Chapter 35: Resistance of the Body to Infection: Immunity and Allergy

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If you were exposed to a dose of botulinum toxin or tetanus that was like 100 ,000 times higher than the lethal limit,

you should, by all biological logic, just be dead in minutes.

But you can actually survive it.

Welcome to this custom deep dive.

Today we are talking directly to you, the college student who's looking at medical physiology for the very first time.

Our explicit mission today is mastering chapter 35 of the Guyton and Hall textbook of medical physiology.

Which covers acquired immunity and allergy.

We're going to decode exactly how your body builds a microscopic defense system capable of that kind of miraculous 100 ,000 -fold protection.

It really is a staggering level of defense,

but to understand how we actually achieve it, we really have to draw a hard line between the body's two main immune systems.

Right.

Because they are completely different.

Exactly.

So you have innate immunity, which you're just born with.

That's your general physical barriers, you know, your skin, acid in your stomach, tears.

Even those generalized white blood cells that just sort of eat anything foreign.

Yeah, exactly.

It's immediate, but it's a blunt instrument.

Acquired immunity or adaptive immunity is completely different.

It's this highly specific customized response built from scratch to destroy one single specific invader.

It doesn't even develop until after your body is attacked, right?

Right.

And that custom built defense is the whole reason you can survive those lethal doses we mentioned.

Okay, let's unpack this.

Because to understand how this highly customized system works, we need to trace the exact physiological chain of events from start to finish.

Step by step.

Exactly.

And since anatomy always supports function,

where exactly does this acquired immune system live?

I mean, we aren't just talking about cells floating aimlessly in the blood, are we?

Oh, not at all.

The acquired system is driven by lymphocytes and their anatomical placement is entirely strategic.

Like military outposts.

Yes.

They're stationed at physiological choke points to intercept invaders before they can spread into the general circulation.

So you'll find them heavily concentrated in the lymph nodes, the spleen, the submucosal areas of the GI tract.

And the thymus and bone marrow, right?

Precisely.

Like the lymphoid tissue in your tonsils is perfectly positioned to intercept anything you breathe in.

Well, the tissue in your GI tract just handles whatever you swallow.

Exactly.

So if innate immunity is like a general castle wall, keeping most things out, the acquired system is a highly trained specialized hit squad hiding in the guard towers waiting for a specific target.

That's a great analogy.

And there are two different branches of this hit squad, both originate in the embryo from multipotent hematopoietic stem cells.

But they take entirely different developmental paths, don't they?

Yeah, they do.

You have the D lymphocytes, which are responsible for humoral immunity.

Meaning they produce weapons antibodies that circulate in the blood plasma.

Right.

And then you have the T lymphocytes, which handle cell mediated immunity.

Instead of producing circulating weapons, they form activated cells that physically go out to destroy the foreign agent hand to hand.

I'm stuck on the logistics here though.

I mean, a castle guard needs a description of the intruder to know who to attack.

If these cells were so specialized, how do they get their specific targets before the invader even shows up?

Ah, so that happens in the pre -processing phase, which is essentially

an intense immune boot camp.

Let's look at the T lymphocytes first.

Okay, the hand to hand fighters.

Right.

After originating in the bone marrow, they migrate to the thymus gland, mostly just before and shortly after birth.

In the thymus, they divide rapidly and during this division, they develop extreme diversity.

Extreme diversity meaning what exactly?

Meaning each individual T cell is programmed to react against one single specific antigen.

So one cell is programmed for one specific target, the next cell for a totally different target until you have millions of different types.

Wait, but if they are just blindly generating millions of random targets, wouldn't some of them naturally end up targeting our own organs,

like a T cell that's accidentally programmed to attack heart tissue?

That exact scenario is why the thymic boot camp is so ruthless.

It utilizes a process called negative selection.

Negative selection.

Yep.

The thymus literally mixes these newly minted T cells with virtually all the specific self antigens from your own body's tissues.

If a T cell reacts to your own tissue, it is instantly destroyed and phagocytized.

Whoa.

So it's just killed on the spot.

Yep.

Up to 90 % of them are killed this way.

Only the cells that completely ignore your own tissues are permitted to graduate and populate the lymph nodes.

So it's a 90 % failure rate just to ensure we don't destroy ourselves.

Yeah.

That is wild.

Yeah, it really is.

So that covers the T cells in the thymus.

What is the boot camp for the B cells?

Well, in humans, B cells are pre -processed in the liver during mid -fetal life and then in the bone marrow late in fetal life and after birth.

And there's a fun historical fact here, right, about the name.

Oh, yeah.

They're called B cells because they were first discovered in birds, which have this specific pre -processing organ called the bursa of Fabricius.

Bursa.

B cells.

Makes sense.

Yeah.

And B cells actually have even greater diversity than T cells, producing millions of unique specificities.

Okay, wait.

I have to pause and challenge the

strains,

viruses and toxins out there.

Human DNA only has about, what, 20 ,000 to 30 ,000 protein coding genes?

Roughly.

How on earth do we have enough genetic material to code for millions of completely unique specific cell receptors?

It doesn't add up.

It's an incredibly elegant genetic hack, actually.

We don't have whole genes for every single cell type.

Oh, we don't?

No.

The original stem cells contain only gene segments, just a few hundred of them.

During this pre -processing phase, those segments are mixed with one another in completely random combinations.

Oh, wow.

So it's like a mix and match situation.

Exactly.

It's the mathematical power of permutation.

When you mix hundreds of segments into complex combinations, you can easily generate millions of unique receptor codes from just a tiny amount of original genetic material.

Oh, I see.

It's like having a limited alphabet, but being able to write millions of different words.

That's a perfect way to put it.

That makes total sense.

So our hit squad has graduated boot camp.

They have their unique permuted receptors.

They survive negative selection so they won't attack our own body, and they're deport to the guard towers, the lymph nodes.

Right.

They're in position.

So let's walk through what happens when an invader actually breaches the castle wall.

Well, the trigger is the antigen.

Antigens are usually large proteins or polysaccharides on the surface of the invading bacteria or virus, typically with a high molecular weight like over 8 ,000.

What makes an antigen trigger the immune system?

Specifically, the immune system is looking for recurring molecular patterns on that antigen.

We call those epitopes.

But here's the catch.

The highly specialized lymphocytes usually can't just spot the antigen floating by on their own.

They can't.

No, they need a scout.

They need help from macrophages.

Wait, macrophages are part of the innate system, right?

The blunt instruments we talked about earlier.

They are.

And this is where the two systems link up beautifully.

Macrophages in

eat or phagocytize the invading organism.

Okay.

They partially digest it, and then they push those specific antigenic products to their own surface.

So they display the enemy's parts.

Exactly.

Then they physically pass those antigens directly to the lymphocytes by cell to cell contact.

Wow.

And while doing this, the macrophage also secretes an activating substance called interleukin 1, which acts like a massive growth stimulant for those specific lymphocytes.

So the innate scout captures the enemy, chops off their insignia, runs up to the guard tower, hands it directly to the specialized hit squad, and basically gives them an energy drink.

Yeah, pretty much.

And that kicks off clonal expansion.

Picture a lineup of millions of dormant B lymphocytes in the lymph node.

Let's call them clones, B1, B2, B3, and so on.

Got it.

Millions of dormant clones.

Right.

And each individual cell has about 100 ,000 identical receptors on its surface that only fit one specific antigen.

So the macrophage runs up with the antigen, and let's say it happens to perfectly match the receptor on clone B2.

Okay.

So B2 is the chosen one.

What happens next?

The moment that match happens, clone B2 wakes up and begins reproducing wildly, creating a massive army of duplicate B2 lymphocytes.

All the cells in that clone are perfectly identical and target that exact same antigen.

Okay.

So now that the specific clone is activated, we transition into the active phase of humoral immunity, the B cell response.

Right.

Here's where it gets really interesting, because the sheer physiological scale of what that B cell does next is, well, it's mind -blowing.

It truly is.

Once activated, it enlarges and turns into a plasma blast.

And for four days, these plasma blasts divide every 10 hours, right?

Yep.

They mature into plasma cells, and these plasma cells act like dedicated microscopic factories.

They start secreting gamma globulin antibodies at a rate of 2 ,000 molecules per cell.

Wait, 2 ,000 per second from a single cell?

Yes.

Just think about the energy required for that.

Those antibodies flood into the lymph and the circulating blood for days or even weeks.

That is insane.

But they don't all become factories, do they?

No, not every single activated B cell turns into a plasma cell.

A moderate number of them hold back and become memory cells.

Memory cells.

Yeah.

They look just like the original B cell, but now there are vastly more of them, and they lay dormant in the lymphoid tissue just waiting.

And that perfectly explains why our bodies react differently the second time we get sick.

If you map this out, the primary response the very first time your body sees an antigen is pretty weak and delayed.

Right.

It takes about a week for the antibodies to even show up in the blood.

But the secondary response, thanks to that massive army of waiting memory cells, is immediate,

overwhelmingly powerful, and lasts for months.

Or even a lifetime.

I mean, we know that long -lived plasma cells can reside in the bone marrow permanently.

Really?

A lifetime?

Yeah.

In one fascinating study, researchers tested 90 -year -old survivors of the lethal 1918 flu pandemic.

Oh, wow.

They found that those individuals still possessed highly functional virus -neutralizing antibodies decades after they were originally exposed.

Decades later.

That is incredible.

Okay, let's talk about the actual weapons these plasma cells are pumping out.

I'm trying to picture this.

Are these antibodies like little guided missiles floating in the blood?

What do they actually look like?

If you look at them structurally, imagine a classic Y -shaped molecule.

It's constructed of two heavy polypeptide chains and two light chains.

Okay, a Y shape.

The very tips of the Y are the variable regions.

That is the part that is entirely customized through that genetic permutation we talked about earlier.

So the tips of the custom lock that fits the key.

Exactly.

Those tips perfectly mirror the antigen's epitopes.

They bind together obeying the thermodynamic mass action law, meaning the affinity constant, you know, how tightly they lock on is exceptionally strong.

And what about the stem of the Y?

The stems are the constant regions which determine the antibodies' general properties and its class.

There are five classes, right?

Yeah, correct.

IgM, IgG, IgA, IgD, and IgE.

IgG is your workhorse, making up about 75 % of all your antibodies.

And IgE is the allergy one, which we'll get to later.

And IgM is uniquely fascinating because instead of the standard Y shape with just two binding sites, it is basically a cluster with 10 binding sites.

That's like a grappling hook.

Exactly.

Making it incredibly effective during that initial primary response when you need to grab as many invaders as possible, as fast as possible.

Okay, so these custom Y -shaped handcuffs or grappling hooks have latched onto the bacteria in the blood.

But just grabbing the invader doesn't kill it.

What actually physically destroys the cell?

Well, there is a direct action and an indirect action.

Directly, because antibodies have multiple binding sites, they can link invaders together.

Like tying them up.

Right.

One antibody grabs a bacteria with its left arm and another with its right.

Then another antibody grabs that bacteria, creating this massive, tangled clump of invaders that can't move or reproduce.

That's called agglutination.

Yes.

They can also cover the toxic sites of a virus, which is called neutralization.

But the text notes that direct action is often too weak to stop a severe infection on its own, right?

The antibodies need an amplifier.

They do.

And that amplifier is the complement system.

The complement system is a collection of about 20 proteins that are normally just floating completely inactive in your blood plasma.

Just waiting to be triggered.

Exactly.

When an antibody locks onto an antigen, the constant region, the stem of the Y, physically shifts and exposes a reactive site.

Oh, like flipping a switch.

Exactly.

This site binds directly to a complement protein called C1, which sets off the classical pathway cascade.

A cascade, meaning it's a domino effect.

One enzyme activates the next, which activates the next, amplifying the sheer volume of the response at every single step.

Right.

The scale grows exponentially, and the end products of this cascade are just devastating to bacteria.

How so?

Well, one product called C3b coats the bacteria to make it highly attractive to macrophages, a process called opsonization.

Basically painting a giant target on it for the innate system to eat.

Exactly.

But the most dramatic destructive result is the membrane attack complex.

That sounds intense.

It is.

This is a combination of complement factors, C5b6 ,7 ,8, and 9.

This complex literally inserts itself into the lipid bilayer of the bacterial membrane and punches a gaping pore right through it.

It punches a hole in the bacteria.

Yep.

Fluid rushes into the bacteria, causing osmotic rupture.

The bacteria literally bursts.

That is brutal.

So,

okay, antibodies and the complement system are incredible for invaders floating around in the blood or tissue fluid.

But what about viruses that have already invaded our own cells or cancer cells hiding inside our own tissues?

Antibodies can't get inside the cells to fight them, can they?

No, they can't.

And that is precisely where the T lymphocytes take over.

This is cell -mediated immunity.

A hand -to -hand fighters again.

Right.

Now, T cells are much kickier than B cells.

B cells can recognize intact antigens just floating by.

T cells completely ignore floating antigens.

Really, they just ignore them?

Yeah.

They only respond to an antigen if it is properly presented to them on a specific molecular platter by an antigen -presenting cell, or APC.

Okay, so going back to our analogy, the scout didn't just chop off the enemy's insignia.

It has to display it on a very specific flagpole for the T cell to even look at it.

That's right.

And that flagpole is called a major histocompatibility complex, or MHC protein.

The macrophage holds up the antigen on the MHC protein, and the T cell receptor finally binds to it.

And depending on what kind of T cell it is, you get a different response.

There are three major types of T cells.

Yep.

If we connect this to the bigger picture, the most vital of these are the T helper cells, which make up about 75 % of all T cells.

75%.

So they're the majority.

By far.

Without T helper cells, the entire immune system is virtually paralyzed.

They act as the central command.

How do they command the other cells?

They secrete protein mediators called lymphokines, like interleukin 2, 4, 5, and 6.

These lymphokines stimulate the growth of other T cells, they supercharge the B cells to produce antibodies, and they just whip the macrophage system into a frenzy.

And this central command role is exactly why HIV is so devastating, right?

Yes, exactly.

The human immunodeficiency virus specifically targets and destroys T helper cells.

It doesn't kill you directly, it just completely removes the general coordinated troops, which leads to AIDS, leaving the body totally defenseless against everything else.

It's a catastrophic loss of command.

Wow.

Okay, so that's the helpers.

What's the second type?

The second type is the cytotoxic T cell, also known as the killer cell.

These are the hand -to -hand combatants.

The actual hit squad.

Yes.

When a cytotoxic T cell finds one of your own body cells that has been infected and is displaying a viral or cancer antigen, it binds tightly to it.

It then secretes hole -forming proteins called perforins.

Oh, like the membrane attack complex we just talked about.

Very similar, yeah.

These perforins punch massive holes in the target cell, causing fluid to rush in until the cell swells and dissolves.

The killer cell then releases its grip, pulls away, and moves on to assassinate the next infected cell.

They truly are a hit squad.

And finally, the third type, regulatory T cells, or TREGs.

Right, the TREGs.

They do the exact opposite of the other two.

They suppress the functions of the cytotoxic and helper cells.

They act as the brakes, keeping the immune system from getting out of control and destroying your own tissues.

Which brings us back to that critical concept of tolerance.

This delicate balance, heavily reliant on those TREGs and the ruthless negative selection we discussed in the thymus, is what stops your immune system from attacking you.

But sometimes,

this tolerance fails.

And when it does, you get autoimmune diseases.

Exactly.

The text highlights some fascinating, albeit terrifying,

examples of this.

Like rheumatic fever, where the body attacks its own heart valves following a streptococcal infection, because the streptoccin happens to look structurally similar to your own heart tissue.

It's a case of mistaken identity.

Right.

Or myasthenia gravis, where the immune system develops antibodies against its own acetylcholine receptors, blocking muscle signals and causing paralysis.

There's multiple sclerosis, where the immune system attacks the myelin sheath covering nerve fibers,

and systemic lupus erythematosus, or SLE, where the body mounts a widespread attack on many different tissues simultaneously.

It really demonstrates how dangerous the acquired immune system can be if its targeting system breaks down.

But modern medicine has also learned how to hijack that targeting system to our advantage.

Through immunization.

Yes.

We deliberately expose the body to an antigen, so it develops that massive army of memory B and T cells without having to suffer the actual disease.

We basically manufacture a fake primary response, so the body is armed with a massive secondary response later.

Precisely.

And we do this in a few ways.

We can inject dead organisms, like the typhoid vaccine.

We can use toxoids, which are chemically neutralized toxins, like for tetanus.

Or we use attenuated live organisms that have been mutated so they can't cause disease, like for polio or measles.

Right.

But the text also details mRNA vaccines, which relies on incredible physiology.

It really does.

mRNA is a large negatively charged molecule, so it cannot enter a cell on its own.

No, it would just bounce off.

Exactly.

So to get it inside, we wrap synthetic mRNA in a livid nanoparticle.

Once injected into your arm, that fatty nanoparticle fuses with the cell membrane of an antigen -presenting cell and forms an endosome.

And then?

The mRNA eventually escapes the endosome into the cytoplasm.

There, the cell's own ribosomes read that mRNA and translate it into an antigenic protein.

It's brilliant.

I love this concept.

We aren't injecting the enemy at all.

We are literally sending a secure, encrypted message, the mRNA in a fatty envelope straight to your body's 3D printers, the ribosomes.

We just email your cells the enemy's blueprints.

Exactly.

The cell prints the protein, breaks it down, and presents it on the MHC flagpole we talked about earlier.

This activates the helper T cells, the cytotoxic T cells, and the B cells.

It flawlessly mimics a real viral infection without the virus.

And just to be thorough, we should mention that you can also bypass this entire active process and provide passive immunity.

Passive immunity?

Yeah.

If someone needs immediate life -saving protection, we can infuse them with antibodies harvested from someone else who is already immune.

Oh, wow.

So you just borrow their weapons.

Exactly.

It only lasts two to three weeks because the body hasn't learned to make its own antibodies, but it provides instant defense.

Okay.

So we've seen how the immune system protects us and how we can artificially train it.

But what about when this highly -tuned system completely overreacts to something totally harmless, like a peanut or pollen?

Ah, that is allergy and hypersensitivity.

And there are two main types, mapping perfectly back to our T cells and B cells.

Okay.

Break them down for me.

First, you have delayed reaction allergy, which is T cell -mediated.

The classic example is poison ivy.

Oh, poison ivy is brutal.

Right.

But here's the thing.

The toxin itself isn't actually what damages your skin.

It causes the formation of activated T cells.

When you're exposed again, those T cells flood into the skin over the course of a day or so.

And what do they do?

They release toxic substances and call in macrosages that cause massive blistering tissue damage.

Hence the delayed part.

It takes a day or two for the T cells to march into the tissue.

But the more immediate ones, the instant hay fever, the hives, those are atopic allergies, right?

Yes.

And those are B cell -mediated, specifically involving that IgE class of antibodies we mentioned earlier.

The allergy antibodies.

Right.

Some people have a strong genetic tendency to overproduce IgE antibodies, which are often called regens.

Now, IgE antibodies have a unique physical quirk.

Their constant region loves to attach to mast cells and basophils.

Just permanently attach.

A single mast cell can have half a million IgE antibodies permanently stuck to its surface, facing outward.

So the mast cell is basically a loaded bomb covered in tripwires.

That is a terrifying but accurate way to put it.

When an allergen like pollen enters the body, it binds to those outward -facing IgE antibodies.

And then boom.

Boom.

The mast cell membrane physically contorts and ruptures, dumping a massive payload of chemicals into the surrounding tissue.

And that chemical payload is potent.

It includes histamine, protease, heparin, and a complex mixture of leukotrienes, which are collectively called the slow -reacting substance of anaphylaxis.

Right.

And for our purposes, focus on histamine and the leukotrienes.

These chemicals cause immediate local vasodilation,

huge fluid leakage from the blood vessels, and severe smooth muscle contraction.

If this bomb goes off in the skin, the fluid leakage causes hives urticaria.

Yes.

If it happens in the nose, the swollen blood vessels give you hay fever.

Which raises an incredibly practical question from the text.

Why do we take antihistamines for hives and hay fever, but they're practically useless for an asthma attack?

Oh, that's a great point.

It comes entirely down to which chemical from that mast cell payload is driving the primary symptom.

Okay.

In hives and hay fever, histamine is the main culprit causing the blood vessels to dilate and leak fluid.

If you block the histamine receptors with an antihistamine, you block the swelling.

Makes sense.

But in asthma, the allergen region reaction happens deep in the bronchioles of the lungs.

And in the lungs, it is primarily the leukotrienes, that slow -reacting substance of anaphylaxis that causes the smooth muscle of the airways to violently spasm.

And antihistamines can't block leukotrienes.

Exactly.

Which is why they don't relieve the asthma.

That distinction is fascinating.

And if that allergen is injected directly into the blood, from a bee sting, triggering those mast cell bombs everywhere all at once, you get widespread systemic vascular collapse.

Because all the fluid leaves your blood vessels at once.

Right.

That is anaphylaxis, and that requires immediate epinephrine to save the person's life.

Precisely.

To round out our understanding of this entire chapter, we also have to recognize that this system doesn't operate in a vacuum.

It is heavily modulated by sex chromosomes and gonadal hormones, like estrogen and testosterone.

There are actual observable sex differences in adaptive immunity.

Significant ones, yes.

Females, generally speaking, have a much stronger adaptive immune response than males.

In what way?

They expand their T -cells faster, they produce more robust humoral responses, they clear pathogens faster, and they even respond better to vaccines.

Wow.

But there is a massive physiological trade -off for having an immune system that is constantly sitting on a hair trigger.

Because their immune systems are so incredibly robust and reactive, females account for about 80 % of all autoimmune disease cases.

Yeah.

That's the dark side of a strong defense.

We mentioned systemic lupus erythematosus earlier.

SLE is 10 times more frequent in women than in men.

10 times.

Yeah.

It is a profound clinical example of how perfectly tuned the immune system must be.

The stronger the baseline defense, the higher the physiological risk that tolerance eventually breaks down.

And that delicate balance actually brings me to a final provocative thought for you to mull over as you study this chapter.

The text mentioned earlier that regulatory T -cells, the TREGs, suppress the immune response to protect our tissues from autoimmune attack.

Right.

It breaks.

But they also accidentally suppress the immune response to tumors,

essentially putting the brakes on before the body can fight off cancer cells.

If researchers can figure out how to temporarily and selectively turn off those regulatory T -cells just in the microenvironment of a tumor, can we take the brakes off and unleash our own innate cytotoxic hit squads to completely cure cancer from the inside out?

It's one of the most fascinating frontiers in modern immunology.

It really is.

You've got the foundation now.

The anatomy, the pre -processing boot camp, the macrophage scouts, the antibody factories, and the T -cell hit squads.

Good luck on your exam and a warm thank you from the Last Minute Lecture team.