Curing autoimmune diseases

Autoimmune diseases are a major cause of human misery and death. The general public seems not grasp their similarity to each other; there are foundations and funds to which you can donate for research on individual autoimmune diseases (MS, Lupus, etc.) but I don't know where to donate for autoimmune diseases in general. (Whereas cancers are regarded as all one disease, which they are not).

Discovery of methods to control the tolerance mechanism would cure all autoimmune diseases, but no telethons are organized (etc.) for that goal. Another use for controlling tolerance would be to allow organ transplants from unmatched donors. (And you can probably think of other uses.)

Random splicing of VDJ base sequences results in a frame shift 2 times out of three. Two splices produce a frame shift 8 times out of 9; three splices result in a frame shift 26 times out of 27. Lymphocytes supposedly can detect frame-shifted antibody DNA, and self destruct. Notice, however, that such frame-shifted antibody DNA can only be detected at the level of synthesized proteins: How the heck can they detect which of the two "do-it-yourself kits" (two, because we are diploid) is which. And four "do-it-yourself kits" for antibody light chains.

But because they are diploid they get two chances to splice together a "good" antibody DNA, and supposedly can suppress either transcription or translation of the frame-shifted antibody gene, while simultaneously allowing "good" antibodies to be made, and that cell to survive. Nobody has proposed mechanisms for how the cell can detect which of its two antibody heavy-chain genes is the good one, and allow its expression, while suppressing the other.

Notice, also, that any mechanism capable of selective destruction of lymphocytes might be usable as a treatment for autoimmune diseases.

Another puzzle is that the binding sites of antibodies and T-cell receptors are lined only with beta sheets (e.g. no alpha helices). The reason this is a puzzle is that random splicing is sure (I think) to produce at least some non-beta sheet secondary structures, in about 90% of cases. Are we to believe that those lymphocytes also get weeded out. How? And also why? I have never heard or read a theory of how this works.


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