A clever way to attack autoimmune disease

The more we study the immune system, the more complicated it becomes.  Take multiple sclerosis.  A recent study looked at just about every immune parameter in blood they could think of in a collection of 42 monozyotic (identical) twins, one of whom had MS, the other didn’t.  They came up with nothing [ Proc. Natl. Acad. Sci. vol. 117 pp. 21546  – 21556 ’20 ].

Classification of anything (particularly diseases) is always a battle between the lumpers and the splitters.  The initial split in the immune system came between B cells and T cells.  The letters have nothing to do with their function, but rather where they were first found (Bursa of Fabricius, Thymus).

B cells are lymphocytes which secrete immunoglobulin antibodies.  Malignancies of them account for 90 – 95% of leukemias and lymphomas.

T cells are involved in the recognition of antigens.  They can stimulate (or repress) B cells.  Others are used to kill other cells. There are 2,000,000,000,000 of them in our bodies, making them comparable in mass to the brain.

T cells have been subdivided in to helper T cells (which Express the  Cd4 antigen ) and cytotoxic/suppressor cells which express the antigen CD8. Splitting didn’t stop there.  There are two types of helper T cells (Th1 and Th2), but the new kid on the block is the Th17 cell, which Janus-like provide protection from bacterial and fungal infections at mucosal surfaces (e.g. gut, bladder) but which can also induce autoimmune disease.

How to stop the second without causing death from infection. A very clever way was found in Cell vol. 182 pp. 641 – 654 ’20.  Areas of inflammation usually have low oxygen.  Bacteria and Archaea from which we are descended did just fine without oxygen, using something called glycolysis to burn glucose without it, so deep within our cells is the ability to use it when the going gets tough (e.g. hypoxic)

What the authors did was knock out one enzyme involved in glycolysis (Glucose phosphate isomerase — aka Gpi1) — which changes glucose 6 phosphate to fructose 6 phosphate.   This kills Th17 cells living in hypoxia.  What about the good Th17 cells protecting us? They can use a pathway I’d long forgotten about the pentose phosphate shunt and oxidative phosphorylation.

Well did it work?  Actually it did in an animal model of multiple sclerosis called EAE.  It was harder to induce when Gpi1 was knocked down, but the animals didn’t get a bunch of infections, if the protective role of Th17 cells had been lost.

Who knew Marshall McLuhan was a molecular biologist

Marshall McLuhan famously said “the medium is the message”. Who knew he was talking about molecular biology?  But he was, if you think of the process of transcription of DNA into various forms of RNA as the medium and the products of transcription as the message.  That’s exactly what this paper [ Cell vol. 171 pp. 103 – 119 ’17 ] says.

T cells are a type of immune cell formed in the thymus.  One of the important transcription factors which turns on expression of the genes which make a T cell a Tell is called Bcl11b.  Early in T cell development it is sequestered away near the nuclear membrane in highly compacted DNA. Remember that you must compress your 1 meter of DNA down by 100,000fold to have it fit in the nucleus which is 1/100,000th of a meter (10 microns).

What turns it on?  Transcription of nonCoding (for protein) RNA calledThymoD.  From my reading of the paper, ThymoD doesn’t do anything, but just the act of opening up compacted DNA near the nuclear membrane produced by transcribing ThymoD is enough to cause this part of the genome to move into the center of the nucleus where the gene for Bcl11b can be transcribed into RNA.

There’s a lot more to the paper,  but that’s the message if you will.  It’s the act of transcription rather than what is being transcribed which is important.

The paper doesn’t talk about the structure of ThymoD — how long it is, whether it binds to anything in the nucleus — etc. etc.  Perhaps I’ve missed it.  I’ve written the lead author. Hopefully I won’t be too embarrassed by what he responds.

Here’s more about McLuhan — https://en.wikipedia.org/wiki/Marshall_McLuhan

If some of the terms used here are unfamiliar — look at the following post and follow the links as far as you need to.  https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/