Let's have class discussions about the following topics:

a) Many biologists and physicians (the majority?) believe a false paradigm about autoimmunity.

b) They believe (or assume, and may have been taught?) that the mechanism by which vertebrate immune systems normally avoid attacking the body's own molecules is that self molecules must have something analogous to a badge or passport, which somehow inhibits the immune system from making antibodies whose binding sites fit anything marked as self.

c) Sometimes people think that histocompatibility antigens are these hypothetical molecules that serve as "self" badges, inhibiting attack. (hint: they aren't)

d) Please discuss how (or whether) such a paradigm suggests tends to steer people's reasoning about autoimmune diseases.

Hints: Are such diseases caused by inability to "recognize" "self"?

e) Does immune "recognition" result from cells having previously contacted a given molecule;
f) Or do anti-myelin lymphocytes "recognize" that the have NOT previously contacted myelin?

g) "My antibodies fit it; and I haven't previously self destructed; therefore I recognize it as foreign?" (Analogous to "I think, therefore I exist". "I exist; therefore molecules I bind to must not be self." Descartes: Ego cogito, ergo sum. Sum, ergo non ipse)

h) Does something need to be wrong with the B cells that attack self?

i) Was the abnormality in the process (i.e. VDJ recombination, that creates genes for binding sites)?

j) Should VDJ recombination have avoided generating amino acid sequences that fit self molecules?

k) Alternatively, was the abnormality in the process that weeds out those B and T cells whose binding sites fit any self protein (or other molecule)?

l) Which of the following might serve as criteria by which B lymphocytes decide to self-destruct?

    Lymphocytes should self destruct if their binding site fits any molecule in the embryo.

    Any molecule present in large enough concentrations might cause destruction of lymphocytes that bind to it.

    The criterion for elimination of lymphocytes could be locations of antigens that they bind to.

m) A mutation which weakens the normal "weeding out" of anti-self lymphocytes would have what phenotype(s)?

n) Invent as many different medical uses as you can think of for a drug or other treatment that could cause weeding out of lymphocytes whose binding sites fit a molecule that is injected simultaneously with the drug (or other treatment). Hint: transplants, cures for what?

o) A large % of identical twins of MS patients also get MS, but a large % percentage don't. So why aren't bone marrow transplants used as a treatment? (I don't know, but have some guesses.)

p) Related to these paradigms are assumptions that binding to self molecules is because something is wrong (defective? abnormal? pathological?) about the lymphocytes.

q) How to cure Multiple Sclerosis? Selectively kill (just) the B and T lymphocytes whose antibodies and receptors have, inactivate, induce apoptosis, sequester anti-myelin lymphocytes.

r) Non-selectively inhibiting all B-lymphocytes can never succeed as a cure? Why not?

s) Development of anti-MS drugs has consisted of trying one non-specific immune inhibitor after another.

t) No serious effort has been made to find a cure, just more expensive drugs that can't succeed.

u) Discuss implications of the NY Times article saying the market for multiple sclerosis drugs is "crowded".

v) Discuss this quote from the Wikipedia page on Tofacitinib:

"The potential significance of JAK3 inhibition was first discovered in the laboratory of John O'Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH). In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the "health and safety needs of the public." The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer. In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments."



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