Biology 466 Unsolved Problems Fall 2011
B lymphocytes are a special cell type that secretes antibodies.
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.
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!).
The total number of autoimmune diseases may be as many as a hundred, but not much more.
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:
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?
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?
Could less misleading words make us effectively smarter? Enough to perceive the breakthrough cures?
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