Trained Immunity, Part 3

ISSUE N.3

The Science & Significance of Trained Immunity

One of the papers that helped me connect the dots was a review by Rahul Suresh and David Mosser on pattern recognition receptors.

Reading it, I realized something that seems obvious now but hadn't been obvious to me before.

Our innate immune system doesn't begin by asking:

“Have I encountered this exact organism before?”

That kind of antigen-specific recognition belongs primarily to adaptive immunity.

Instead, innate immunity begins by asking:

“What kind of biological pattern am I looking at?”

These patterns are called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).

The receptors that recognize them are called pattern recognition receptors (PRRs).

TLR4 is one of those receptors. So are dozens of others.

Suddenly, the story of LPS wasn't just about inflammation anymore, but part of a much larger communication system.

What struck me was what all these PRRs have in common. They're recognizing patterns that carry biological meaning. And that realization shifted my perspective.

For years, I'd been thinking primarily about what these pathways cause.

Inflammation.

Cytokines.

Symptoms.

Disease.

But I had never stopped to ask a much simpler question.

What is their purpose?

Before a coordinated innate response can begin, something meaningful first has to be recognized.

Recognition comes first. The nature and context of that recognition help shape what happens next.

So much of medicine is taught through the lens of pathology.

LPS causes inflammation, cytokines cause symptoms, reactive oxygen species cause damage, and complement contributes to tissue injury.

Those statements can all be true, but they can also cause us to see these systems primarily as problems to suppress.

The immune system doesn't see them that way – it sees information.

The immune system evolved to recognize important signals from the natural world. Our role as clinicians isn't to overpower those signals, but to better understand them – and to support the body's intelligent capacity to respond, adapt, and heal.

Innate immune cells are constantly interpreting signals from microbes, damaged tissues, and the environment. Pattern recognition receptors are one of the ways they make sense of those signals.

Once we begin thinking of the immune system as an information-processing network instead of only an inflammatory network, new questions emerge.

Instead of asking:

"How do I suppress this pathway?"

or

"How do I boost the immune system?"

we begin asking:

"Is there a way to help the immune system recognize, coordinate, and adapt more intelligently?"

For me, that's one of the most exciting ideas behind trained immunity.

Not because it replaces everything we already know...

But because it invites us to see the immune system through a different lens.

Next Week

If our immune system evolved receptors to recognize particular molecular patterns…

Why beta-1,3/1,6-glucan?

What made it important enough for evolution to preserve an entire recognition system around it?

That’s where we’ll go next week.

​References:
Suresh R, Mosser DM. Pattern recognition receptors in innate immunity, host defense, and immunopathology. Adv Physiol Educ. 2013;37(4):284–291. doi:10.1152/advan.00058.2013. PMID: 24292903. PMCID: PMC4089092.

Quintin J, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12(2):223–232. doi:10.1016/j.chom.2012.06.006. PMID: 22901542.