The Nature of Science

Showing posts with label adaptive immunity. Show all posts

The Dirt On Staying Healthy

Biology concepts - hygiene hypothesis, immune regulation, bacterial drug resistance

Christian Slater starred in a 2008 American TV

series called, “My Own Worst Enemy.” Slater was

a secret agent with a chip in his brain that allowed

his employers to turn him from a mild mannered

family man to a super spy without each knowing

of the other’s existence. The showed last only nine

episodes; apparently the drama was its own

worst enemy.

Is everyone their own worst enemy? Google it---- apparently scientists are their own worst enemy; Christians are too. Chad Johnson is, and so was Whitney Houston. Someone out there even thinks bassists are their own worst enemies! I think that if this is true, everyone must be leading pretty lucky lives; the only thing stopping us appears to be us.

So it comes as no surprise that some scientists believe that people are their own worst enemies when it comes to protecting their health. Good intentions can have bad results. How might this relate to our topic of the past few weeks, the benefits of disease and infection?

Some diseases have had a positive effect on survival in specific conditions (like hemochromatosis and plague) and even how malarial fever can kill bacteria. This goes against the popular idea that less disease is better, and that whatever we do to kill infectious organisms is good. We try to be as sterile as possible; just look at what surgeons do before entering the operating room. The health industry has given us antibacterial soaps, cleaning products, plastics, cosmetics, toothpastes, pencils, and even antibacterial computer keyboards!

The majority of these products use triclosan as the active ingredient. First introduced as a pesticide in 1972, triclosan (chemical name: 2,4,4’-trichloro-2’-hydroxydiphenyl ether) is an antibacterial and antifungal agent. Triclosan’s mechanism of action at low concentrations is to disrupt fatty acid synthesis as a bacteriostatic agent (slows bacterial growth and reproduction); at high levels it can disrupt membranes and act as a biocidal agent (kills organisms).

Just because something is an antibiotic, it doesn’t mean it kills

bacteria. Many of the common antibiotics we use are bacteriostatic,

meaning that they inhibit the growth. This allows our immune

system time to overcome the intruder on its own.

Bactericidal agents do actually kill the bug, but they still need

help from the immune system. If you took enough to

kill all the bacteria, you’d need a capsule the size of a bus!

Triclosancan control bacterial contamination on hands and skin; hospital staff are encouraged to bathe or shower in triclosan solutions to prevent the spread of MRSA (pronounced “mersa” – methicillin resistant Staphylococcus aureus) in hospital wards. However, this is for control of contamination, not necessarily infection.

Triclosan has been proven effective in reducing infections rates only in cases of gingivitis (inflammation of the gums). However, a 2009 study stated that 75% of Americans over the age of six years have detectable levels of triclosan in their urine. This is significant since there is emerging data that suggests that triclosan might be harmful to people’s health.

High triclosan levels in urine and the environment mean high levels around microorganisms as well. But this shouldn’t be bad – it is supposed to kill germs, isn’t it? Many scientists worry that high triclosan levels also promotes bacterial evolution, selecting for the mutants that are resistant to the chemical. We all have good reason to worry about this because it’s happened before. Many bacteria, from MRSA to Mycobacterium tuberculosis, to vancomycin-resistant enterococcus, are wreaking havoc because we have fewer drugs that are effective against them.

In the laboratory, triclosan exposure has resulted in resistant strains of E. coli, salmonella, and rhodospirillium, and other organisms. Industry scientists argue that there is no data that triclosan causes resistance to develop in the wild, but a 2011 EU report suggests that this very well may be taking place; the levels of triclosan seen in people and the environment are similar to the levels used to drive resistance in the laboratory.

The bacterial resistance mechanism at work might be more dangerous than the resistance to triclosan itself. Several studies have deduced that triclosan interacts with proteins in the bacterial multidrug efflux pump. Many prokaryotes have this system; it works to pump non-bacterial small molecules, including antibiotics and toxins, out of the cell.

This cartoon represents a model of the E. coli

multidrug efflux pump. Protons pumped out are

allowed back in, and this produces the force needed

to pump out the drugs. This is another reason that

you need your immune system to overcome a

bacterial infection – the little buggers are working

against you!

In a situation where an organism is exposed to low or medium levels of triclosan, the multidrug efflux pump actually becomes more active because the triclosan binds to, and suppresses, the pump’s off switch. Think about that - you’re taking an antibiotic for a respiratory infection. But your household products are contaminating your body with triclosan. As a result, the respiratory organism is very efficiently expelling the antibiotics you are taking! Now the bacteria are being exposed to lower levels of antibiotic and will have a better shot at developing resistance! Perhaps anti-bacterials aren’t such a great idea.

Want more evidence? An August 2012 study showed that triclosan has an immediate and dangerous affect on muscle activity. You remember your heart?- it’s a muscle. In mice, triclosan exposure caused a 25% reduction in cardiac muscle function, and an 18% reduction in mouse grip strength. An idea for your next arm wrestling contest – wear a glove and slather it with liquid hand soap. You now have an 18% better chance at winning….if you are competing against a mouse.

Triclosan also affects endocrine function. A new study indicates that triclosan exposure in pregnant rats lowers mother, fetal, and neonatal levels of thyroid hormone. Triclosan has a structure similar to a thyroid hormone; it may trick the body into believing it has enough hormone. The thyroid would then reduce the production of the hormone, leaving the system starved of thyroid hormone. Most of this work has been done in amphibians, fish and rats, but a similar affect on human thyroid function is predicted.

Your body is exposed to many antigens from many sources.

If you are an only child or have parents that microwave

your toys, you are exposed to many fewer antigens. Many

scientists hypothesize that your immune system needs

these exposures to balance your developing system

between the Th1 responses and Th2 responses. Too much

Th2 and you will start to overreact to innocuous antigens –

allergies, asthma, and autoimmunity can result.

Antibacterial agents might be harmful through their actions on us and on bacteria. But does being too clean have other effects? Consider the hygiene hypothesis; mounting evidence indicates that efforts to produce near-sterile living environment, or even the movement from a rural to an urban environment, can negatively affect our health.

Case in point - most everyone has an idea that food allergies and asthma seem to be on the rise. The CDC stated in 2008 that there had been a 20% increase in food allergies in the years between 1997 and 2007. In a large number of these cases, children with food allergies also had eczema or skin allergies (27%) or respiratory allergies (30%), compared to only 8-9% of kids without food allergies. Basically, allergies are significantly on the rise, and if you have one, you are much more likely to have more than one.

Importantly, the rise isn’t occurring everywhere. Rural Africa - no increase in allergies or asthma. The arctic inuit peoples – very little allergy or asthma despite high levels of childhood smoking. Farm kids in just about every country – far lower levels of respiratory allergies, food allergies, asthma, and autoimmune diseases.

The hygiene hypothesis states that a lack of immune stimulation when young leads to exuberant responses to antigens that would normally be innocuous. Isn’t it interesting that the increase in allergies and asthma also correlates with the onset of antimicrobial agents being added to everything?

Different ideas abound as to how being clean might lead to increased immune hypersensitivities. One hypothesis is that a lack of antigen exposure in urban kids leads to a loss of balance between different T lymphocyte responses (see picture above). Infections tend to stimulate Th1 responses. A too clean, urban environment results in less stimulation of Th1 and therefore a relative over stimulation of the Th2 response. Increased Th2 leads to the kinds of responses seen in asthma and allergies. Indeed, atopic (allergy) patients do show an increase in Th2-driven cytokines.

Are we too clean as a society? Maybe we can back off

on the antimicrobial agents and spend more time in

the woods and the park. A brisk hike is as good for

your health as a spotless bathtub – and its more fun.

Then again, increased immune hypersensitivity in at risk populations might be due to an imbalance between the innate and adaptive immune systems. Many of the microbiologic antigens to which neonates and children need exposure stimulate innate immune receptors. The innate immune system then stimulates the adaptive immune system and balances the Th1 and Th2 responses. An absence of innate immune stimulation leaves the adaptive system to its own devices, and Th2 will often win this battle.

Additionally, the exposure to bacteria, viruses and parasites stimulates the immune regulatory system as well. Antigen presentation can be stimulatory or suppressive; suppressive presentation leads to regulatory (suppressive) lymphocyte production. It is hypothesized that regulatory lymphocytes help to balance the Th1 and Th2 responses and reduce the incidence of allergy.

We see that several portions of the immune system could be involved in helping the natural environment fine tune our immune responses. But what is it that induces this wonderful balance and state of good health?

A 2010 study suggested that the important molecule is something called arabinogalactan. This is a ubiquitous polysaccharide made of arabinose and galactose monomers. It is a component of many cell walls – bacterial, parasite, worm, grasses and other plants, and is in farm (unprocessed) milk.

Arabinogalactan is present in cow’s milk, in the grasses

that cows are fed, and in the dung patties that they leave

behind. And they last as well – there is a cowshed in

Wales that dates to 1402, making it the oldest building

in Wales. Cowshed – uninterrupted immune stimulation

for six centuries!

The hygiene hypothesis can be expanded to test the idea that farm kids' exposure to farm milk and cowshed dust (big sources of arabinogalactan) stems allergy and asthma development. However, there are studies that do not support the hygiene hypothesis, such as influenza virus actually promoting the development of asthma and the fact that daycare children have more respiratory infections, but do not have lower incidence of allergy. More needs to be known before we start shipping our infants to the country for the summer.

Two final notes to bring this full circle. Triclosan use has now been linked to higher rates of allergy. In particular, urinary triclosan levels correlate with development of food allergy. Correlation does not equal cause and effect, but it does ask a question that needs to be answered.

Lastly, increases in autism parallel increases in asthma and allergy, and a recent study shows that kids with autism and behavioral fluctuations have less stimulation of regulatory immune response after infection. Like allergy and asthma, autism definitely has a genetic component, but could the hygiene hypothesis and autism be linked as well?

With Halloween approaching, let's take a three week break from our "disease benefits" stories to look at the biology of some of our Halloween traditions and myths.

Gennady Cherednichenkoa, Rui Zhanga, Roger A. Bannisterb,Valeriy Timofeyevc, Ning Lic, Erika B. Fritscha, Wei Fenga, Genaro C. Barrientosa, Nils H. Schebbd, Bruce D. Hammockd, Kurt G. Beame, Nipavan Chiamvimonvatc, and Isaac N. Pessaha (2012). Triclosan impairs excitation–contraction coupling and Ca2+ dynamics in striated muscle PNAS DOI: 10.1073/pnas.1211314109

For more information or classroom activities, see:

Anti-microbial products –

http://www.protectiveindustrialpolymers.com/Antimicrobial_Products.html

http://drbenkim.com/articles/triclosan-products.htm

http://greenandcleanmom.org/triclosan-and-a-non-toxic-classroom/

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CEEQFjAA&url=http%3A%2F%2Fwatoxics.org%2Ffiles%2Fantimicrobials.pdf&ei=IsNgUNysAqiBywGUkYDYCg&usg=AFQjCNEf06t0FZ-MaPjDxJXgGQPxlhlffA

http://npic.orst.edu/ingred/ptype/amicrob/select.html

http://www.epa.gov/oppad001/influenza-disinfectants.html

http://www.rtpcompany.com/products/color/antimicrobials.htm

http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm185542.htm

https://asunews.asu.edu/20120816_antimicrobials_riverslakes

http://healthychild.org/blog/comments/antibacterials_and_disinfectants_are_they_necessary/

Triclosan and health –

http://www.prnewswire.com/news-releases/canadian-government-urges-removal-of-triclosan-from-personal-care-products-146140385.html

http://www.washingtonpost.com/wp-dyn/content/article/2010/04/07/AR2010040704621.html

http://toxsci.oxfordjournals.org/content/107/1/56.abstract

http://www.healthiertalk.com/antibacterial-products-aren-t-just-useless-they-can-be-killers-0595

http://www.mnn.com/health/healthy-spaces/blogs/more-bad-news-about-triclosan

http://www.grinningplanet.com/2005/10-04/triclosan-article.htm

www.vkm.no/dav/f97997ef0d.pdf

http://ourneedtoknow.com/2012/06/the-dangers-and-effects-of-triclosan/

Hygiene hypothesis –

http://coolimmunology.blogspot.com/2007/03/hygiene-hypothesis.html

http://www.pbs.org/wgbh/evolution/library/10/4/l_104_07.html

http://www.sciencedaily.com/releases/2007/09/070905174501.htm

http://www.scientificamerican.com/podcast/episode.cfm?id=can-it-be-bad-to-be-too-clean-the-h-11-04-06

http://www.naturalnews.com/035447_hygiene_hypothesis_dirt_health.html

http://www.medscape.org/viewarticle/452170

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=8&ved=0CF4QFjAH&url=http%3A%2F%2Fccis.stanford.edu%2Fnewsarticles%2Fumetsu2%2FNIReview.pdf&ei=9r9gULavDsWDywHH8YGQCw&usg=AFQjCNGMt5pyarrUN7EUMUqw8BjxbHmang

http://www.infection-research.de/perspectives/detail/pressrelease/parasites_and_the_hygiene_hypothesis/

http://www.mydr.com.au/asthma/asthma-and-the-hygiene-hypothesis

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=24&ved=0CC8QFjADOBQ&url=http%3A%2F%2Fimb.usal.es%2Fformacion%2Fdocencia%2Falergenos%2FAsma%2C%2520rinitis%2C%2520conjuntivitis%2Fasthma.pdf&ei=rcBgULjzEsX5ygGthoDQCg&usg=AFQjCNEYyUl8LMU5UIyk21_YnfO5tcYmkQ

Ironing Out The Black Death

Biology concepts – iron, genetic disease, infectious disease, immune evasion

It is strange to think of people as rusting, but there are

days when I get up and swear that my joints have

frozen – my age makes me assume it is rust.

In truth the molecules of rust are very much like

some molecules in your body; too many of these in

the wrong places, and maybe you are rusting.

Believeit or not, someone you know is rusting - and it probably saved his/her ancestor’s life.

Animals require iron to survive; normal adult humans carry about 3.5-4 grams of iron in their bodies. It’s vital for every cell. Red blood cells use iron as part of the hemoglobin molecule that carries oxygen, But all other cells use iron in part of electron transport chain that makes ATP, and in the synthesis of DNA.

In plants, iron is used in chlororphyll production, in nitrogen fixation, and in regulation of transpiration (moving water and nutrients up to the leaves). Plants are a decent source of dietary iron, but heme iron (from meat) is much more easily absorbed.

In both plants and animals, the amount of iron is highly regulated. Iron is most often bound to proteins; one type in cells, another in the blood, and they lock it up tight. When you need more, your gut cells (enterocytes) release some of their stored iron and then take in more from the food you eat.

People who absorb too little iron (from poor diet or absorption defects) have a hard time carrying oxygen to their tissues because they don’t have enough hemoglobin. They are fatigued, dizzy, lose their hair, and less able to fight off infections. Weirdly, they may demonstrate pagophagia; a compulsion to eat ice! The reason for this is open for discussion, but one hypothesis says there is an ancient crunching desire, related to chewing on bones to get at the iron-rich marrow.

Pagophagia (eating ice) is one type of pica. In pica, a

person craves to eat something that is not a food source.

Some people with pica will eat hair (trichophagia)

or dirt (geophagy). I guess if you have to have pica,

ice craving isn’t so bad. And yes, some people crave

plastic, like parts of your keyboard.

Too little iron keeps you sick - and apparently always refilling the ice tray. But too much iron is just as bad; both ends of the scale can kill you.

Hereditary hemochromatosis (HH) is an autosomal recessive (need two mutated copies) disease of iron storage and transport. Patients with this disease may have as much as 20-40 grams of iron in their bodies; they can even set off metal detectors at airports!

All this iron causes medical problems too. People with HH will accumulate iron in their liver, heart, skin and other tissues. Excess iron plus fats can produce free radicals and oxygen radicals. The radicals can react with many molecules, including those you need in order to keep your cells functioning properly.

Radicals can break down enzymes, destroy mitochondria, and even react with the iron itself to produce iron oxide – rust; biological rust being called hemosiderin. Could HH patients be like the frozen Tin Man that Dorothy finds in the Wizard of Oz? Of course not, tin doesn’t rust – it’s a good thing L. Frank Baum was a writer and not a metallurgist!

The brown color is hemosiderin pigment that has been

deposited in the tissues. Most times, your body will

resorb this colored material, like when a bruise goes

away over time. In hemochromatosis, there is too

much hemosiderin to be completely removed.

Over time, the damage from free radicals and from hemosiderin buildup causes systems to shut down. Without treatment HH is lethal - so it is important to know how all that iron gets there.

We said above that enterocytes are the storage area for iron absorbed from your diet. In HH, the export signal is broken and they keep dumping their stored iron into the bloodstream. Even worse, the enterocytes lose the ability to sense if the body needs more iron. As a result of HH, gut cells keep absorbing more iron and releasing it into the bloodstream.

It’s a bad thing to inherit hemochromatosis…..EXCEPT if Yersinia pestis is lurking in the environment. Y. pestis is the bacterium that causes the plague. The organism can be passed from person to person, but also from fleas to people, and from fleas to animals to people.

You can read about how Y. pestis ensures it is transmitted to a new host from the flea’s midgut, but for reasons of decorum, I won’t go into it here. And I suggest you don’t eat before you read about it.

Y. pestis plague comes in three flavors; septicemic(travels through the blood), bubonic(causing swellings), and pneumonic(some organisms go to the lungs). In the case of pneumonic plague, coughing promotes transmission from person to person and is more lethal. But bubonic plague is more painful.

The plague has been a killer throughout human history, but Y. pestis’ relationship to the flea is evolutionary rather new. About 20,000 years ago, Yersinia killed the flea as well. According to new research, it took relatively few genetic changes to allow plague bacteria to keep the flea alive and to survive in its midgut. It was at this point that humans' trouble really began. It is estimated that a third of the population of Europe was lost to plague in 14^th century. The infection still occurs today, but is highly treatable with antibiotics. Your immune system has problems getting rid of Y. pestis on its own.

Normally, your immune system recognizes foreign organisms and eliminates them, through either innate or adaptive mechanisms. However, Y. pestis has several tricks up it sleeve to avoid recognition and destruction by your immune system.

The lymphatic system is comprised of vessels, and

is considered part of your circulatory system. It

helps in eliminating wastes from the blood and

tissues, aids in absorbing fats and fat soluble

vitamins, and regulates fluid levels. A main function

is to move fluid and cells through the checkpoints,

the lymph nodes. Here, the fluid is checked for

foreign molecules and antigen presentation to the

immune cells in the nodes.

Immune cells can circulate in your blood, move in and out of your tissues, or may be located in your lymphatic system. In the lymph nodes, they gather to exchange information, like workers gossiping around the water cooler. If an antigen processing immune cell (APC) has encountered a foreign antigen, the APC will break it down and place pieces of the antigen on its surface, so the antigen can stimulate other immune cells.

The processed antigen is presented to the many types of immune cells in and moving through the lymph nodes, including B cells that make antibodies, and T cells that direct immune responses or directly kill organisms. This quickly increases an immune response; one cell encounters the invader, but by going to a central location (lymph node), thousands of cells can be stimulated.

Amazingly, Y. pestisactually lives and reproduces in your lymph nodes! The painful swellings in bubonic plague are the inflamed lymph nodes where the organism is reproducing. Each swollen node is called a buboe, hence the name of the plague. Buboes occur most commonly in the armpit (axilla), on the neck, or in the groin area – not a pleasant way to spend a weekend - maybe your last weekend.

The lymph nodes are the headquarters for stimulating immune responses, yet the Y. pestis lives here very happily. It manages this through several evasion mechanisms:

1) antiphagocytic proteins – Y. pestis can inject proteins into phagocytic cells that makes them poor at eating and killing. These proteins also makes immune cells unable to signal other immune cells that Y. pestis is there.

2) invasion proteins – plague bacteria can avoid immune detection by living insideseveral different host cell types; the macrophage is the major example.

3) survival proteins – Y. pestis can live inside the macrophages that are supposed to destroy them by turning off macrophage killing mechanisms.

4) heme stealing proteins – Y. pestis can steal iron from the host. And here is where HH comes in.

Here is a buboe on a plague patient’s neck. It is not unlike the parotid

salivary gland swelling that takes place during the mumps, just

bigger, more painful, and more lethal. I chose to show one from the

neck precisely because I didn’t want to show you one from the groin.

Hereis an organism that is perfectly happy living inside and in the company of the cells that are supposed to kill it - we’re doomed. Yet having a disease like hemochromatosis can save us. How can that be? Well, microorganisms need iron too. For much the same reasons as animals and plants, bacteria and other microorganisms must have a supply of iron. They may get it from their diet, or, as is the case with Y. pestis, they steal it from their host.

I can hear what you're saying - this doesn’t seem to make sense since HH results in lots of iron in cells. True, but there is an exception. HH leaves two cell types starved for iron - the enterocyte, which we already know about, and the macrophage. The reason for iron-poor macrophages during hemochromatosis is not completely understood, but one possibility is that the HH mutation affects macrophages the same way it affects enterocytes.

One important function of macrophages is to eat and destroy old host cells, including erythrocytes. The iron of the hemoglobin from all those degraded RBC’s is stored and recycled; this is an important mechanism that the body uses to reuse the iron it already has. But in HH, the macrophages may be pumping out the iron they take up from old RBCs, just as the enterocytes keep pumping out the iron they take up from the gut contents.

The iron-poor macrophage essentially starves the intracellular plague bacteria by not providing them with iron. This is a happy accident for us, but it isn’t as if the macrophage doesn’t already know this trick. Iron can be an important immune weapon. In mycobacterial infections (that cause pneumonia), macrophages actually raise the iron concentration in the ingested bacteria and kill them that way. In other infections, macrophages sequester their iron and starve the organisms.

Bloodletting is an old time treatment for nearly every

disease. They thought that disease was caused by too

much blood. Strange, but bleeding (phlebotomy) is now

the accepted treatment for hemochromatosis. Leeches

are now used as anti-clotting mechanisms, and fly

maggots are used to clean out dead tissue – all are

gross, and all are effective!

Macrophageiron manipulation is not a natural immune response to Y. pestis, but HH helps to bring about the same effect, and this makes HH valuable. It is believed that many survivors of the plague in the 12^ththrough 15^th centuries had hemochromatosis. What is more, the gene is present in as many as 1/3 of living people of European descent, meaning that HH is probably massively underdiagnosed. It is likely that you know someone with HH, whether they not it or not.

Natural selection kept this mutation in the gene pool because it presented a reproductive advantage in times of plague. With antibiotics, we probably do not need this mutation any longer, but it is here and will take quite a while to be bred out of the population, especially since HH treatments (like bleeding, see the picture at right) help people live with the disease long enough to pass on their genes.

There are more examples of bad genes saving us from disease, like chemokine receptor mutations preventing HIV infection and aldehyde dehydrogenase mutations discouraging alcoholism. But next week we will focus on immune systems run amok and how parasites can reel them in.

Chouikha I, Hinnebusch BJ. (2012). Yersinia-flea interactions and the evolution of the arthropod-borne transmission route of plague. Curr Opin Microbiol. DOI: 10.1016/j.mib.2012.02.003

For more information or classroom activities, see Survival of the Sickest, by Dr. Sharon Moalem, or the following sites:

Iron in biochemistry –

http://www.webelements.com/iron/biology.html

http://www.ncbi.nlm.nih.gov/pubmed/11160590

http://bloodjournal.hematologylibrary.org/content/112/2/219...

http://www.chemistry.wustl.edu/~edudev/LabTutorials/Ferritin/Ferritin.html

http://astrobiology.nasa.gov/articles/finding-iron-s-role-in-life-on-early-earth/

http://nautilus.fis.uc.pt/st2.5//scenes-e/elem/e02640.html

http://serc.carleton.edu/sp/mnstep/activities/36016.html

http://healthymeals.nal.usda.gov/hsmrs/Illinois.../Classroom_Activities.pdf

http://kidshealth.org/parent/medical/heart/ida.html

http://www.doctoroz.com/vp-videos/iron-absorption-animation

http://www.youtube.com/watch?v=g97zy_G_mYk

Hereditary hemochromatosis –

https://koshland-science-museum.org/sites/all/exhibits/exhibitdna/inh05text.jsp

http://www.youtube.com/watch?v=UeRr-S2aWrY&feature=related

http://www.authorstream.com/Presentation/MKDah-923675-hereditary-hemochromatosis/

http://kidshealth.org/parent/general/aches/hh.html

http://thisisnotaperfectworld.blogspot.com/

http://www.jbcc.harvard.edu/programs/manville/Sci_genetic%20sym.html

Y. pestis plague –

http://medievaleurope.mrdonn.org/lessonplans/plague.html

www.michrenfest.com/the_black_plague_classroom_simulation.pdf

http://www.mademan.com/mm/bubonic-plague-facts.html

http://theweek.com/article/index/233008/the-7-year-old-who-caught-the-bubonic-plague

http://www.themiddleages.net/plague.html

http://rarediseases.about.com/cs/bubonicplague/a/111602.htm

http://plague.emedtv.com/yersinia-pestis/yersinia-pestis.html

http://www.who.int/mediacentre/factsheets/fs267/en/

http://web.uconn.edu/mcbstaff/graf/Student%20presentations/Y.%20pestis/Yersinia%20pestis.html

http://www.atsu.edu/faculty/chamberlain/Website/lectures/lecture/plague.htm

http://www.youtube.com/watch?v=7l4gLPzE-B4

Immune evasion strategies –

http://crohn.ie/archive/primer/imunevad.htm

http://www.ncbi.nlm.nih.gov/books/NBK27176/

http://textbookofbacteriology.net/antiimmuno.html

http://www.nature.com/news/2011/110921/full/news.2011.550.html

http://www.science20.com/catarina_amorim/how_friendly_bacteria_avoid_immune_attack_to_live_happily_in_the_gut

http://www.wellcome.ac.uk/news/2009/news/wtx053411.htm

http://www.thepigsite.com/pigjournal/articles/1284/porcine-immunology-the-battle-between-the-immune-system-and-pathogens

http://f1000.com/reports/b/3/1/

http://www.sciencedaily.com/releases/2010/05/100523205818.htm

http://www.genengnews.com/gen-news-highlights/researchers-discover-how-some-pathogens-evade-the-immune-system/81243811/

Your Body Has A Photographic Memory

Biology Concepts – innate immunity, acquired immunity, memory response, influenza

Your body is exposed to tens of thousands of foreign molecules every day. Some can do you harm, some can’t. Your immune system sorts them by matching receptors on immune cells to molecules on the foreign objects.

Legos and biology are a good fit. They can be used to analogize the

rearrangement T cell receptor genes or hypervariable regions

of antibody genes, or they can be used to model the entire

body. One scientist uses them to model building

complex systems from repetitive units. And they’re fun.

Thinkof the receptors as Legos; your DNA provides for several different types of Lego blocks to be made, and your immune cells can rearrange the different types and put them together as a receptor, so there can be millions of different receptors. Each immune cell has just one type of Lego receptor, although it may have many copies of that one form. Each different Lego receptor will fit, key in lock style, with a specific foreign molecule.

The receptors exist on many types of cells, and antibodies sometimes function as receptors when attached to the surface of specialized immune cells. Even circulating antibodies (Ab) in the blood take the form of key and lock systems, whether as single Ab, dimers (2) or pentamer (5) complexes.

The immune system of higher animals can be described as several sets of pairs. Each member of a pair attacks a problem in a certain way, and has independent pathways, but each pair also has overlap and must work together in an overall response. We could spend weeks just on this system, but lets look at the major parts by describing each pair, from largest to smallest.

Innate immunityvs. adaptive immunity – the innate immune responses are fast but short. They don’t depend on your immune system recognizing the specific foreign molecule (antigen) with a specific receptor, but respond with the same types of reactions no matter what it is. Almost all plants and animals have some form of innate immune system.

Vertebrates take the immune system further. They have developed an adaptive immune system that does depend on your immune system recognizing the specific foreign invader. It then generates a tailored response to that one foreign organism or molecule. The faster, but more general, innate response helps the slower, but longer lasting and more specific, adaptive response to kick in.

These are cartoons of an antibody. The model on the left is a much

more realistic image. The Fc portion is the same through most

antibodies (c= constant), while the gene rearrangement takes place

in the light chain and heavy chain variable regions. The

different variable regions are the Lego blocks that can be put

together differently to make the millions of different antigen

binding sites.

Humoral immunityvs. cellular immunity – when an antigen is recognized by an adaptive immune cell (often through antigen presentation by the innate system), an early response is for the cell to divide and make more of itself. You don’t get sick from one bacterium infecting you; many infect you at once and then divide to become many more. You need many copies of that specific immune cell in order to battle the invading horde of bacteria.

The immune cells can generate an antibody response (humoral immunity) and/or trigger specific killing and directing cells to be produced (cellular immunity). The antibody (produced by B lymphocytes) is a protein that recognizes the specific antigen. The cellular immune response is mediated primarily by T lymphocytes.

However, B cell-produced antibodies are important for T cells to do their work, and antibodies also help the innate immune response to keep working after specific recognition has been made. In addition, the cellular immune response can control and ramp-up the humoral response. You see what I mean about each pair being separate but connected.

Effector T cellsvs. regulatory T cells – There are pairs of T cells as well. I use the term “effector T” cells to lump CD8⁺and CD4⁺ lymphocytes together (CD = cluster of differentiation markers on the cell surfaces). Effector T lymphocytes are either directly cytotoxic (CD8⁺, cyto = cell and toxic = damaging) or command (CD4⁺) the many adaptive responses. Effector cells are contrasted with regulatory cells, which include regulatory and suppressor T lymphocytes. The purpose of these cells is to stem the effector response so it doesn’t get out of hand; parts of the immune response are inflammation and non-specific cell killing – too much of that and you die too.

Memory Immune System – This last part of the immune response is not a member of a pair. When your innate immune system is activated, it ramps up, does its job, and hopefully is turned back off. The adaptive immune system responds to the antigen by producing more cells, antibodies and chemical signals (cytokines), and after the invader is vanquished you want this response to diminish as well. The innate system always starts over from zero, but the adaptive system remembers the infection you had.

The dendritc cell on the left is an innate immune cell that works

to present the antigen to the adaptive immune cells (Th1,

Th2, and B cells). The adaptive cells reproduce and make

cytokines to stimulate other immune cells. They also generate

some memory cells that recognize the same antigen, but stay

around for a long time and can react strongly and quickly.

Duringthe adaptive response, some of the produced immune cells become “memory cells,” they still recognize the antigen from the initial infection, but hang around in larger numbers; in many cases they circulate in your body for the rest of your life. If your body sees that specific antigen again, the memory response can be re-initaited very quickly and very aggressively. You might be infected again, but your memory response is so fast and effective that you never know it.

In a world without vaccines, you are infected, get the disease, recover (hopefully), and then have a memory immune system for that antigen. Vaccines take the initial infection and disease out of the equation; you get to develop a memory without having had the experience!

As we discussed last week with smallpox, vaccines present your immune system with the antigen in the form of a dead or weakened pathogen, or just the antigen molecule itself. Your body doesn’t know the difference, it develops an adaptive and memory response just as if it were the real infection.

In the majority of cases, you develop memory B and T lymphocytes when infected or vaccinated. However, there are exceptions. Most antigens cannot fully activate B cells to make antibody, they have to be helped along by antigen-activated T cells. But there are T cell-independent antigens that can fully activate B cells on their own. In these infections, you can develop a B cell memory without a T cell memory.

On the other hand, there are other infections that develop a full memory response, but it is not useful. Influenza is an example of this. Influenza has been around for thousands of years; some years we have severe epidemics or even world-wide pandemics. The 1918-1919 Spanish flu pandemic killed over 50 million people, many more than the contemporaneous WWI (16 million deaths).

Flu is difficult to vaccinate against because it keeps changing. Influenza virus has two antigens, called H (hemagglutinin) and N (neuraminidase). These are the molecules on the virus particle that your body mounts an immune response against.

The H molecule on the viral coat binds to sialic acid receptors on respiratory cells and allows the virus to enter. When the newly produced viruses bud off of the cell, they place H on the cell surface, but there are still host sialic acid receptors there as well. These receptors would bind up the H and prevent the new viral particles from attaching to and infecting other cells, so the N molecule cleaves the sialic acid receptors from the new viral particles.

Influenza virus can mutate by antigenic drift or antigenic

shift. The top line shows that by passing from person to

person, the antigens (and virulence) shift slightly. The lower

line shows that by passing through other animals and

recombining, the antigens can have small or big changes. When

shifted virus moves into humans, it’s a recipe for a pandemic.

Theproblem arises when the H and N antigens mutate.... and they do. Scientists have identified 16 different classes of H’s and 9 different N’s, and they can be paired up in many combinations. Small changes (antigenic drift) usually mean that memory might have a slight protective effect, and major epidemics do not occur. But major changes in H and N (antigenic shift) mean that previously infected people have no memory protection.

Different strains of influenza virus can infect the same animal (often pigs and ducks – thus avian flus and swine flus) and can mix their H’s and N’s. What emerges and might be transmitted to humans can be a virus with H’s and N’s similar to years past, or with new H’s or N’s. That is why a new vaccine must be produced each year, after scientists see which H’s and N’s the new virus has and how much they have drifted. Avian flu is H5N1, while swine flu is H1N1. However, antigenic drift means that each H1N1 will not be exactly like the previous H1N1 to emerge. The 1918 pandemic was caused by an antigenically shifted H1N1 sub-strain.

Like flu, other infections may not provide life-long memory. If the memory response is weak or the initial response was not strong, then memory may fade over time. This is why some vaccinations require boosters in later years. A fading of the memory response to influenza is also implicated in the need for yearly vaccinations.

Here's a great book that discusses both the biology

and sociology of influenza. There are great personal

stories as well as medical detective work. This

pandemic was a jolt that brought infectious

disease research into a new century. I highly

recommend it.

Now for the exception to the exception. Influenza changes each year, so memory does not help much, but a 2010 report from scientists in Hong Kong suggests that prior exposure to any seasonal influenza (either by infection or vaccination) might have been a contributing factor as to why the 2009 pandemic of antigenically shifted swine flu (H1N1) was much milder than expected.

The 2009 seasonal flu vaccine did not have any cross-reactivity with pandemic H1N1, so the scientists suggest that previous years seasonal influenzas did generate some memory response that was partially effective against 2009’s H1N1 swine flu. Cross-reactivity means that the H and N antigens were not identical to previous version; the Legos don’t fit together exactly, but they were similar enough to fit together and initiate a partial response. Once again, we see that getting sick may save your life down the line.

Next week will look at examples wherein having one disease can protect you from catching another.

For more information or classroom activities, see:

innate immunity:

http://pathmicro.med.sc.edu/ghaffar/innate.htm

http://www.arthritis.org/innate-immunity.php

http://highered.mcgraw-hill.com/sites/0072507470/student_view0/chapter22/animation__the_immune_response.html

http://www.virology.ws/2009/06/03/innate-immune-defenses/

www.garlandscience.com/res/pdf/9780815342434_ch02.pdf

www.youtube.com/watch?v=2CPbXaXKREg

http://missinglink.ucsf.edu/lm/immunology_module/prologue/objectives/obj02.html

http://www.nobelprize.org/educational/medicine/immunity//immune-detail.html

http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/phagoprocess.html