April 18, 2016
Autoimmune Diseases in one easy Lesson:
Theories in ITALICS.Facts in REGULAR TYPE.
Matters of life and death, UNDERLINED.
1) Shapes on binding sites are randomly created by DNA splicing.
2) Vaccination works by stimulation of just those lymphocytes whose binding sites fit germ chemicals.
3) The reason your own molecules rarely get bound by antibodies is because of (i) apoptotic self-destruction of any lymphocyte whose binding site fit any of your own chemicals.
[Or maybe...because of (ii) reduced sensitivity of anti-self lymphocytes.]
(iii) Can't detect antigens? (iv) Can't secrete antibodies? (v) Can't divide?
[Or maybe...because anti-self lymphocytes (vi) go to some hidden location.]
[Or maybe...because anti-self lymphocytes went through (vii) more VJD splicing]
[Or maybe...the same (viii) suppression as VJD splices that have frame shifts.]
[Or maybe...because( ix) anti-self lymphocytes get attacked by T-lymphocytes.]
Anti-self lymphocytes are (i, ix) dead, (ii, iii, iv, v, viii) insensitive, or (vii) have changed their binding site shapes.
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Possible causes:
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Survival
of apoptotic self-destruction.
Re-activation of inactivated lymphocytes.
Re-activation of VJD recombination, perhaps on the homologous chromosome.
Escape from hidden location.
NOTE: Childhood Diabetes is an autoimmune disease, that starts in babies.
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Alternative criteria for distinguishing self versus alien-shaped molecules.
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a) Presence in the early embryo.
b) Continuous presence.
c) High concentrations
Clues that may narrow the range of possibilities:
Double, triple or ten-fold higher frequency in women.
One third correlation in identical twins.
Delayed onset until age 10, 20, 30, 50. (this must tell us something)
Double frequency in New York, if you live there as a child (age 1-15)
Half frequency in Texas, & Mexico.
(Can eating barbecue reduce multiple sclerosis frequency to one quarter?
Or is it the sunshine? Hot weather? Exposure to parasitic worms?)
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Immunity is an embryological phenomenon because...
1) The Thymus organ induces differentiation into T-lymphocytes.
2) The Bursa of Fabricius induces differentiation into B-lymphocytes.
3) Contact with antigens sometimes produces increased attack (vaccination);
But other times (normally) causes decreased attack (self-tolerance).
Please notice a symmetry (or anti-symmetry) between vaccination versus self-tolerance.
What causes us to make lots of antibodies specific to germs? Exposure to antigens.
What causes us NOT to make ANY antibodies specific to ourselves? Exposure to antigens.
Can opposite results have the same cause?
Medawar's theory was early exposure when we are embryos would produce tolerance, and exposure to antigens later in life produces allergy-immunity.
Vaccines induce many more antiserum lymphocytes when combined with "adjuvants" (irritants, that include "alum" (potassium aluminum sulfate)
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How To Cure Multiple Sclerosis
Make monoclonal antibodies whose own binding sites fit the binding sites of the anti-Central-Nervous-System-Myelin (Anti-CNS-Myelin) antibodies and T-cell receptors.
The effectiveness of this approach (antibodies whose binding sites fit the binding sites of targeted lymphocytes) has been proven by researchers studying non-Hodgkin's Lymphoma. [Miller, R.A., D.G. Maloney, R. Warnke, and R. Levy (1982). Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. New England Journal of Medicine 306(9):517-22.]
Each B-lymphoma patient makes antibodies whose binding sites are the same as each other, but different shaped than 99.999% of lymphocytes (except in that patient).
Lymphoma researchers:
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1* purified these antibodies (the ones made by a particular patient's cancerous B-lymphocytes),
2* injected these into young mice,
3* then took B-lymphocytes from the mouse's bone marrow,
4* fused these lymphocytes with fast-growing myeloma cells.
5* and separated out those fused cells that made antibodies that fit the antibody binding sites made by that patient's cancerous B-lymphocytes.
The only reason this method isn't being used as a treatment for B-lymphomas is that different monoclonal antibodies would need to be made for each patient, which is not economically profitable enough.
However, preparation of only one or a few anti-binding site antibodies would be needed to attack all MS patients' anti-myelin binding sites.
Therefore, this method would be economically very practical for treating MS.
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Questions for class discussion:
MS is unusual in that both B and T lymphocytes produce the harmful anti-self binding sites.
What does this suggest to you about what went wrong, that caused the anti-myelin lymphocytes to escape removal by the normal tolerance mechanisms, for both B and T lymphocytes?
Unlike most autoimmune diseases, in which binding sites are produced that fit only one self molecule, Lupus Erythematosus patients make antibodies against histones, collagen, DNA, RNA and many other "self" molecules.
Imagine what could go wrong with the immune system that would cause formation of many different anti-self antibodies.
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If a protein is sufficiently "hidden" from lymphocytes during embryonic development, then the normal tolerance mechanism won't be stimulated to destroy the anti-self lymphocyte clones.
If the random DNA splicing mechanism were reactivated after birth, then antibodies with many different binding site shapes would be produced, and it would be too late for the normal mechanism of self-tolerance to weed out those whose binding sites fit normal body molecules.
Which of these two possible causes:
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* Would result in producing both B and T lymphocytes which attack the same self molecules?
** Would result in producing many different anti-self antibodies, each fitting a different molecule?