The Nature of Science

Showing posts with label innate 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

Don’t Be So Sensitive!

Biology Concepts – immune hypersensitivity, allergy, autoimmune disease

Stone Mountain in Georgia is one big hunk of

granite. There is a bas-relief carving of Jefferson

Davis, Robert E. Lee, and Stonewall Jackson that

covers three full acres of space! Stonewall Jackson

is on the far right. Stonewall immortalized on a

stone wall, interesting…. but didn’t their side lose?

C.S. Lewis was a 20^th century British writer who penned the Chronicles of Narnia books. Thomas “Stonewall” Jackson was a brilliant general in the Army of the Confederacy during the American Civil War. Can you name something these men had in common, but wish they didn’t?

---– They were both shot by their own troops during battle. It wasn’t on purpose; Lewis was wounded by a British shell that didn’t have enough oomph to get over the British’s own lines during World War I. One piece of metal lodged deep in his chest and could not be safely removed. It remained near to his heart until 1944.

During the Battle of Chancellorsville in 1863, Stonewall Jackson led a night reconnaissance mission that was mistaken for Union scouts. A confederate patrol fired on Jackson as he looked over the Northern lines from horseback. His left arm was amputated in an effort to save his life, but he died of pneumonia eight days later.

These were incidents of “friendly fire,” in which people meant to help you fend off the enemy end up hurting you. Too often, incidents of friendly fire take place in your body as well. In biology, these are called immune injuries and they can be dangerous exceptions. The immune system is designed to help the body fight off foreign invaders and dangerous molecules, but there are those instances when its actions harm the host.

Allergies are a good example of immune reactions gone wrong. Originally (1906) meant to denote any immune injury, we now we look at allergic reactions as immune responses to non-pathogenic, and in many cases, non-harmful antigens. Who could be harmed by a peanut, except for those allergic to it.

Peanut allergy is nothing to take lightly. It is

estimated that 3 million people now react to

peanuts, even to foods prepared in kitchens

where there are peanuts. This is an immediate

anaphylaxis response, with inflammation and

often respiratory distress.

A person can have an allergic reaction to an aeroallergen – something carried in the air, like dust, pollen, or pet dander. Food allergies occur generally with milk, wheat, peanut, or egg; many of these dissipate as children mature. Drug allergies can develop when small molecule pharmaceuticals break down, combine with host proteins or cells, and are then recognized as foreign. Some people are allergic to some venoms, like bee venom; their reactions can go beyond the pain of the sting.

In allergic reactions (atopic reactions – atopy is from Greek for “out of place”), there is first a sensitizing dose, wherein your body develops a hypersensitivity to the allergen. This is when your body builds an immunologic memory for the antigen, like we talked about a few weeks ago. Any exposure to the allergen after this brings a stronger response.

The exception to this sensitizing dose idea is when a new allergen looks like another allergen, ie. cross reactivity. Many latex allergies do not seem to have a sensitizing dose, but the patients also happen to have an allergy to banana, kiwi, or avocado. This is called the latex-fruit syndrome…catchy name, isn’t it?

Allergic reactions can occur just where the allergen contacts the immune system, like itchy hives (urticaria) for contact dermatitis, or a runny nose for pollens grains that are breathed in. Sometimes the hypersensitivity goes further and there is a life threatening reaction. We should describe the different kinds of hypersensitivity so you can diagnose your friends at parties.

Type I hypersensitivity is an immediate reaction, with symptoms lasting for a short time. Sometimes there is a more chronic response, especially if the antigen sticks around. Type I reactions are the allergies we all know and hate. The term for the reaction is scary, “anaphylaxis” (ana = exceedingly, and phylaxis = guarding), but it isn’t always life threatening.

In type I hypersensitivity, the allergen is recognized by specific IgE antibodies. Antibodies come in several flavors, including IgG (circulating antibody), IgM (antibody as cell receptors for first encounters), and IgA (in saliva and tears, etc.). IgE immunoglobulins are present in the tissues or on the surface of certain immune cells from some previous, sensitizing dose. The antibody has a variable end that recognizes the antigen and a constant end (Fc) which is recognized by other immune cells. When two or more IgE antibodies bind to the antigen (called crosslinking) and the Fc portion attaches to a mast cell or basophil, these immune cells will release their contents.

On the left is an electron micrograph of a mast cell,

an innate immune cell that mediates allergic responses.

On the right, you can see the granules inside the mast

cell that contain histamine, bradykinin, and other mediators.

When IgE and an antigen crosslink on the surface of the

cell, the granules release their contents into the

extracellular space.

Mast cells contain histamine, which causes blood vessels to dilate, airway smooth muscle to contract, itching, and stomach acid secretion. Mast cells also have bradykinin that increases mucous production, as well as other chemicals. Mast cell degranulation (release of internal granules containing the histamine, etc.) makes your eyes water, your skin get hot and itch, makes it harder for you to breathe, and might produce hives on your skin.

The reaction might remain local, but if it triggers the same reaction throughout your circulatory system, it can cause anaphylactic shock, a true medical emergency characterized by low blood pressure and respiratory difficulty. It can and will kill you if not treated immediately. And all this because some innocuous small molecule and an IgE antibody caused your immune system to over react!

Type II hypersensitivity reactions are also mediated by antibodies (IgM or IgG type). The triggering antigen might be some foreign molecule bound to a host cell or even an antigen on your own cells that your body has mistaken for foreign. In the case of penicillin allergy, the drug becomes bound to your cells; this complex triggers the immune response. If the antibodies are directed toward your cells or mistake your cells as foreign, this is called an autoimmune reaction. Examples could be systemic lupus erythematosus (SLE), some type I diabetes, or Hashimoto’s thyroiditis.

In some type II reactions, the antibodies that bind to the antigens trigger the complement system in your tissues to activate. Complement is part of your innate immune system that ends up marking cells for destruction by phagocytosis, or destroys them itself by punching holes in the target cells. In some cases, the antibodies bound to the cell trigger innate immune cells called natural killer lymphocytes – you can guess what they do to the target cell. I guess everyone is a natural born killer on the inside.

Natural killer cells are lymphocytes, but are part

of the innate immune system. These two are

attacking a cancer cell (red). Natural killers

specialize in killing cancer cells and virus-infected

cells. Natural killers are unique in that they can

recognize stressed cells in the absence of binding

antibodies.

The last type of immediate hypersensitivity is type III. The danger of this type of reaction comes from masses of antigens surrounded by antibodies. When these immune complexes (also called Ag-Ab complexes) become large, they can get stuck in tight places and bring an inflammatory response. Examples of immune complex diseases are autoimmune rheumatoid arthritis, some types of glomerulonephritis (inflammation of the filtering units of the kidney), and SLE also triggers this response.

Type IV hypersensitivity is the exception; this response can take several hours to develop and is the only hypersensitivity reaction that does not involve antibodies. Lymphocytes of the adaptive immune system interact with the antigen (be it foreign or domestic) and release many chemical mediators, called cytokines, that mediate immune and inflammatory reactions. Allergic contact dermatitis from poison ivy is a common, but relatively benign, example of this type of hypersensitivity.

Most hypersensitivities are reactions to things that shouldn’t have been problems in the first place. Allergies are just the most common manifestation of immune hypersensitivity. I don’t have them to any degree, but I see the havoc they wreak on my wife and our son. He is so allergic to wool that he breaks out when he counts sheep in bed!

But even allergies might have a hidden benefit. A study in 2008 indicated that people with allergies actually have a 25% less chance of developing a certain type of immune cell cancer, called B-cell non-Hodgkin’s lymphoma (NHL). If that person has three different allergies, they are 40% less likely to develop NHL.

This seems amazing, but it is supported by a 2011 study showing that people with allergies are 25% less likely to develop a type of brain tumor called a glioma. Glial cells protect and support the neurons in the brain; abnormal growth of these cells can lead to pressure and death of brain cells. Still think allergies are annoying?

Sneezes leave your mouth at over 100 miles and

hour and can spread droplets over 30 feet. Sneezes

may help get ride of unwanted antigens, but other

people don’t want them either, so cover your mouth.

Sneezing into the crook of your elbow is best for

limiting spray and contamination – I saw it on

MythBusters.

Researchersdon’t know the reason for this benefit yet, but hypotheses include that allergic reactions (watery eyes, sneezing, runny nose) help to eliminate potentially carcinogenic pollutants from our bodies, or that allergies stimulate the immune system and make it better at detecting and destroying cancer cells.

Learning that allergies might prevent cancer may make you less likely to take that antihistamine capsule. In fact, the treatment for all immune hypersensitivity reactions involve avoiding the molecule, removing the offending antigen and antibodies, and/or suppressing the immune system. We take corticosteroids, antihistamines, and other drugs to prevent the actions that might be saving us from cancer. However, you can help protect yourself without drugs as well—just catch a parasitic infection.

Parasitic worm infections, whip worm (Trichuris trichiura) or schistosoma for example, have a tendency to dampen the immune response, and can prevent some relapses in autoimmune diseases such as multiple sclerosis. A 2005 study indicates that some success has been had after dosing Crohn’s disease patient’s with intestinal worms.

Meet Pediculus humanus capitis, the common head

louse magnified only 80x. It is an ectoparasite,

meaning it lives on the host, not in the host. They

have been around for a long time; they have been

found on Egyptian mummies. This is why most

Egyptians shaved their heads and wore wigs.

For those of us without life-threatening autoimmune disorders, a 2009 study suggests that Pediculus humanus capitis infestations (head lice) can dampen the immune system enough to prevent allergies and some asthma attacks. Your choice - but don’t let anyone borrow your comb!

Parasites seem to have evolved specific mechanisms that inhibit the reactions that would eliminate them from the host, so they dampen immune responses as a defense. The mechanisms have not been worked out and may be parasite specific. Even malarial and leishmaniasis parasites can suppress the immune response, but I don’t recommend that you contract a deadly infection just to alleviate your allergies.

These last studies suggest that we may be living too cleanly – let’s take a look at that next week.

Calboli FC, Cox DG, Buring JE, Gaziano JM, Ma J, Stampfer M, Willett WC, Tworoger SS, Hunter DJ, Camargo CA Jr, Michaud DS. (2011). Prediagnostic plasma IgE levels and risk of adult glioma in four prospective cohort studies. J Natl Cancer Inst. DOI: 10.1093/jnci/djr361

Joseph A Jackson, Ida M Friberg, Luke Bolch, Ann Lowe, Catriona Ralli, Philip D Harris, Jerzy M Behnke, Janette E Bradley (2009). Immunomodulatory parasites and toll-like receptor-mediated tumour necrosis factor alpha responsiveness in wild mammals BMC Biology DOI: 10.1186/1741-7007-7-16

For more information or classroom activities, see:

Allergy –

http://onwebmanager.net/asthma/view/view.php?read_id=158

http://www.instructables.com/id/How-to-Teach-an-AllergyTissue-Lesson-for-the-Seas/

http://cilie-yack.org/sousclubcurriculum/99-unit-2/163-food-allergy-craft.html

http://missbakersbiologyclass.com/blog/2010/10/18/have-no-fear-food-allergy-prevention-is-here/

http://www.coloradoent.com/is-pediatric-atopy-preventable/

http://www.youtube.com/watch?v=JgTLBe2BfXY&feature=relmfu

Immune hypersensitivity –

http://pathmicro.med.sc.edu/ghaffar/hyper00.htm

http://archive.ajpe.org/view.asp?art=aj7308144&pdf=yes

http://sciencecases.lib.buffalo.edu/cs/files/immunology_notes.pdf

http://kidshealth.org/parent/firstaid_safe/emergencies/anaphylaxis.html

http://www.authorstream.com/Presentation/doctorrao-1213853-hypersensitivity-reactions-basics/

http://highered.mcgraw-hill.com/sites/0072556781/student_view0/chapter33/animation_quiz_5.html

http://highered.mcgraw-hill.com/sites/0072507470/student_view0/chapter22/animation__immune_complex_type_3_hypersensitivity.html

http://www.kosvi.com/courses/vpat5200/inflammation/imi/imi04.html

http://www.cehs.siu.edu/fix/medmicro/hyper.htm

http://highered.mcgraw-hill.com/sites/0073525634/student_view0/chapter14/animation__delayed__type_iv__hypersensitivity.html

http://www.proprofs.com/flashcards/story.php?title=lesson-17immune-disorders

http://loudoun.nvcc.edu/vetonline/vet211/immune%20dx.htm

http://www.enotes.com/topic/Type_III_hypersensitivity

http://www.lessonplanet.com/search?keywords=delayed+hypersensitivity

http://passel.unl.edu/pages/informationmodule.php?idinformationmodule=1014407503&topicorder=2&maxto=20&minto=1

http://www.youtube.com/watch?v=e1qpbOivO_Y

http://www.youtube.com/watch?v=JBLHPBRHHl8&feature=related

http://www.youtube.com/watch?v=hfODOGuKvEI&feature=relmfu

Autoimmune diseases –

http://www.nlm.nih.gov/medlineplus/ency/article/000816.htm

http://www.lessoncorner.com/Health/Disease_Prevention?page=13

http://ebookbrowse.com/lesson-7-autoimmunity-lesson-plan-eng-f1-doc-d74948975

http://www.scienceteacherprogram.org/biology/mjoseph201.html

http://www.lessonplanet.com/lesson-plans/autoimmune-disease

http://www.fas.org/immuneattack/teachersguide/lesson-plan

http://www.ck12.org/concept/Autoimmune-Diseases/

http://labtestsonline.org/understanding/conditions/autoimmune/

http://www.cidpusa.org/disease.html

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