a broader perspective. What I will however ask a priori is that we do not here inlude alternative philosophical issues regarding homeopathy and alternative medicine.

Not becacuse I think these may be "wrong" but because there is a sort of translation difficulty. We begin talking about and comparing areas that do not translate to eachother. For those that want to add these "Alternative Theories and Methods" I suggest an alternative thread that develops and addresses such theory constructively and consistently and after we develop these side by side perhaps some overlap and parallels may be better understood.

Review
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The nature of molecular recognition by T cells
S J DAVIS, S IKEMIZU, E J EVANS, L FUGGER, T R BAKKER & P A VAN DER
MERWE
http://www.nature.co...303-217_fs.html

---------------------
Article
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Lineage relationship and protective immunity of memory CD8 T cell
subsets
E J WHERRY, V TEICHGRÄBER, T C BECKER, D MASOPUST, S M KAECH, R ANTIA,
U H VON ANDRIAN & R AHMED
http://www.nature.co...s/ni889_fs.html

Selective, stable demethylation of the interleukin-2 gene enhances
transcription by an active process
D BRUNIQUEL & R H SCHWARTZ
http://www.nature.co...s/ni887_fs.html

CDR3 loop flexibility contributes to the degeneracy of TCR recognition
J-B REISER, C DARNAULT, C GRÉGOIRE, T MOSSER, G MAZZA, A KEARNEY, P A
VAN DER MERWE, J C FONTECILLA-CAMPS, D HOUSSET & B MALISSEN
http://www.nature.co...s/ni891_fs.html

TCR ligand discrimination is enforced by competing ERK positive and
SHP-1 negative feedback pathways
I STEFANOVÁ, B HEMMER, M VERGELLI, R MARTIN, W E BIDDISON & R N GERMAIN
http://www.nature.co...s/ni895_fs.html

Defective thymocyte apoptosis and accelerated autoimmune diseases in
TRAIL-/- mice
S-E LAMHAMEDI-CHERRADI, S-J ZHENG, K A MAGUSCHAK, J PESCHON & Y H CHEN
http://www.nature.co...s/ni894_fs.html

Homozygous loss of ICOS is associated with adult-onset common variable
immunodeficiency
B GRIMBACHER, A HUTLOFF, M SCHLESIER, E GLOCKER, K WARNATZ, R DRÄGER, H
EIBEL, B FISCHER, A A SCHÄFFER, H W MAGES, R A KROCZEK & H H PETER
http://www.nature.co...s/ni902_fs.html

[Lazarus Long]

The following article is about a finding of immense importance. I am posting this both as an example that addresses how the immune system operates but also how it doesn't.

It is a demonstrable example of why I insist that the study of AIDS overlaps our endeavor here because of how much we will learn about the entire immune function, and the genetics governing it. I don't have time at the moment to search for the substantial source material and I would appreciate anyone who wants to pursue this to please make the assist. I would also suggest linking back to the original because of the value of the links there that can be datamined.

New Clues Emerge on How HIV Evades Antibodies

New Clues Emerge on How HIV Evades Antibodies
Wed Mar 19, 5:47 PM ET

LONDON (Reuters) - Scientists in the United States said on Wednesday they had found a new way in which the virus that causes AIDS (news - web sites) manages to evade the body's immune system.

In a report in the science journal Nature, researchers from the Howard Hughes Medical Institute at the University of Alabama said the HIV virus (news - web sites) uses different strategies to evade the human antibodies that attack invading viruses and bacteria.

"We've shown in this paper that the virus has an additional mechanism by which it escapes antibodies, an additional mechanism that was not previously recognized," said Dr George Shaw, who headed the research team.

"It allows us to better understand how HIV (news - web sites)-1 is able to avoid immune elimination," he added in an interview, referring to the common strain of the virus.

HIV infects cells of the immune system and destroys or impairs their function, leaving patients vulnerable to other infections.

Viruses usually vary the protein sequence, or epitope, of their outer envelop, preventing the immune system's antibodies from targeting it. But HIV works differently.

"We found that the neutralizing epitopes on the virus did not change, but instead other parts of the viral envelope mutated," Shaw explained.

He and his colleagues dubbed the new evasion tactic the "evolving glycan shield" and said it mutates at a faster rate than the immune system can adapt.

The research has also been used in a new method to test for antibodies which can be applied to developing a vaccine for the disease.

"On a practical level it provides a tool to assess the activity of candidate vaccines," Shaw said.

By December 2002, 42 million people around the globe were living with HIV/AIDS, according the UNAIDS (news - web sites), the United Nations (news - web sites) agency leading the global battle against the illness.

[caliban]

Autoimmune diseases such as rheumatoid arthritis currently affect up to 10% of the population in the Western world and cost billions of pounds in health care. Autoimmune diseases occur when the body's immune system, that is normally essential for protection against infections, turns against itself and attacks host tissues. For example, the body normally makes antibodies against viruses and bacteria to fight off infection. In arthritis, the body makes antibodies that attack tissues in the joint including cartilage and some sections of bone. In thyroid disease, the antibodies can attack the thyroid gland and either induce hormone release or destroy the gland and stop hormone release. Either way there is a change in the way a patient feels. New therapies rely on understanding why the body’s immune system has turned on itself and turned from 'friend' to 'foe'.

- Common autoimmune diseases include:
o rheumatoid arthritis
o psoriasis
o diabetes
o inflammatory bowel disease (Crohn's disease and ulcerative colitis)
o thyroid disease
- The following are less common, but very serious, autoimmune diseases:
o systemic lupus erythematosis
o scleroderma
o polymyositis
o vasculitis

-Other common diseases in which inflammation is a major factor are:
o asthma
o coronary artery disease
o excema
o aging


There are currently no cures for most autoimmune diseases. Existing treatments tackle the condition by suppressing the body's immune system, leaving the patient less able to fight off other infections.

Recently, researchers at the University of Strathclyde have found that filarial nematodes, a class of parasitic worm that infects humans and animals, secrete an anti-inflammatory molecule known as "ES-62" into its host, without producing any obvious side effects or compromising the immune system.

[kevin]

An interesting wrinkle in T-cell self-recognition of peripheral proteins. It seems thymic epithelial cells produce a whole range of proteins that would not normally be present in the tissue in order to educate the T-cells as to what is self/non-self. It was thought before that the T-cells finished their education in the periphery but this study proposes this is not the case.

Shadow Proteins In Thymus May Explain How Immune System Gets to Know Its Own Body

[Lazarus Long]

I am introducing this article to address the findings and discuss them. I don't have access to the source info so if anybody can get the orginal abstracts and studies it would be greatly appreciated.

It appears that there is another mechanism at work as well that operates at the RNA/DNA interface and works to "self regulate" by "self destructing" cells that are not "normal". We have skirted around this issue with the discussion of Telomeres but this study directs our attention to specific biochemical processes.

Web Text & Links

Study Shows Why Aspirin, Fiber Prevent Cancer
Wed Apr 9, 1:10 PM ET

WASHINGTON (Reuters) - Painkillers such as aspirin and ibuprofen may help prevent colon cancer by preventing tumor cells from becoming immortal, and eating fiber may work in a similar way, U.S. scientists reported on Wednesday.

Studies have shown that people who regularly take aspirin and other related drugs known as non-steroidal anti-inflammatory drugs or NSAIDS have a lower risk of cancer. So do people who eat a high-fiber diet.

But the mechanisms remain unclear.

In one study that may help explain why, Dr. David Frank of the Dana-Farber Cancer Institute and Harvard Medical School (news - web sites) in Boston and colleagues noted that colon cancer cells have abnormally high levels of an immune system protein called interleukin-6 or IL-6.

Frank's team treated colon cancer cells in the laboratory with NSAIDs such as ibuprofen, aspirin and sulindac. They also tested butyrate, a compound produced when the body breaks down dietary fiber.

They found that IL-6 in turn activates another protein called STAT1, which shuts down a process called cell suicide. Cells are programmed to self-destruct when they become abnormal, as in cancer, but STAT1 interferes with this process. The cells become immortal, starting the out-of-control proliferation that results in a tumor.

The painkillers stop IL-6 from activating STAT1, Franks' team found. Butyrate also blocks IL-6, but through a different mechanism, they found.

They were scheduled to present their findings to an annual meeting of the American Association of Cancer Research in Toronto this week, but the meeting was canceled because of fears about an outbreak of a new virus causing severe acute respiratory syndrome.

The next step is to find more direct ways to block the STAT1 protein in patients who have already developed cancer, Frank said.

In a second study that was to be presented at AACR, a team at Ohio State University said they found that women who took the painkillers regularly had a lower risk of breast cancer (news - web sites).

"These results suggest that even women at high risk for breast cancer may be protected by taking NSAIDs," said Dr. Randall Harris, who led the study.

But more research is needed before doctors start telling women to take ibuprofen to prevent breast cancer, Harris said in a statement.

His team looked at data from the National Cancer Institute (news - web sites)'s Women's Health Initiative, which follows tens of thousands of women, their habits, and their health.

They found that women who took two or more NSAIDs a week for five to nine years reduced their risk of breast cancer by 21 percent. Low-dose aspirin, often recommended to protect against heart disease, had no effect, but regular-dose aspirin did.

Edited by Lazarus Long, 11 July 2003 - 01:14 PM.

[Lazarus Long]

One step closer to a true nano-gene interface technology that can be integrated into the immune system to expand our resistance to numerous forms of infection.
LL/kxs

http://story.news.ya...nce_detector_dc
Cell-Based Detector Lights Up for Deadly Germs
Thu Jul 10, 2:05 PM ET Science - Reuters
By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - A new biodetector made with the body's own immune system cells literally lights up when it encounters anthrax, plague or other deadly germs, U.S. researchers said on Thursday.

The sensor could be a quicker and more straightforward way to detect a biological attack than current methods, the researchers said.

It uses B cells -- the immune system cells that produce the antibodies that in turn seek out invaders, said inventor Todd Rider of the Massachusetts Institute of Technology (news - web sites).

"Rather than trying to invent something from scratch, I decided to simply borrow what nature already had," Rider said in a telephone interview.

"These are a type of white blood cell designed by nature to detect bacteria and viruses. Other people had developed relatively artificial methods using PCR (polymerase chain reaction) and amino acids, which are time-consuming."

Such methods try to mimic natural processes by looking for specific genes or proteins produced by a pathogen. Rider lets the B cells do the work.

Rider's method, described in Friday's issue of the journal Science, uses mouse B cells that have been genetically engineered in two ways.

First, they contain a gene from jellyfish that lights up.

"It comes from the same jellyfish that is tortured to give us green fluorescent protein," said Rider. GFP is commonly used in scientific experiments because it is easily spliced into an animal or plant and glows under ultraviolet light.

Rider, a biologist and engineer, used a different jellyfish protein called aequorin that emits a blue light.

Second, the B cells were also engineered to recognize specific pathogens.

"Our funding comes mainly from DARPA (the Defense Advanced Research Projects Agency) and of course they are interested in military-type applications," Rider said.

"We can detect smallpox, anthrax, the Yersinia pestis bacteria that cause plagues, equine encephalitis," Rider said.

"We also developed cells to detect a few non-military pathogens such as the foot and mouth disease virus, so it will be useful for agriculture."

The team has named the sensor Canary, for cellular analysis and notification of antigen risks and yields.

It found a toxic form of E. coli bacteria (news - web sites) in vegetables, fruit and meat in less than five minutes, they reported -- which could make it useful for screening food samples for the increasingly common cause of food poisoning.

The team is working on a system that would make the detector useful for testing air, too, Rider said.

"You might be interested in airborne pathogens -- for example with all these things about bioterrorism these days," he said. "We designed hardware that would suck in a large amount of air and deliver it to these cells."

In the body, immune cells often detect an infection but can quickly become overwhelmed. "We don't have to worry about this," Rider said, adding that his system merely has to detect the pathogen. Special, sensitive light sensors pick up the telltale glow, he said.

Rider, who has numerous patents on the system, said he has no plans to spin off a company to develop and sell it. "I am not really expecting to become rich from this," he said.

[Lazarus Long]

http://news.bbc.co.u...lth/3363225.stm
Immune boost 'widens cancer fight'
Monday, 5 January, 2004, 00:11 GMT

Scientists hope to use the body's immune system to fight tumours
Scientists may have found a way to harness the immune system and strike at hidden tumours throughout the body.
Animal tests suggest that a treatment given to just one tumour produces an immune response that targets secondary growths in other places.

Researchers from Chicago University now hope the same effect can be reproduced in humans with cancer.

If so, it could offer a way to tackle cases where more advanced cancers have a foothold in many parts of the body.

At the moment, once a cancer has spread beyond its initial site, it becomes far harder to treat in many cases - and the chances of overall survival begin to fall.

One way that researchers are trying to improve these odds is by boosting the body's own immune system so that it can mount a body-wide assault on cancer cells.

Hidden enemy

Unlike foreign invaders such as bacteria, cancers can often evade immune defences and go unrecognised as a threat.

Some tumours appear capable of throwing up a "barrier" around their fringes which stops immune cells getting hold of fragments of the tumour which can be used to coordinate an attack on the abnormal cells.

In addition, other types of cancer can interfere with the activation of "killer T cells" - immune cells which arrive to destroy tumour cells.

The Chicago team overcame this problem by activating the production of a body chemical called LIGHT within a tumour.

This protein then produced a two-pronged attack on the cancer.

Not only did it increase production of a chemical which attracts "killer T cells" to the tumour site, it also switched these cells into an active state once they arrived.

This had a marked effect on the size of the treated tumour, and also seemed to encourage tumour regression in other parts of the body.

However, while this worked well in different types of mice, it is by no means certain that it would happen in humans.

In the journal Nature Immunology, the researchers wrote: "Here we have shown that the expression of LIGHT in the tumour microenvironment acts as a potent immunotherapy for cancer by targeting the tumour barrier."