Embryology   Biology 441   Spring 2011   Albert Harris


Embryology of the Immune System



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.


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 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 include Multiple Sclerosis, Lupus, Rheumatoid Arthritis, Childhood Diabetes & dozens of other of the most cruel and life-ruining diseases


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.


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



 in 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.


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.

(But lots of people who should know better still assume that!)

Instead, it's random generation of lymphocytes will 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.


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 only 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.


#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.


One last connection between Embryology and Immunology

* Differentiation of precursor cells to become T-lymphocytes is induced (in Spemann's sense of "induced" 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 lymphocytes 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.

Autoimmune Diseases

1) When your immune system attacks molecules or cells that are normal parts of your own body, then the result is called an "autoimmune disease".

2) Autoimmune diseases include Multiple Sclerosis, Childhood Diabetes (= type one diabetes), Lupus, Rheumatoid Arthritis, Mumps-induced male sterility and dozens of others.

3) Each of these diseases is caused by having lymphocytes that make protein binding sites that have just the right shape to bind some particular normal molecules of your body. MS results from lymphocytes attacking the myelin sheaths of nerves: Lupus is caused by lymphocytes that make antibodies whose binding sites fit DNA, histones, collagen and many other normal molecules.

4) Tens of millions of Americans suffer (and hundreds of thousands die) from autoimmune diseases.
A fundamental cure for any one of these diseases should quickly lead to cures for the others.
A student in this class could be the one to discover such a cure.

5) Instead of finding actual cures, modern medicine is satisfied to treat only the symptoms, by non-specific suppression of the whole immune system (especially with corticosteroids) although this weakens your immune resistance to infectious diseases, and has no chance of actually curing autoimmune diseases.

6) Vertebrate immune systems work by random generation of billions of clones of lymphocytes, each of which makes different-shaped antibody (protein) binding sites or T-cell receptor binding sites. You do NOT inherit genes for these binding sites. What you inherit amounts to a do-it-yourself kit which each lymphocyte uses to create randomly-shaped binding sites.

7) During everyone's embryonic development, as soon as T and B lymphocytes begin to differentiate, every person randomly generates billions of clones of lymphocytes, each of which produces antibodies (or equivalent proteins) with that lymphocytes own special shaped binding site.

8) Everyone develops thousands or millions of anti-self lymphocytes, that will cause autoimmune diseases if these antiself lymphocytes are not inactivated, desensitized, disabled, hit on the head, persuaded to repeat the randomization process for generating binding site DNA sequences, locked up somewhere, or something!

9) This (still unknown!) mechanism for selectively eliminating antiself lymphocytes is called "The Tolerance Mechanism" (or the Self-Tolerance mechanism).

10) Nobody really knows for sure how this self-tolerance mechanism works, except that it acts by weeding out lymphocytes that somehow detect that they are making binding sites that would bind to some "self" protein or other molecule.

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