Biology 466    Unsolved Problems Fall 2011

Key facts about antibodies and immunity (in [higher]vertebrates) Albert Harris, September 20, 2011

B lymphocytes are a special cell type that secretes antibodies.
Antibodies are (several) special kinds of protein, that have 2 or more binding sites where their amino acid sequence folds to form shapes that are all the same for all the millions of antibodies made by a given B lymphocyte, and for its mitotic daughter cells. They only make one shape binding site. The shape of these binding sites result from their amino-acid sequences, which result from the DNA base sequences of "variable sequence regions" in the genes that code for antibodies. Unlike other genes, these variable sequence regions are not inherited, and did not evolve.
Variable sequence regions are spliced together during embryonic development, using multiple V, D and J DNA sequences, plus random additions of base pairs where these join. The randomness of this splicing means that each embryo produces billions of different-shaped binding sites, including binding sites that fit all the normal proteins (and all other molecules of a person's body).
Auto-immune diseases result from failure to eliminate any of the lymphocytes whose binding sites happen to fit any molecule of your own body. This is very, very important to understand, but most biologists and biology textbooks miss the point.
"Self" molecules have no special property that can be recognized, although 50 to 100 years ago, that was one of the theories about how the immune system might work.
Another mistaken idea is that antibody binding sites are 'made to order', in the sense that when binding sites of a certain shape are needed (to attack a germ, for example), then some mechanism picks out the correct combination of V, D and J regions of DNA, and splices them together. I have heard this taught in more that one section of this department's Cell & Development core course.
The word "antigen" means any molecule to which an antibody binds selectively, and its etymology reflects the false belief in induction of particular shapes of antibody binding sites.

There are several different kinds of T-lymphocytes, with different functions. Some stimulate B-lymphocytes, and "natural killer cells" attack cancer cells non-specifically (based on lack of histocompatibility antigens). "T" stands for the thymus "gland", where T cells are induced to differentiate. The thymus develops from the third & fourth gill slits in land vertebrates.
Fish use their gill slits to breath, and I don't know what induces differentiation of their T-lymphocytes. Most T-lymphocytes use random DNA splicing (of different DNA sequences than B-lymphocytes use) to create randomly-shaped binding sites, very much like antibodies, that remain attached to the cells.
Immunity to viruses is caused by T-lymphocyte binding sites binding to ("recognizing") virus peptides that are being held by binding sites on type I histocompatibility antigens (better if these were called "peptide grabber-displayers"). Virus infected cells are induced to undergo apoptosis by T-lymphocyte binding specifically to their outer surface. Poison ivy kills skin cells by binding of the chemical urushiol to cells, which somehow induces binding of T-lymphocytes, but only after a person has enough prior exposure to urushiol. Ironically, people who think that they are "immune" to poison ivy (because they are not sensitive) actually are not yet immune. This and all other allergies are actually immunity. Allergies are the immune system attacking some antigen that would not otherwise be harmful, like pollen, poison ivy, animal fur, "dust mites" etc. That's why the symptoms are so much like colds & other mild viral diseases.

Autoimmunity is self-allergy: immune attack against one or more normal specific proteins of your own body. For example, if you have B-lymphocytes that secrete antibodies that fit DNA, RNA, and/or collagen or histones, the result is called Lupus Erythematosus, which sickens tens of thousands and kills thousands, including children. Another auto-immune disease is named Multiple Sclerosis; it is caused by T-lymphocytes whose binding sites (misleadingly named T-cell receptors) bind a specific protein in the myelin sheaths surrounding nerve axons inside the brain & spinal cord (but don't attack myelin made by Schwann cells of the peripheral nervous system; nobody has any good idea why!).
If antibodies attack connective tissue of joints, that's called Rheumatoid Arthritis. Sometimes lymphocytes destroy the beta cells that secrete insulin, and this is the cause of Type I Diabetes.
Pernicious anemia is caused by immune destruction of an intestinal protein needed to absorb vitamin B12.

The total number of autoimmune diseases may be as many as a hundred, but not much more.
One unsolved problem is why there are not thousands of such diseases, one or more for each kind of protein in the body. Injection of rats with nearly any human protein will stimulate antibodies against it.

Most people (and most textbooks) make the fundamental mistake of thinking that it's an unsolved problem why and how the body generates antibodies against its own molecules (& T-Lymphocyte binding sites). The reason for this is one of the few things that is absolutely understood.

It's because the DNA sequences for the binding sites are generated by random recombination. Imagine we have some cards, & each card has a letter of the alphabet printed on it. If we randomly take a series of these cards, occasionally they will spell my name or your name. Random "choices" produce every different possible result. Genes for antibody binding sites are produced by random choices of DNA base sequences. This produces antibodies "against" (meaning "that bind to, specifically") every shape molecule. Your immune system started with lymphocytes specific against every molecule in your body, and against every molecule in a rat's body, and every organic molecule that's ever been made, or can ever be made. The miracle is that we don't all have every autoimmune disease, and thousands more. The reason we don't is that some mechanism (that really IS unsolved) weeds out every lymphocyte whose binding sites fit any molecule in your body. We can call this "the self-tolerance mechanism". The favorite theory about how this works is that during embryonic development contact of any lymphocyte with antigens that fit its binding sites induces apoptosis of that lymphocyte. Although, ~98% of immature lymphocytes really do undergo apoptosis, and injection of antigens can sometimes induce tolerance to them, nobody really knows how tolerance is produced, or what went wrong in victims of autoimmune diseases, or how to fix whatever went wrong.

The real unsolved problems are:

    What mechanism detects which lymphocytes are making anti-self binding sites?
    Are these anti-self lymphocytes caused to die, or inactivated, stored somewhere, or what?
    What goes wrong, producing autoimmunity? Reactivation? Mutation? Further recombination?
    (How) Can the normal mechanism of tolerance be reactivated, so as to cure autoimmunity?

Plus some lesser questions, the answers to which might open the path to cures:
    Two thirds of random recombinations ought to produce frame shifts: 5 times 1/3 is small.
    How do lymphocytes detect "non-productive recombinations"?
    Every diploid cell has two do-it-yourself-kits for random generation of heavy chain sites,
    And four such two do-it-yourself-kits for light chains.
    (& tetraploid cells would have four heavy chain 'kits' & 8 light chain kits.
    (Many species of animals are tetraploid, Xenopus laevis is an example.)

    Nearly all autoimmune diseases occur at much higher percentages in women than men (nine to one ratio in Lupus). Is this because one or the other X chromosome is suppressed randomly in each cell of mammals (except marsupials, which always suppress the father's X) Or is it because of sex hormones, &/or increased overall strength of females' immunity? (That would imply that quantitative excess of amount of immunity is a problem)

    Why is the frequency of multiple sclerosis twice as high in people who spent their childhood north of the Mason-Dixon line, as compared with The South, and still lower in the tropics?

    What causes tissue damage by multiple sclerosis and lupus to occur in sudden attacks, and at localized anatomical positions?

How much are our effective IQs held back by misleading vocabulary, such as "Antigen", "Recognize" "Self", "Immunity", "Tolerance", and "Histocompatibilty".

Could less misleading words make us effectively smarter? Enough to perceive the breakthrough cures?


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