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Month: October 2020

Fc Receptor Therapy

Fc Receptor Therapy

There are five types of immune proteins called immunoglobulins (Ig):  IgG, IgD, IgA, IgM and IgE.  In general, these immune proteins are an integral part of our host defense system.  However, just as Benedict Arnold turned traitor to the American cause, so too our immune proteins can sometimes go awry.  This is the definition of auto-immune disease, i.e. our own immune proteins attack us. 

There are two ends of all five immune proteins and they are called the F ab end and the Fc end.  F ab stands for “fraction that binds antigen”.  It is the end of the protein that has specific target recognition capabilities.  For instance, our Ig proteins we make from having been vaccinated for Tetanus have a very specific F ab end that only recognizes Tetanus, and thereby protects us from the disease by binding to it.

Fc stands for “fraction that is crystallizable” referring to how it was first discovered chemically – by crystallization techniques.  But the Fc end of the molecule controls the immune function of the protein.  The Ig exerts its effect when the Fc end of the protein fits into an Fc-receptor (much like an electric plug fitting into an outlet). 

In the case of auto-immune diseases this has provided a mechanism to treat these diseases.  To date, one of the most effective therapies for some auto-immune diseases is using intravenous immunoglobulin infusions (IVIG).  This treatment has been a God-send in a number of auto-immune diseases such as Kawasaki disease, dermatomyositis, toxic epidermal necrolysis, immune thrombocytopenic purpura (ITP) and Guillain Barre syndrome to name a few.  Basically, it works in part by flooding the body with Ig molecules containing Fc ends making it difficult for the abnormal Ig proteins to find an available Fc receptor.  Think of the plastic devices used to “childproof” electrical outlets.

New on the horizon is the development of monoclonal antibodies to block Fc receptors.  Currently there are seven

different monoclonal antibodies being developed for this purpose.  So far, they seem to be both safe and effective, but

none have been developed long enough to be FDA approved.  In addition to providing help for a whole variety of auto-immune diseases they may also find a very special niche in treating some fetal diseases during pregnancy.  Of special research interest in this regard are hemolytic disease of the fetus, fetal alloimmune thrombocytopenia and anti-Ro disease which causes fetal heart block. 

Air Pollution and Health

Air Pollution and Health

It may seem hard to believe but every day we breathe in more than 10,000 liters of air.  Depending on the degree of pollutants in that air, the human lungs can either cope with it or not. As I write these words, I can’t help but think of one of the “I Love Lucy” episodes where she and Ethel get a job in a candy factory hand wrapping expensive chocolates as they come down a conveyor belt.  Early on, the belt moves slowly and the girls do fine.  But as it speeds up, they can no longer keep up with the wrappings and resort to what many of you will remember as hilarious alternatives.  Unfortunately, our lungs don’t have a sense of humor and when overtaxed they become ill. 

Luckily our lungs have a number of good coping mechanisms, both mechanical and immunologic.  The airway epithelium cells have very tight junctions which create an excellent barrier.  In addition, the micro-cilia in the lungs are constantly beating to “fan” pollutants out of the lungs.  Finally, mucus production can trap particulates and dilute gases and vapors thereby reducing their toxicity.  Surfactant, a second cousin to mucus, also is very effective in diluting and detoxifying gaseous pollutants including ozone. 

There are a variety of immunologic defense mechanisms, most of which work by removing free radicals and reducing oxidative stress on the delicate lung tissues.  However, when exposure is too great or prolonged over time these systems fail with two negative consequences.  One is inflammation which leads to lung damage and scarring and the development of COPD.  The other is greater propensity for infection.  If the tight junction barrier is faulty it allows microbes easier penetration into lung tissue.  And, if the protective immune responses are over-taxed, they can’t adequately shift from pollution protection to microbial defense. 

T3SS and T4SS

T3SS and T4SS

Even though bacteria far predate human existence, we have co-evolved once humans hit the scene.  It may be hard to believe in terms of cell count but our total number of human cells (10 trillion cells) is exceeded by a logarithm by the number of bacteria in our microbiota (100 trillion cells).  We humans carry roughly 35,000 different species of bacteria on us and in us.  Despite the very large variety of bacteria on planet earth only about 100 species cause human illness.  But, these 100 have endured in large part because of adaptations to evade human defense mechanisms. 

One such system is the “secretion system”.  The two most common of which are: type 3 secretion system (T3SS) and type 4 secretion system (T4SS).   One such system made the news the year one of this newsletters authors was born, 1976.  Legionella has used T4SS for a very long time to avoid destruction by one of its natural predators: amoeba.  At an American Legion meeting in Philadelphia in 1976 amoebas (containing Legionella) contaminating the air conditioning ducts in the hotel were inhaled by conventioneers.  Thirty-four people died from the bacteria leaving its safe haven of the amoeba and entering the lungs of the humans.  Hence, the bacteria using this T4SS survival tactic was christened “Legionella”. 

Enterohemorrhagic E. coli (O157) uses a T3SS protein to cause the severe bloody diarrhea that can occur from ingesting contaminated/undercooked meat.  In this case the E. coli uses the T3SS protein to lock itself to the human intestinal cells so it can’t be displaced, meanwhile releasing a toxin that causes the bloody stools. 

H. pylori (another GI pathogen) uses T3SS to lock itself on to stomach cells.  Once firmly attached it then releases another protein called urease, which neutralizes stomach acid so the acid can’t destroy the bacteria.  H. pylori causes stomach ulcers and if it remains untreated over time can cause stomach cancer.  To date, it’s the only bacteria known to cause cancer.

One final example is Yersinia pestis the bacteria that causes plague.  Once Yersinia enters the human blood stream via a rat bite, it is immediately swallowed by our white blood cells.  But before the white blood cells can destroy the bacteria, the Yersinia releases T3SS which inactivates the immune proteins.  The Yersinia then uses its inactivated white blood cell as a taxi cab to carry it throughout the human body.  Perhaps the early Greeks had already known about Yersinia’s trickery leading to their application of treachery via the Trojan horse. 

As bad as this all sounds, the good news is that humans have evolved a multi-dimensional brain.  This in turn has led to many new strategies to fight the pathogenic bacteria.  Two therapies currently being developed are glycodendrimers and pilicides, both of which inactivate the T3SS/T4SS molecules.  Also, in the works is a genetic vaccine that also inactivates the T3SS/T4SS molecules.  Finally, a chemical called salidylidene acylhydrazide is being researched for its ability to prevent bacteria from secreting the T3SS/T4SS proteins. 

Dear Dr. K,

Dear Dr. K,

Recently I got a severe leg abrasion when I had an accident on my motorcycle.  I needed surgery to clean the leg and stop all the bleeding.  Three days later my leg got red and swollen and itched.  My surgeon gave me an antibiotic thinking it was infected.  But the culture was negative, and the leg kept getting worse.  Then, he gave me prednisone and the leg got better quickly.  Any ideas?

Well, I’m no Dr. House, but since I know your food allergies include gelatin, I suspect you reacted to a hemostatic agent containing gelatin.  “Hemostatic” means to stop bleeding and hemostatic agents are vital to surgeons.  Gelatin is used in many of them because its’ protein structure provides a scaffold that promotes clot formation.  It is available in two forms:   a matrix (sponge, film or powder) or as a foam.   Examples in common use today include:  Surgifoam, Surgiflo, Gelfoam, Floseal, MeroPack, Thrombi-Gel, Gelfoam, and Optisphere.  There are non-gelatin products available that are made from cellulose. 

Unfortunately, the story doesn’t end there as you need to be aware of gelatin exposure in other medical settings.  Some medical devices contain gelatin.  Some vascular grafts contain gelatin as do some heart valve replacements.  Some bone replacement implants contain gelatin and are used in both skeletal and dental products.  IV fluids are generally safe but some of what are called colloid fluids (often used for patients in shock) contain gelatin.  As it turns out, no colloid fluids in the USA contain gelatin, but gelatin containing fluids are frequently used in Europe. 

Many medicines contain gelatin either to form the capsule (for example Advil Liqui-gels) or as a binder.   Since the number of OTC and prescription drugs is so large, it is advisable to read labeling on any medication you plan to take.  A few intraocular lens implants (used in cataract surgery) contain gelatin, but most do not. 

Finally, some vaccines contain gelatin.  Most notable is the MMR vaccine.  There is an interesting side story to the MMR vaccine that is worth mentioning.   Although allergic reactions to MMR are rare, when they do occur doctors initially thought it was due to egg allergy as the vaccine is prepared in an egg medium.  But when these cases were more closely studied, it turned out that the gelatin, not egg, was the provocateur.  Actually, children with egg allergy an receive MMR without any concern for allergic reaction.  A few other vaccines may contain gelatin depending on the manufacturer:  rabies vaccine, typhoid vaccine, yellow fever vaccine, and one type of flu vaccine.