Wednesday, May 25, 2016

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 20th 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.
Researchers don’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 –

Immune hypersensitivity –

Autoimmune diseases –