March 26 and 28, 2018

Immunology, Allergies, and Autoimmune Diseases in Relation to Embryology

 

Immunity and Autoimmune diseases (Multiple Sclerosis, Lupus, Rheumatoid Arthritis)

Multiple sclerosis paralyzed, tortured and killed the young cellist Jacqueline du Pré
who is playing Elgar's Cello concerto in this recording.

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I want to persuade you that immunity, allergy and autoimmune diseases are embryological phenomena,
caused by events that happen in the embryo, and processes that go wrong in the embryo.
You may be the person who invents a cure for MS, Lupus, RA & the many other autoimmune diseases.

    b cells (b lymphocytes) make antibody proteins, with special binding sites

    t cells (t lymphocytes) make "t-cell receptors", which have special binding sites

T-cell differentiation is induced by induction in the thymus "gland".
In birds, b-cell differentiation is induced by the "Bursa of Fabricius"
(an intestinal organ that mammals don't have; but we do have b-cells)
[everybody hopes they are induced by something that starts with the letter b!]

What goes wrong is THE FAILURE TO WEED OUT a lymphocyte whose binding sites selectively fit some normal molecule that is part of your body.

EVERYBODY STARTS LIFE WITH MILLIONS OF LYMPHOCYTES, WHOSE BINDING SITES
FIT EVERY MOLECULE IN YOUR BODY, AND FIT EVERY POSSIBLE GERM OR MOLECULE.

WE THEN WEED OUT EVERY LYMPHOCYTE WHOSE BINDING SITES FIT ANY NORMAL MOLECULE OF OUR BODY.

But suppose some lymphocytes escape this weeding out?

Then they will make antibodies that bind and attack your own molecules.

It is NOT abnormal to create these anti-self lymphocytes. Everyone creates them.
The weeding-out mechanism works almost perfectly.

How does this weeding-out work? ...so we can fix it when a lymphocyte escapes weeding.

      This is one of the greatest, most demonic, evil of all unsolved questions, in all of science.

A major reason this problem can't be solved is that most biologists get taught something wrong;
they think the mystery is why the immune system should ever make anti-self lymphocytes.

But that's not the mystery.
We completely KNOW how and why the immune system can't avoid creating anti-self lymphocytes.

For every possible molecular shape, b and t cells develop whose binding sites fit that specific shape.

As an analogy, imagine synthesizing all possible chemicals,
               then getting rid of all the poisonous chemicals,
                                  and keeping all the rest.

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *

Antigens are molecules that fit antibody binding sites, or fit t-cell receptor binding sites.

Antibodies fit the shapes and charge distributions of their particular antigens
the way a glove fits a hand or the way an enzyme fits its substrate chemical.

Germs are attacked by making antibodies that exactly fit their surface molecules.
This fitting causes germs to be chemically damaged and chemotactically attracts leucocytes.

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *

BUT ANTIGENS DON'T STIMULATE SHAPES OF BINDING SITES

For many years, scientists believed that antigens stimulated shaping of binding sites;
and the word antigen deliberately implies shapes being made-to-fit.

The true explanation was figured out in the 1950s, 1960s & 1970s.
This was a huge revolution, that turned the whole field upside down.

First proposed by Jerne as the Natural Selection Theory of antibody formation
It was soon changed into The Clonal Selection Theory by McFarlane Burnet.

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *

Your life depends on the proper functioning of your immune system:

1) Specifically the ability of your B-lymphocytes to make antibodies
(antibodies are a certain kind of protein)
with binding sites whose shapes exactly fit and bind to germs.

2) Your survival depends even more on the ability of your T-lymphocytes to make another kind of binding sites located on the outer surfaces of T-lymphocytes and called "T-cell receptors". One of their functions is to stimulate apoptosis [self-digestion] of virus-infected cells.

You can survive without B-lymphocytes,
but lacking them makes you much more susceptible to infectious diseases, especially diseases caused by bacteria.

Without T-lymphocytes, you can't live long,
partly because some of the T-lymphocytes serve to control B-lymphocytes.

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4 key words and concepts:

Antigen; Immunity; Allergy; Autoimmune Diseases.

Any molecule that fits the binding site of an antibody is called an antigen.

Proteins, sugars, plastics, anything, even other antibodies, can all be antigens, in that some antibody binds them.

The word antigen came from the false idea that antigens somehow shape the binding sites of antibodies.

Unless you make binding sites that fit germs, then the germs kill you.
If you make enough binding sites that fit a kind of germ, then they make you immune to that kind of germ.

If some of your antibody binding sites fit pollen, or some plastic, etc. the result is called an allergy
= immune attack against anything harmless, except for this attack.

Autoimmune diseases are anti-self allergies.
If you make antibody or T-cell receptor binding sites that fit any of the thousands of molecules that your own cells & body is made of, the result is an autoimmune disease.
(which amounts to a self-allergy).

++++++++++++++++++++++++++++++++++++++++++++++++++

Autoimmune diseases result from failure of a certain embryonic mechanism that normally gets rid of lymphocytes whose binding sites fit any molecule normally found in your own body.

The abnormality is not getting rid of those anti-self lymphocytes.
It's normal to for embryos to start by creating anti-self lymphocytes, but then a (mysterious!) mechanism is supposed to get rid of them.

90% of biology students (& textbooks) never get this straight;
I think that's why cures for autoimmune diseases haven't yet been invented.

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You do not inherit the genes for antibody binding sites!
Instead your genes contain a "do-it-yourself-kit" for random generation of DNA sequences that code for all possible shapes of binding sites.

All the nuclei in your embryo start with several sets of repeated DNA sequences like this,

 

      

  and there are separate V and J sequences for making light chains,

plus different equivalents for T lymphocytes.

During the differentiation of B lymphocytes, random recombination occurs like the following:

 

      

 

There would be a total of 160 different possible combinations, if you had just ten Vs and 4 Ds and 4 Js, butin addition...
* there are more than a hundred Vs,
* heavy and light chains of antibodies form separately (so 160 x 160 =?),
* there is more randomness in the exact sites of recombination,
* in B-lymphocytes, the binding site genes have very high mutation rates.

The following drawings are meant to help you visualize these strange concepts:

By means of this random VDJ recombination, your embryo created billions of clones of lymphocytes, each making different shaped binding sites.

All the binding sites made by any one lymphocyte have all the same shape; and when that lymphocyte divides mitotically, then both the daughter cells make binding sites with that same shape (except for mutations), etc.

Millions of those lymphocytes made binding sites that fit some molecule that is part of your body. Some mechanism either killed or inactivated those anti-self lymphocytes. Unfortunately, this weeding-out mechanism is not understood well enough to be controlled.

When the weeding-out fails (even a little) you get an autoimmune disease.

If you discover how to stimulate weeding-out, you could cure those diseases.

REVIEW OF THE SUBJECT UP TO THIS POINT:

a) Why do we need an immune system?

b) What two differentiated cell types do the attacking?

c) Do they ever attack anything other than germs? 2 examples.

d) An "antigen" is any molecule that is selectively bound to by (what parts of?) proteins called what?

e) Which are made and secreted by what differentiated cells?

f) Virus-infected cells are induced to do what?

g) This is accomplished by what other differentiated cell type?

h) The "Generator of Diversity" accomplishes what?

i) What is unusual about the genes for antibody binding sites?

j) Which is more surprising? That people EVER make anti-self binding sites, or that this doesn't happen much more frequently?

k) How much did you already learn about immunity in High School, Introductory Biology, or "Cell and Development"?

* My blood is type A.

** None of my lymphocytes make antibodies whose binding sites would fit the type A blood group antigen. If any did, those antibodies would kill me.

*** All such (Anti-A) lymphocytes were selectively eliminated or inactivated (or something!?) selectively by an unknown mechanism during my embryonic development (or maybe later).

EMPHASIZE: Anti-Self lymphocytes are generated by the same random recombination process that generates all the anti-germ and anti-pollen lymphocytes.

You generate all possible anti-anything lymphocytes, and then some unknown mechanism gets rid of the anti-self lymphocytes.

IT'S DEFINITELY NOT THAT YOU HAVE ANY METHOD THAT AVOIDS FORMING THE ANTI-SELF LYMPHOCYTES IN THE FIRST PLACE.
(But lots of people who should know better still assume that!)

Instead, it's random generation of lymphocytes with all possible shaped binding sites,

     followed soon by selective elimination of anti-self lymphocytes,

          followed later in life by selective increases in anti-germ lymphocytes.

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The Parable Of Identifying Outsiders Based On Whether Glass Slippers Fit Their Feet

I) First, have a glass-blower make thousands of different glass slippers, each one slightly different in shape, and fitting different shaped feet.

II) Second, at the beginning of the semester, have everybody in the class try on all of these thousands of differently shaped glass slippers.

III) Any time a particular glass slipper actually fits somebody's foot, that slipper is completely broken, beyond repair.

IV) Later in the semester, everyone who comes into the room is required to try on all the remaining glass slippers.

V) Whenever one of the remaining glass slippers fits the feet of someone, we know that person must be an outsider.

[Please, don't anybody suggest this method to the airport security people.]

Discussion question: Try to invent a glass slipper analogy to the "self-non-self" mistake about how the immune system works.

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2 key concepts: Vaccination & Adjuvant

Vaccination works by stimulating this selective increase in lymphocytes, without having to suffer from the actual diseases.
Vaccines consist of molecules from a particular kind of germ, combined with irritant chemicals like alum salt and mineral oil, that (somehow!) increase the stimulation of lymphocytes.

These irritant chemicals are called "adjuvants".

A Wikipedia article calls these adjuvants "the dirty little secret of vaccination", because they aren't mentioned much and nobody really understands how they work, nor how to find better ones.

Imagine inventing the equivalent of an adjuvant, that would stimulate the selective elimination stage of the immune process (producing self-tolerance).

For example, imagine co-injecting myelin proteins plus your "tolerance-adjuvant", and curing Multiple Sclerosis by causing the same normal selective elimination of anti-self lymphocytes.

Or you could cure Lupus by injecting your "tolerance adjuvant" combined with DNA, RNA, histones & lipids.

Or you could cure rheumatoid arthritis by injecting your "tolerance adjuvant" combined with the appropriate antigens, which in that case might include cartilage, collagen and antibody molecules.

You could be the first person ever to win the "Swedish Lottery" 8 times in succession!

(Those dental schools would be eating their hearts out, wishing they had admitted you.)

?????????????????????????????????????????????????????????????

Why haven't such cures already been invented? 4 main reasons:

#1) Cortico-steroid drugs are available to suppress and delay the symptoms of autoimmune diseases, and so are cancer chemotherapy drugs, beta interferon, etc. none of which have the slightest chance of curing people. But it's a full time job adjusting their dosages, and this process feels kind of as if the disease were being treated.

#2) The words "recognize" and "self" sound like explanations , but badly confuse, muddle & misguide people's thinking.

The "r" word and the >"s" word should be banned, in my opinion!

These two tricky words make people assume that the reason their lymphocytes don't attack their red blood cells, for example, is because all their own cells and molecules must carry something analogous to little badges or passports, that lymphocytes detect and avoid, maybe because they match the lymphocytes' own badges. That's completely the wrong way to think about immunity.

#3) Textbook "Aesop's Fables"

Cowpox, vaccination, Edward Jenner, and all that.

Somewhere in Asia, in the middle ages, someone discovered that deliberately infecting healthy people with weak cases of smallpox will produce life-long immunity to this disease, although killing around 1 or 2 % of those deliberately infected.
Compare this with the 30-50% death rates of those who caught smallpox by accident, and the large fraction of the population who got smallpox at some stage of their life!

The wife of the British Ambassador to Turkey had her own children "variolated" (=deliberately infected with scabs from smallpox victims in 1718), and told Queen Caroline about this method. The British Royal family then did experiments, first variolating convicts who had been condemned to death, and then putting them in close contact with people dying of smallpox. The prisoners did not catch smallpox. Then this same experiment was repeated using orphans. They also became immune.

Then the children of the King and Queen were variolated (in 1722, according to Wikipedia)
The variolation method was widely used by English and American physicians for the rest of the 1700s, and was a major part of the medical practice of the famous Dr. Edward Jenner, who invented vaccination around 1799.

When variolating patients, Jenner noticed that many people who worked around horses and cows (blacksmiths, farriers and milkmaids) seemed already to be immune to smallpox, from which Jenner (eventually) concluded that infection with cowpox is a safer way to become immune to smallpox. (For a while, he believed cowpox was a disease of horses' hoofs).

During the early 1800s, vaccination (= deliberate infection with cowpox) replaced variolation (deliberate infection with smallpox). Vacca is Latin, for cow; similar to Spanish "Vaca".

Elementary textbooks copy from each other a sort of Aesop's fable about Jenner having noticed the smooth complexion of milkmaids. Everyone gets taught this.

Pasteur invented the key idea of deliberately weakening or killing germs, as a means of generalizing the basic variolation method, in order to extend the method to unlimited ranges of other diseases.
Pasteur generously proposed using the word "vaccination" for all methods of this type, in honor of Jenner
- but this choice of words launched a thousand milkmaids.

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Cowpox was a very unusual case. Usually, viruses produce worse symptoms in species other than the species that they usually infect, and are often fatal.

For example, AIDS somehow jumped from chimpanzees and a kind of monkey, to humans; and in recent years there have been several such epidemics (Parvo in dogs, SARS in humans, and many other examples) that killed high percentages of the newly-infected species.
Viruses usually evolve toward being less lethal for new species.

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#4) Propaganda against Darwin holds back discoveries in immunology.

Inside each person's body, beginning in embryonic development, lymphocytes evolve the shapes of their binding sites by random variation and selective elimination. Understanding Darwinian evolution is therefore essential for scientists to be able to make sense of the immune system. You don't have to believe it; but if you don't understand Darwin, then immunity won't make sense to you.

Opponents like the movie "Expelled" hold back finding cures for immune diseases.
Not believing in natural selection makes as much sense as not believing in germs.

Research science is the area of modern life with the best system for submitting even far-out ideas for fair, unbiased judging of the evidence and arguments followed by international publication.

My own work on cell traction and muscle formation was very far-out, but it was judged and accepted by Nature, Science and other journals.

Darwin himself proposed and carefully considered possibilities that would now be called "Intelligent Design", but the evidence eventually confirmed natural selection as the true explanation.

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One last connection between Embryology and Immunology

* Differentiation of precursor cells to become T-lymphocytes is induced (in Spemann's sense of "induced"), i.e. stimulated to differentiate by signals they receive when staying in the thymus "gland".

The thymus develops from the third and fourth gill slits, and was believed to be vestigial until the 1970s.

Vestigial in the sense of serving no function, but just being left over from our evolution from fish.

Mutations (or early surgery) which prevent formation of the thymus result in failure of T-cells to differentiate.
("Nude mice" have hardly any T-lymphocytes)

** Differentiation of B-lymphocytes is induced (again, in Spemann's sense of embryonic induction) by (and also IN) an outpocketing of the intestine called the Bursa of Fabricius, found only in birds.

T is for thymus, although fish don't have them.
B is for Bursa, although only birds have them.

Some other tissue must induce differentiation of B lymhocytes in mammals!? and everybody hopes the name of this tissue must start with a B.

Textbooks confidently claim that bone marrow serves this inductive function, but this is mainly because bone marrow starts with a B.
The real evidence has not been strong.

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