What is the role of inflammation in the immune system?

As I’ve pursued my independent research into biotech, one of my enduring mysteries has been what exactly the role of inflammation is in the immune system.

Now, I know the orthodox answer. The orthodox answer is that the immune system recognizes and fights pathogens. Inflammation is part of the immune system and helps it function, like in a localized infection or a fever. Sometimes the immune system goes awry and causes inflammation where it shouldn’t, like in asthma or rheumatoid arthritis.

This is the answer I believed for a long time. But, if this were true, inflammation should be a helpful part of the immune system. Blocking inflammation should be really dangerous, leading inevitably to infection.

This isn’t the case, though. We block inflammation all the time with ibuprofen and acetaminophen, like when we give these drugs to children for their fevers. Overall, these drugs both reduce fever and are, generally, as safe as placebo.

Now, you might think, “Oh, well that’s just because fever is an excess of inflammation. Surely some inflammation is necessary”.

Well, let’s take a look at a more serious anti-inflammatory drug, adalimumab, which you might know as Humira. Adalimumab is a monoclonal antibody, which are compounds designed to bind to certain receptors on cells. In autoimmune diseases, they’re used to bind to certain types of immune cells to stop them from working or even to destroy them.

Adalimumab targets tumor necrosis factor alpha (TNFα). TNFα is an incredibly important part of the inflammation process, implicated throughout the body in all sorts of inflammatory processes. Arthritis, diabetes, skin infections, obesity, asthma, sepsis: basically, if there’s inflammation, it’s a safe bet TNFα is involved. 

Adalimumab is a very efficient blocker of TNFα. Almost all TNF-alpha in treated patients is blocked by adalimumab. As a result, TNFα is also a very efficient blocker of inflammation. For example, up to 36% of Crohn’s Disease patients go into remission with adalimumab, compared to 12% on placebo. 50% of patients see a significant decrease in their Crohn’s.

But, despite the fact that these patients have their body’s ability to create inflammation significantly decreased, they are generally ok. 0.9% of treated patients develop cancer over the course of 3-12 months, compared to 0.2% of those on placebo. About 45% of adalimumab-treated patients with Crohn’s disease do develop infections over the course of year, which sounds high, except that 37% of placebo-treated patients also do (note that placebo-treated patients are likely on other immunosuppressive drugs as well).

This also fits in with other data. When we look at COVID-19, which has been studied a lot among patients on immunosuppressants like adalimumab, we find that adalimumab is not associated with severe COVID-19 among patients with inflammatory bowel disease. Similarly, ibuprofen is also not associated with severe COVID-19.

Meanwhile, promoting inflammation is not helpful for infections. We know this because we have a big group of people in the United States who are constantly in a low level of inflammation: obese people. Fat cells produce inflammation, which is why obesity is associated with both systemic inflammation and a range of inflammatory-related disorders.

You might naively think that this means their body’s on high alert all the time, always ready to fight off any infection. But this isn’t the case. Obese people are more likely to get skin infections, severe COVID, and shed influenza A (but not B) for longer than nonobese people. All that inflammation is somehow worse for their ability to fight off these infections.

At this point, you might just be ready to throw inflammation out. But I wouldn’t recommend that. In the same study that studied adalimumab in COVID-19, they found that corticosteroids, which are also anti-inflammatory, are associated with a 7 times greater risk of severe COVID 19 in those patients.

Now, corticosteroids are not the same thing as ibuprofen or adalimumab. Corticosteroids are naturally occurring compounds in the body with a huge range of effects. They generally upregulate anti-inflammatory proteins and down regulate proinflammatory proteins, but they also have effects on metabolism, cognition, and arousal.

Still, I’m left in confusion. Exactly how necessary is inflammation? If it’s not that necessary, then evolution has somehow left us with a useless, metabolically expensive system that frequently breaks down and makes us sick. If it is necessary, then it’s surprising that inhibiting it in such drastic ways is generally an ok thing to do.