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.

Post a comment or leave a trackback: Trackback URL.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: