Dr. Andy

Reflections on medicine and biology among other things

Monday, May 16, 2005

More cool immune system evolution

Or how did an inhibitory receptor turn into a activating one.

NK (natural killer) cells are a special kind of white blood cell that specialize in killing tumor and virally infected cells. Unlike T and B cells they can’t shuffle segments of DNA to generated diverse antigen receptors (antibodies from B cells and T cell receptors) to recognize “foreign" material. Instead they integrate signals through a number of cell surface receptors to make a decision about whether or not to lyse another cell

Some of these receptors, such as one’s that recognize the body’s own MHC molecules, are inhibitory and prevent NK cell activation and subsequent killing of the targeted cell. Others, expressed preferentially by cancerous or infected cells, are stimulatory. The balance of inhibitory and activating signals allows NK cells to ignore normal cells, but, hopefully, kill "abnormal" cells such as those that are infected or cancerous. What all the NK cell receptors recognize, how they signal and how the NK cells sums their signals is just beign worked out

2B4 is an one NK receptor. In mice it is clearly inhibitory; that is, signaling through it prevents NK cell mediated killing. But in humans it appears to be stimulatory, when it binds CD48, its ligand, it activates the NK cell. This activation requires binding of it’s intracellular tail to another protein called SAP. Mouse 2B4 can't bind SAP.

Why the difference? No one knows for sure, but one possibility (as detailed by Kumar and McNerney in the May Nature Reviews Immunology is the evolutionary pressure brought to bear on humans by a particularly successful virus, Epstein-Barr, has driven evolution of 2B4's function.

EBV, as Epstein Barr Virus is abbreviated, infects 90+% of US residents by the time they reach adulthood. Most people have either no symptoms or a mild illness similar to a cold, but for some it can cause significant enlargement of lymphoid organs (tonsils, spleen and lymph node) and relatively severe illness called mononucleosis, because of the proliferation of characteristic white blood cells, called atypical lymphocytes.

The infection is never really cleared but lays dormant in most people not causing much problem. But rarely EBV infected cells can turn cancerous, causing lymphoma, and emerging data links EBV infection to multiple sclerosis, although infection is so prevalent and MS so rare, it is clearly not sufficient to cause the illness.

EBV infection leads to upregulation of CD48 which is the ligand for 2B4 (that is it binds it). In mice (and probably humans many years ago) this binding leads to inhibition of NK cell lysis of infected cells. Presumably, evolutionary pressure from severe EBV infection lead to 2B4 gaining the ability to bind SAP and activate, rather than inhibit NK cells.

Speculative? Yes, but consider that there is a rare genetic defect of SAP, called the X-linked lymphoproliferative syndrome (XLP). In XLP patients, 2B4 can’t bind SAP and acts as an inhibitor of NK cells, as in mice. XLP patients are uniquely sensitive to EBV, developing a fulminant infection that is almost uniformly fatal.

So many years ago, EBV was a severe, often fatal illness that decimated early human populations. When, by chance, a mutation in 2B4 lead to the ability to bind SAP, an enormous selective advantage was obtained, allowing individualswith the new variant to fight off EBV infection (as most of us have). Not surprisingly, this mutation became established and spread throughout the population.

Cool, huh?

Of course, this is probably an oversimplification. It probably wasn't just one mutations, but several, over time, that allowed efficient binding of SAP by 2B4.


At 10:40 AM, Anonymous Anonymous said...

Very cool. Thanks for the interesting post!

At 1:08 AM, Anonymous multiple sclerosis said...

My visit to your site, Dr. Andy, was the results of the glyconutrients search for information regarding the subject More cool immune system evolution. Even though some of the articles on the site may not support the glyconutrients project, I must say, it’s an informational and very interesting site and its content will benefit many. Thank you for reading my comment.

At 3:46 AM, Anonymous Anonymous said...

Hi Dr, getting all this much information on Multiple Sclerosis was interesting. Keeping this interest in mind, did we compile this informative article on Multiple Sclerosis.

At 2:13 AM, Blogger Traver corat said...

Hi this information is great how to grow cell. we should need immune booster herbal medicine to increase cell amount.Joint Pain


Post a Comment

<< Home