Here at ERV, Ive talked about all kinds of pathogens and all kinds of vaccination strategies against those pathogens and cancers how our immune systems respond to these pathogens and vaccines and cancers and blah blah blah.
When you think ‘immunology’ you think ‘your body protecting itself’, or if you watch ‘House’, you think of an autoimmune diseases like lupus.
You dont think “I feel fine, and Im not infected with anything, and I dont have an autoimmune disease… but my immune system is still FREAKING OUT.”
But you should be. Because that is obesity, and how/why people develop Type II Diabetes. The field is absolutely exploding, as more and more pro-inflammatory cytokines, and ways they are induced, and what they are doing, and what cells (especially immune cells) are releasing them is being discovered every day.
As it has nothing to do with a virus, its not something I usually think about either. But I realized how epic this field is while reading up on immunology/obesity in response to some big breakthroughs recently reported in Nature:
The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes
(review) Type 2 diabetes as an inflammatory disease
I am just going to touch on one issue in this post. Like I said, this field has gotten epic, and this is just *one* aspect of how obesity screws around with your immune system and causes damage.
An inflammasome is a multiprotein structure in all of your cells (innate immunity), on the lookout for trouble. Like all forms of innate immunity, it looking for patterns– patterns that are not supposed to be there. Patterns pathogens or messed up cells make, not ‘normal healthy me’. There are lots of variants, but if an inflammasome is just hanging out, floating around the cytoplasm of a cell, and it comes up upon some double stranded DNA, it sounds the alarm that SOMETHING IS WRONG! SOMETHING IS WROOOOOONG AAAAAAAHHHHH!!! DOUBLE-STRANDED DNA FOOOK!
Double stranded DNA is fine– thats what our genome is made of. But our dsDNA should be in the nucleus, not hanging out in the cytoplasm. dsDNA in the cytoplasm could be virus, or an aborted intracellular bacteria, or a sign of a messed up cell, but it means something is not right.
When an inflammasome is activated, it starts the caspase-1 cascade, which initiates cell death.
Now sometimes when cells notice something is wrong, they kill themselves in a nice, civil, dignified manner: apoptosis. Its a neat, clean death.
But in the case of activated inflammasomes, the cell kills itself in a less dignified but still tightly controlled manner: pyroptosis. Pyroptosis is kinda like necrosis (where cells are just blowing up from damage) except still tightly controlled and on purpose. As opposed to apoptosis, which is an non-inflammatory cell death, pryoptosis is a pro-inflammatory cell death. Its a way for the dead cell to tell your immune system that shit has hit the fan, and backup is needed ASAP.
In the case of obesity, its free fatty-acids (oxidized LDL) and islet amyloid polypeptides (maybe more stuff) that are triggering NLRP3 inflammasome. This leads to cells dumping out pro-inflammatory cytokines. This freaks out the beta-islet cells, which freak out the immune cells in adipose and the pancreas (macrophages and mast cells and T-cells luvs adipose), which freak out the beta-islet cells, which freak out the immune cells in adipose and the pancreas, which freak out the beta-islet cells… pyroptosis all over the place.
A snow-ball effect of inflammatory cytokines/proteins leading to dead beta-islet cells (no more insulin, aka Type II Diabetes).
Which leads to an interesting idea for therapies for Type II Diabetes… What if you could stop the snow-ball effect? Interrupt the self-perpetuating pro-inflammatory cycle? Apparently there are current therapies for Type II Diabetes in trials right now, using stuff like antibodies which inhibit some of the inflammatory cytokines (IL-1B), or molecules that inhibit the IL-1B receptor. Keep the pro-inflammatory molecules from delivering their message, all the cells can simmer down and relax, so more damage isnt done.
My initial concern when seeing this, was that pro-inflammatory cytokines are a normal part of your immune system. Whats the good in treating people for Type II Diabetes just to have them fall over dead from a cold or the flu? These therapies should be pretty specific– they dont tell the immune system as a whole to ‘shut up’ (like the drugs you put transplant recipients on)– just a little branch of it. And theoretically this kind of treatment wouldnt have to be long-term, assuming people were altering their diet/activity levels (this would just prevent more damage from being done in the mean time). We will just have to see what happens in clinical trials.
But I think its neat and weird that immunologists have a place in addressing the obesity epidemic, and had to share