Tag Archives: CD4+

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.

Never stop thinking, never stop looking for an angle

Derek Lowe may soon be a very rich man if he owns some Vertex stock. An incredible pair of papers in the current Nature (vol. 505 pp. 492 – 493, 509 – 514 ’14, Science (vol 343 pp. 38 – 384, 428 – 432 ’14) has come up with a completely new way of possibly treating AIDs. Instead of attacking the virus, attack the cells it infects, and let them live (or at least die differently).

Now for some background. Cells within us are dying all the time. Red cells die within half a year, the cells in the lining of your gut die within a week and are replaced. None of this causes inflammation, and the cells die very quietly and are munched up by white cells. They even send out a signal to the white cells called an ‘eat me’ signal. The process is called apoptosis. It occurs big time during embryonic development, particularly in the nervous system. Neurons failing to make strong enough contacts effectively kill themselves.

Apoptosis is also called programmed cell death — the cell literally kills itself using enzymes called caspases to break down proteins, and other proteins to break down DNA.

We have evolved other ways for cell death to occur. Consider a cell infected by a bacterium or a virus. We don’t want it to go quietly. We want a lot of inflammatory white cells to get near it and mop up any organisms around. This type of cell death is called pyroptosis. It also uses caspases, but a different set.

You just can’t get away from teleological thinking in biology. We are always asking ‘what’s it for?’ Chemistry and physics can never answer questions like this. We’re back at the Cartesian dichotomy.

Which brings us to an unprecedented way to treat AIDS (or even prevent it).

As anyone conscious for the past 30 years knows, the AIDS virus (aka Human Immunodeficiency Virus 1 aka HIV1) destroys the immune system. It does so in many ways, but the major brunt of the disease falls on a type of white cell called a helper T cell. These cells carry a protein called CD4 on their surface, so for years docs have been counting their number as a prognostic sign, and, in earlier days, to tell them when to start treatment.

We know HIV1 infects CD4 positive (CD4+) T cells and kills them. What the papers show, is that this isn’t the way that most CD4+ cells die. Most (the papers estimate 95%) CD4+ cells die of an abortive HIV1 infection — the virus gets into the cell, starts making some of its DNA, and then the pyroptosis response occurs, causing inflammation, attracting more and more immune cells, which then get infected.

This provides a rather satisfying explanation of the chronic inflammation seen in AIDS in lymph nodes.

Vertex has a drug VX-765 which inhibits the caspase responsible for pyroptosis, but not those responsible for apoptosis. The structure is available (http://www.medkoo.com/Anticancer-trials/VX-765.html), and it looks like a protease inhibitor. Even better, VX-765 been used in humans (in phase II trials for something entirely different). It was well tolerated for 6 weeks anyway. Clearly, a lot more needs to be done before it’s brought to the FDA — how safe is it after a year, what are the long term side effects. But imagine that you could give this to someone newly infected with essentially normal CD4+ count to literally prevent the immunodeficiency, even if you weren’t getting rid of the virus.

Possibly a great advance. I love the deviousness of it all. Don’t attack the virus, but prevent cells it infects from dying in a particular way.

Never stop thinking. Hats off to those who thought of it.