Chapter 8: Alterations in Immunity

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Welcome, Deep Divers.

Ever stop to think about what happens when your body's own defense system, you know, your immune system, kind of messes up?

It's a really fascinating and sometimes scary situation, isn't it?

Totally.

Like maybe it goes completely over the top reacting to something totally harmless, or worse, it starts attacking your own healthy cells.

Or even the flip side, when you actually need it to fight something off, it just doesn't really show up with enough force.

Exactly.

And that's what we're diving into today.

We're looking at those times the immune system's protective responses go, well, wrong.

We'll break it down into two main areas.

First, these things called hypersensitivity reactions.

That's where the immune system is exaggerated or misdirected, or maybe targets beneficial foreign tissues, like a transplant.

OK, exaggerated or misdirected.

And the second area.

That's immune deficiencies.

This is where the system just isn't strong enough.

It's insufficient to properly protect us from pathogens, from germs.

Gotcha.

So our mission today is basically to unpack how these inappropriate immune responses work, right?

We'll look at the mechanisms, some real world examples, and really try to get at the why behind it all.

The goal is for you to get a solid grasp of this immunity gone awry without needing the textbook right in front of you.

All right.

Let's jump in with hypersensitivity reactions, the over the top ones.

So the basic definition is an altered immune response to an antigen that actually causes disease or damage.

Precisely.

And we tend to classify them in a couple of ways.

First, by the actual immunologic mechanism, how it happens at a cellular level.

That gives us types one, two, three, and four.

OK, four types based on mechanism.

Right.

And second, we can classify them by the source of the antigen, what triggered it.

Is it an allergy to something environmental?

Is it autoimmunity, attacking self,

or alloy immunity, attacking tissues from another person?

And it's worth remembering, this stuff doesn't happen in a vacuum.

They're genes, infections you've had, stuff in the environment.

It all plays a part.

Absolutely.

Now, those four mechanisms, they're laid out nicely in Table 8 .1 in the textbook.

It breaks down each type by name, how fast it develops, the antibody involved, the main cells where the complement joins in.

Can you walk us through those four types briefly, just the highlights?

Sure.

Type I is IgE -mediated.

Think of it like within minutes.

It involves IgE antibodies and mast cells.

No complement, usually.

Classic example.

Seasonal allergies, hay fever.

OK.

Type one, fast allergy.

Type two is tissue -specific, also immediate, but uses IgG or IgM antibodies that bind directly to antigens on specific cells or tissues.

Natural killer cells, macrophages are involved, often complement too.

Graves' disease, the thyroid condition, fits here.

Type two, targeting specific tissues.

Type three is immune complex -mediated.

So immediate, IgGM again, but here the antibody binds to a soluble antigen first, forming a complex that then deposits in tissues.

Neutrophils get involved, complement is definitely active.

Lupus or SLE is a major example.

Type three, floating complex is causing trouble.

And finally, type B.

This one's different.

It's cell -mediated, driven by T cells and macrophages, not antibodies.

And it's delayed, takes hours or days, complement isn't involved.

Think poison ivy, that delayed rash.

That immediate versus delayed thing seems pretty key.

It is.

Immediate reactions are usually antibody -driven, happening fast, minutes to hours.

Delayed ones are cell -driven, taking hours to appear and peaking days later.

And the most extreme immediate reaction.

That would be anaphylaxis, super rapid, systemic, life -threatening.

You get itching, redness, vomiting, breathing trouble, lead to shock, even death.

B -stings, peanut allergies, those can trigger it.

It's a whole body emergency.

Wow, OK, let's zoom in on type I, IgA -mediated reactions, the ones we usually just call allergies.

How does that sensitizations process work?

Right, so imagine your first encounter with, say, pollen.

Your immune system mistakenly flags it as dangerous and tells your B cells to make specific IgE antibodies against it.

OK, so you make these IgE antibodies.

Exactly.

And these IgE antibodies then go and latch onto the surface of special cells, called mast cells.

They just sit there, waiting.

The mast cell is now sensitized, kind of like it's armed.

And then you encounter the pollen again.

Bingo.

The pollen antigen now physically links together those IgE antibodies sticking out from the mast cell.

This cross -linking is the trigger.

The mast cell instantly degranulates, dumps out a whole bunch of preformed chemicals.

And the main chemical is?

Histamine.

It acts super fast, 15, 30 minutes.

It hits H1 receptors, causing things like bronchial constriction, making it harder to breathe, increased vascular permeability, leaky blood vessels, causing swelling, edema, and vasodilation, redness.

Ah.

So that's what causes the immediate symptoms like itching, the hives, the tight chest, maybe even a drop in blood pressure in severe cases.

That's histamine doing its thing.

And if you can see figure 8 .1 in the text, it laid this out visually.

First exposure, IgE binding, then the re -exposure and degranulation.

It's a clear chain reaction.

And are there other chemicals involved besides histamine?

Oh, yes.

The mast cells also start making new mediators, like leukotrienes and prostaglandins.

These act a bit slower, over hours, and they contribute to what's called the late phase reaction.

This can keep symptoms going for 2 to 24 hours, even longer, and it draws other immune cells into the area, keeping the inflammation going.

Okay, so it's not just the immediate hit.

Let's talk about specific examples.

Food allergies.

Right.

Gastrointestinal allergy, often triggered by things like milk, chocolate, nuts, shellfish, causes vomiting, diarrhea, abdominal pain.

And you mentioned peanuts earlier.

That's a big one.

Yeah, the advice totally changed on that, didn't it?

It really did.

The 2015 study showing early introduction actually prevents allergy was a game changer.

It led to the 2017 guidelines recommending introducing peanuts early to high -risk infants.

Really interesting stuff.

Definitely.

What about skin reactions?

Erticaria or hives.

That's the classic skin manifestation.

Local histamine release makes capillaries leaky, causing those white fluid -filled bumps, wheels surrounded by redness, the flare, and they itch like crazy.

And respiratory stuff.

Big category.

Conjunctivitis, itchy eyes, frinitis, runny nose, sneezing hay fever, and asthma.

Asthma is a really common type I reaction.

You get bronchospasm, airway swelling, thick mucus,

all making it hard to breathe.

Some people just seem more prone to allergies, right?

What's that about?

That's atopi.

It's basically a genetic predisposition.

Atopic individuals tend to produce more IgE and have more Fc receptors for IgE on their mast cells, making them hyper -responsive to allergens.

So how do we deal with type I reactions?

Avoidance, I guess.

Avoidance is key if you know the trigger.

Testing helps identify them, food challenges, skin tests, checking IgE levels in the blood, medications like antihistamines block histamine, corticosteroids reduce inflammation, and others block those later mediators like Lugatrenes.

What about allergy shots?

Desensitization?

Yeah, clinical desensitization.

It involves injecting tiny, gradually increasing doses of the allergen over time.

The idea is to slowly build tolerance.

It can work quite well for respiratory allergies like pollens and insect venom allergies, less so for food allergies, unfortunately.

And there's always a risk, albeit small, of triggering a systemic reaction during the process.

Okay, let's switch gears to type II.

Tissue -specific hypersensitivity.

Here the antibodies are attacking antigens right on our own cells or tissues.

Exactly.

The antibody binds directly to an antigen that's part of a specific cell surface or tissue.

Sometimes it might even be an external antigen, like a drug that has attached itself to the cell surface, making the cell look foreign.

And how does the damage actually happen?

Is it just one way?

No, that's what's really interesting here.

As shown in figure 8 .3, there are actually about five main mechanisms.

First,

the antibody, IgG or IgM, can activate the complement system.

Complement proteins assemble into a structure that basically punches holes in the cell membrane, causing lysis to cell bursts.

Think autoimmune hemolytic anemia, where red blood cells are destroyed, or a bad blood transfusion reaction.

Okay, so complement punches holes.

What else?

Second mechanism, phagocytosis.

The antibody, or even a complement fragment like C3b, acts like a flag, coating the target cell.

This causes opsonization.

It makes the cell incredibly tasty to phagocytes, like macrophages, which then engulf and destroy it.

This happens with antibodies against platelets, for example.

So flagging for cleanup?

Mechanism three.

Neutrophil involvement.

Antibodies and complement proteins attract neutrophils to the site.

The neutrophils try to engulf the antibody -coated stuff, but in the process, they release toxic enzymes and reactive oxygen species that damage the surrounding tissue.

This can contribute to conditions like acute respiratory distress syndrome.

Neutrophils causing collateral damage.

Number four.

Antibody -dependent cell -mediated cytotoxicity, or ADCC.

Here, natural killer NK cells recognize the antibodies found to a target cell.

The NK cell then releases toxic substances that kill the target cell directly.

This is seen in some forms of acute transplant rejection.

NK cells as targeted killers.

And the last one.

This one's a bit different.

The antibody binds to a cell surface receptor, but instead of causing destruction,

it modulates the receptor's function.

It might block the receptor, preventing it from working normally, or it might actually activate the receptor inappropriately.

Oh, so it messes with the cell's signals without killing it.

Exactly.

In Graves' disease, antibodies bind to and activate the TSH receptor on thyroid cells.

Causing hyperthyroidism, the thyroid goes into overdrive.

In myasthenia gravis, antibodies block acetylcholine receptors at the neuromuscular junction, causing muscle weakness because the nerve signals can't get through properly.

Wow.

So type two is really versatile in how it causes damage, from outright destruction to just messing with cell function.

Okay, on to type three.

Immune complex mediated reactions.

How is this different from type two?

The key difference is where the antigen is when the antibody binds.

In type two, the antibody binds to an antigen already on a cell surface.

In type three, the antibody,

IgG, or IgM, binds to a soluble antigen floating around in the blood or body fluids first.

This forms an antigen -antibody clump, an immune complex.

And these clumps are the problem.

Yes.

These immune complexes circulate, and then they get deposited in various tissues, often in the walls of blood vessels.

It's the deposition of these complexes that triggers the damage.

Why do they deposit in certain places?

It seems intermediate -sized complexes are the main culprits.

They aren't cleared easily and tend to settle out in areas with lots of filtration or slower blood flow.

Pick the tiny vessels in the kidneys, chlamyriole, joints, skin, lungs, heart.

Figure 8 .4 illustrates this deposition process.

Okay, so the complexes lodge in tissues.

Then what?

Once deposited, they activate the complement system.

Complement activation generates signals that attract neutrophils to the site.

The neutrophils try to engulf the deposited complexes, but they can't always manage it effectively, especially if the deposits are large.

In the process, they release their lysosomal enzymes and other damaging molecules, causing inflammation and tissue injury right there, often leading to vasculitis, inflammation of the blood vessels.

Can you give some examples of type 3 diseases?

Sure.

A systemic example is serum sickness, historically seen after receiving anti -serum from animals, causing fever, rash, joint pain due to widespread complex deposition.

A really specific example is Raynaud phenomenon,

where fingers turn white in the cold.

In some cases, it's caused by immune complexes called cryoglobulins that literally precipitate or solidify in colder temperatures, blocking blood flow in peripheral capillaries, fingers, toes, nose.

This causes the pallor, numbness, sometimes cyanosis, or even gangrene.

And localized examples.

There's the Arthus reaction, which is localized vasculitis from repeated local exposure to an antigen.

Think of celiac disease, gluten -sensitive enteropathy, where gluten exposure leads to immune complex formation and damage in the gut, or allergic alveolitis like farmer's lung from inhaling fungal antigens in moldy hay, causing lung inflammation.

Got it.

Now, for the last type, type of IV,

cell -mediated hypersensitivity.

You said this one is different because it's driven by T cells, not antibodies.

That's the defining feature.

No antibodies involved directly in the damage.

Instead, it's orchestrated by T lymphocytes.

How do the T cells cause damage, then?

Two main ways, as shown in figure 8 .5.

First, you have cytotoxic T lymphocytes, TC cells, that can directly recognize and kill target cells displaying a specific antigen.

Second, you have T helper cells, specifically TH1 and TH17 cells.

When they recognize an antigen, they release cytokines chemical signals.

And what do the cytokines do?

They act like a call to arms, recruiting and activating other immune cells, especially macrophages.

These activated macrophages then contribute significantly to the tissue damage, either by trying to engulf things and releasing their damaging enzymes, or sometimes by direct effects.

And this one is called delayed hypersensitivity.

Why the delay?

It takes time.

After exposure to the antigen, the sensitized T cells need time to migrate to the site, recognize the antigen again, and then produce enough cytokines to recruit and activate the macrophages.

This whole process typically takes 24 -72 hours to really develop, which is why the reaction isn't immediate.

Makes sense.

What are some classic examples of type IV?

Graft rejection involves type IV mechanisms, which we'll discuss more under Alloimmunity.

The tuberculosis skin test, the PPD test, is another perfect example.

You inject a little tuberculin antigen under the skin.

If the person has been sensitized previously, T cells migrate there, get activated, and cause that characteristic hard red bump in duration in erythema that appears 48 -72 hours later.

And poison IV.

Yes, allergic contact dermatitis.

That's a very common type IV reaction.

It's triggered by small molecules called haptans, things like the urushiol oil from poison IV, metals like nickel and jewelry, chemicals in cosmetics or latex.

These haptans aren't antigenic by themselves, but they bind to proteins in your skin.

Uh -huh.

So they modify your skin proteins.

Right.

The haptan protein complex is then recognized as foreign by T cells.

The first exposure just sensitizes you, like figure 8 .6 shows.

It's the second time you encounter it that the T cells react strongly, causing the characteristic itchy blistering rash days later.

It's kind of amazing the body mounts such a strong delayed defense against something like plant oil.

It really is.

It highlights the sensitivity, maybe sometimes oversensitivity, of the cell -mediated system.

Okay, let's shift from reacting to external things to reacting to ourselves.

Autoimmunity.

This is when the immune system loses tolerance to self -antigens.

Normally, our immune system is trained to recognize self and not attack it.

That's immunologic tolerance.

In autoimmunity, there's a breakdown in that tolerance.

The immune system starts reacting against the body's own antigens as if they were foreign invaders.

Do we all have some autoantibodies?

We do, actually.

Low levels are common and usually harmless.

Autoimmune disease happens when that reaction against self becomes strong enough to cause actual tissue damage and symptoms.

What triggers it?

Is it just bad luck?

It's complex.

Usually, it seems to involve an interaction between genetic predisposition, some people are just more susceptible, and an environmental trigger.

This could be an infection,

exposure to certain chemicals, maybe even hormonal changes.

And autoimmune diseases are significantly more common in women, suggesting hormones might play a role.

You mentioned infections triggering it.

How does that work?

A key mechanism is called antigenic mimicry.

A pathogen, like a bacterium or virus, might have antigens on its surface that look very similar structurally to some of our own self -antigens.

So the immune system gets confused?

Precisely.

A classic example is acute rheumatic fever following a group A streptococcus infection.

Certain proteins on the strep bacteria mimic proteins found in human heart valves.

The antibodies your body makes to fight the strep can then cross -react and attack your heart valves, causing damage.

That's essentially a type 2 hypersensitivity triggered by mimicry.

Strep antigens can also form immune complexes, leading to kidney inflammation, a type 3 reaction.

That's rough.

Are there many autoimmune diseases?

Oh, dozens.

Table 8 .3 in the book gives a good overview.

They can affect nearly any system.

Endocrine glands, like Hashimoto's thyroiditis for type 1 diabetes,

skin psoriasis, neuromuscular junctions, myasthenia gravis, connective tissues, rheumatoid arthritis, lupus, so the list goes on.

The targets, the self -antigens, are incredibly diverse.

Let's use systemic lupus erythematosus, SLE, as a case study.

You mentioned it's common and serious.

What's going on there?

SLE is really the archetypal systemic autoimmune disease.

The core problem is the production of a wide array of autoantibodies against various self -components, especially things found inside the cell nucleus like DNA, RNA, histones.

The hallmark is often the presence of antinuclear antibodies, ANA, in the blood.

And how do these autoantibodies cause damage in lupus?

Primarily through type 3 and type 2 hypersensitivity mechanisms.

Circulating immune complexes, especially those containing DNA and anti -DNA antibodies,

deposit in small blood vessels in places like the kidneys, skin, brain, and joints, triggering inflammation.

Type 3.

Also, autoantibodies can directly target red blood cells, white blood cells, and platelets, leading to their destruction.

Type 2.

Who tends to kill lupus?

It has a striking female predominance, about 9 to 1, typically diagnosed between ages 20 and 40.

There's also a higher risk in individuals of black ancestry.

Genetics definitely play a role, but environmental factors are likely triggers.

What are the symptoms like?

Very variable.

And they tend to wax and wane periods of flares and remission.

But common ones include joint pain or arthritis in about 90 % of people, rashes, especially a characteristic butterfly -shaped rash on the face that worsens with sun exposure, photosensitivity, kidney disease, blood count abnormalities, inflammation of linings around the heart or lungs, cirrhositis, and sometimes neurologic problems.

This variability can make it tricky to diagnose.

How is it diagnosed, then?

An ANA test is a good screening tool.

It's positive in about 98 % of SLE cases, though false positives can occur with other conditions.

More specific antibody tests, like anti -double -stranded DNA, anti -DS DNA, or anti -Smith anti -Cinema antibodies, help confirm the diagnosis along with the clinical picture.

And treatment?

Is there a cure?

Unfortunately, no cure yet.

Treatment aims to control symptoms, reduce inflammation, and suppress the overactive immune system to prevent organ damage.

This involves NSAIDs for pain, corticosteroids during flares,

immunosuppressive drugs like metaltrexate for more severe disease,

and endomelarial drugs like hydroxychloroquine, which surprisingly help with fatigue, joint pain, and rashes.

Protecting from sun exposure is also important.

Okay, moving from autoimmunity, self versus self, to alloimmunity.

This is reacting to tissues from another person of the same species.

That's right.

Your immune system recognizes antigens on the cells of another individual as non -self and mounts a response.

We see this mainly in three situations.

Blood transfusions, organ tissue transplantation, and sometimes during pregnancy.

What are these non -self antigens called in this context?

They're called allointigens or sometimes isoantigens.

The major ones we deal with are the blood group antigens, like ABO and RH, and the major histocompatibility complex, MHC antigens, which in humans are called human leukocyte antigens, HLAs.

So it's our genetic diversity that causes this.

We all have slightly different cell surface markers.

Exactly.

Our immune systems are exquisitely tuned to recognize these differences.

Let's take transfusion reactions first, focusing on the ABO blood group.

As figure 8 .7 shows, your red blood cells have carbohydrate antigens on their surface.

Type A has A antigen, type B has B, type AB has both, type O has neither.

And we make antibodies against the ones we don't have?

Correct.

And crucially, these are naturally occurring IgM antibodies called isohemagglutinins.

So if you're type A, you have anti -B antibodies, if you're type B, you have anti -A, if you're type AB, you have neither antibody, and if you're type O, you have both anti -A and anti -B antibodies.

That explains why mismatched transfusions are bad.

The recipient's antibodies attack the donor's red blood cells.

Yes, causing agglutination, clumping, and complement -mediated lysis destruction of the transfused cells, which can be very severe.

That's why type O is the universal donor.

No A or B antigens to attack.

And type AB is the universal recipient.

No anti -A or anti -B antibodies to attack incoming cells.

What about the RH factor?

The RH blood group is another important system, primarily involving the D antigen.

If you have the D antigen, you're RH positive.

If you don't, you're RH negative.

Unlike ABO, RH negative people don't naturally have anti -D antibodies.

They only make them if they get exposed to RH positive blood.

Like an RH negative mother carrying an RH positive baby.

Exactly.

During pregnancy or delivery, some fetal RH positive red blood cells can enter the mother's circulation.

She then develops IgG anti -D antibodies.

This usually doesn't affect the first RH positive baby, but in subsequent RH positive Those maternal IgG antibodies can cross the placenta and attack the fetus's red blood cells, causing hemolytic disease of the newborn.

But we have a way to prevent that now, right?

Yes, thankfully.

Giving the RH negative mother injections of anti -D immunoglobulin, Rojoam, during pregnancy and after delivery, prevents her from forming her own anti -D antibodies.

It's been incredibly successful in reducing hemolytic disease of the newborn.

Now let's talk transplant rejection.

What are the key antigens here?

The main players are the human leukocyte antigens, HLAs, which are the human version of the major histocompatibility complex, MHC proteins.

As shown in figure 8 .8, these are molecules on our cell surfaces that present antigens to T cells.

They are encoded by genes on chromosome 6, and these genes are incredibly diverse, highly polymorphic.

Meaning everyone has a very unique set of HLAs.

Extremely unique.

We inherit one set of HLA genes, a haplotype, from each parent, and both sets are expressed codominas, as illustrated in figure 8 .9.

This immense diversity means finding an unrelated individual with a perfect HLA match is highly unlikely.

It's like a cellular fingerprint.

So your immune system immediately recognizes a transplanted organ with different HLAs as formin?

Pretty much.

That's the basis of rejection.

We classify rejection based on timing and mechanism.

Hypercute rejection happens within minutes.

It's caused by pre -existing antibodies in the recipient that react against HLA antigens on the donor organ's blood vessel lining.

It's a type 2 reaction, causes the graft to turn white and die quickly.

Thankfully, it's rare now because we screen for these antibodies before transplant.

Cross matching.

What about rejection that happens later?

Acute rejection occurs days to months after the transplant.

This is primarily a cell -mediated type IV response.

The recipient's T cells recognize the mismatched HLA antigens on the graft cells and attack them.

You'll see lymphocytes and macrophages infiltrate in the graft on biopsy.

This is often manageable with immunosuppressive drugs.

And rejection can happen even years later.

Yes.

That's chronic rejection.

It develops slowly over months to years, causing progressive loss of graft function.

It involves a mix of factors, including a slow, low -grade cell -mediated type IV reaction, antibodies and non -immune factors causing inflammation and scarring within the graft.

It's often associated with less optimal HLA matching initially or damage to the graft over time.

Unfortunately, treatments are less effective and it often leads to graft failure and the need for re -transplantation.

Okay, so we've covered hypersensitivity and reactions to self and others.

What about the opposite problem?

Deficiencies in immunity.

Right.

This is when the immune system or the inflammatory response just fails to function normally.

The consequence is increased susceptibility to infections.

Are these deficiencies something you're born with?

They can be.

We classify them into two broad groups.

Primary or congenital immune deficiencies are caused by genetic defects.

You're born with them.

Secondary or acquired immune deficiencies develop later in life due to some other condition like infections, cancer, malnutrition or medical treatments.

Secondary deficiencies are actually much more common.

What's the main sign that someone might have an immune deficiency?

The clinical hallmark is a tendency to develop unusual infections, recurrent infections or infections that are unusually severe.

Think frequent bouts of pneumonia, sinusitis, otitis media, meningitis or infections caused by opportunistic microorganisms that don't usually bother healthy people.

Can the type of infection give clues about the deficiency?

Yes, often it can.

For example, recurrent viral infections like chickenpox, CMV, fungal infections like Candida or infections with atypical microbes often suggest a problem with T cell function.

Frequent infections with encapsulated bacteria like pneumococcus or certain viruses tend to point towards B cell or phagocyte deficiencies.

And disseminated infections with Neisseria bacteria, which cause meningitis and gonorrhea, are characteristic of complement deficiencies.

How does this affect routine medical care?

People with immune deficiencies often require prolonged courses of antibiotics.

And importantly, you have to be very careful with live attenuated vaccines like MMR or varicella as these could potentially cause disease in someone with a weak immune system.

Let's briefly touch on the primary congenital immune deficiencies.

Are they common?

Individually, each specific type is rare.

But collectively as a group, they're actually more common than some other well -known genetic conditions like cystic fibrosis or childhood leukemia.

Most are caused by single gene defects.

While some of you are very early in infancy, others might not show up until later childhood or even adulthood.

Can you give a couple of examples?

Sure.

Among the most severe are the combined deficiencies affecting both T and B cells.

Severe combined immunodeficiencies, SCIDs, are life -threatening.

Infants born with SCID have very few lymphocytes and an underdeveloped thymus.

There are various genetic causes.

Another combined type is DeGeorge syndrome, caused by a deletion on chromosome 22, leading to poor thymus development, low T cells, and often absent parathyroid glands, causing low calcium.

Figure 8 .10 shows some characteristic facial features associated with it, like wide -set eyes and a small chin.

What about problems just with antibodies?

Those are predominantly antibody deficiencies.

The most common primary immune deficiency overall is selective IgA deficiency.

Many people are asymptomatic, but others get recurrent sinus, lung, or GI infections.

Brutal agamaglobulemia is more severe.

B cells fail to develop, leading to very low antibody levels and repeated bacterial infections.

And problems with the cleanup crew cells.

Phagocyte defects.

A key example is chronic granulomatous disease, CGD, where phagocytes can't produce the reactive oxygen species needed to kill certain bacteria and fungi effectively.

This leads to recurrent pneumonias and granuloma formation.

Are there deficiencies in the complement system, too?

Yes, complement deficiencies.

Deficiencies in early components like C3 are very severe, leading to recurrent, life -threatening infections with encapsulated bacteria.

Deficiencies in the later components, C5, C9, mainly increase susceptibility to Neisseria infections.

How are these primary deficiencies evaluated and treated?

Evaluation starts with screening tests, like a complete blood count, CBC, with differential, measuring immunoglobulin levels, IgG, IgM, IgA, and assessing total complement activity.

Treatment often involves replacement therapies.

For antibody deficiencies, regular intravenous immunoglobulin IgG infusions provide temporary replacement antibodies.

What about more permanent solutions?

For severe defects in lymphocyte development, like SCID,

stem cell transplantation from bone marrow or umbilical cord blood can potentially rebuild the immune system.

Gene therapy is also showing promise for correcting the underlying genetic defect in some conditions like ADA, SCID, and CGD.

A major risk with transplantation, though, is graft vs.

host disease, GVHD, where T -cells from the donor graft attack the recipient's tissues.

Okay, now let's turn to secondary acquired immune deficiencies.

You said these are much more common.

Far more common.

Many different conditions can impair immune function later in life.

Box 8 .1 lists quite a few.

Like what kind of conditions?

Well, even normal physiological states like pregnancy, infancy, and aging are associated with some immune changes.

Psychological stress can have an impact.

Dietary insufficiencies certainly.

Many infections themselves can temporarily suppress immunity.

Malignancies, particularly blood cancers, often severely impact the immune system.

Physical trauma like major burns, and importantly, many medical treatments.

Medical treatments can cause immune deficiency.

Absolutely.

Think about surgery and anesthesia.

They cause temporary suppression.

Drugs intentionally used to suppress the immune system, like corticosteroids for autoimmune diseases or asthma, have broad immunosuppressive effects.

Chemotherapy and radiation for cancer kill rapidly dividing cells, including immune cells.

And anti -rejection drugs used after transplants suppress the immune system globally to prevent rejection.

But this increases the risk of infections and even some cancers.

It's always a balancing act.

Which brings us to probably the most well -known acquired immune deficiency, AIDS.

Right.

Acquired Immunodeficiency Syndrome, AIDS, is specifically caused by infection with the

HIV.

HIV is devastating because it primarily infects and destroys CD4 plus T helper cells, which are absolutely crucial for coordinating almost all adaptive immune responses.

HIV is still a huge global problem, isn't it?

A massive one.

Millions are living with HIV -AIDS worldwide, with the heaviest burden still in sub -Saharan Africa.

However, in resource -rich settings, the development of effective therapy has transformed HIV infection from a near -certain death sentence into a manageable chronic condition for many.

How is HIV transmitted?

Primarily through blood or blood products, less common now with screening, sharing needles for IV drug use, sexual activity, the most common route globally, and from mother to child during pregnancy, delivery, or breastfeeding.

Can you walk us through how HIV actually causes AIDS?

What does the virus do?

Sure.

HIV is a retrovirus.

Its genetic material is RNA, not DNA.

Figure 8 .11 shows its structure.

It has the RNA genome, essential enzymes like reverse transcriptase, integrase, and protease, all packaged inside a capsid and surrounded by an envelope studded with glycoproteins, particularly GP120 and GP41, which are crucial for getting into cells.

So how does it infect a T helper cell?

Figure 8 .12 outlines the life cycle, right?

Yes.

Figure 8 .12 shows the steps.

First, attachment.

The GP120 protein on the virus binds specifically to the CD4 molecule on the surface of a T helper cell, or other CD4 plus cells like macrophages.

It also needs to bind to a co -receptor, usually CCR5 or CXCR4.

Okay, it docks onto the cell then.

Second, fusion.

Binding triggers changes that allow the GP41 protein to fuse the viral envelope with the cell membrane, releasing the viral core into the cell's cytoplasm.

And inside the cell?

Third, reverse transcription.

The viral enzyme reverse transcriptase copies the viral RNA genome into double -stranded DNA.

This is a key step you need to retroviruses.

Fourth, integration.

Another viral enzyme, integrase, inserts this newly made viral DNA into the host cell's own DNA in the nucleus.

The virus is now part of the cell's genetic blueprint.

So the cell is permanently infected?

Essentially, yes.

From then on, whenever the host cell is activated, it can start transcribing and translating the viral genes along with its own.

Fifth, replication assembly.

The cell produces viral RNA of proteins.

The viral protease enzyme cuts long viral proteins into smaller functional pieces.

These components then assemble into new viral cores near the cell membrane.

And finally, release.

Sixth, budding.

The newly assembled virions push out through the cell membrane, taking a piece of the host membrane with them as their envelope.

These new viruses are then ready to infect other CD4 plus T cells.

And the gradual loss of these T helper cells is what causes the immunosuppression?

Exactly.

HIV preferentially infects and kills activated T helper cells.

Over time, this leads to a profound decline in CD4 plus T cell numbers, crippling the adaptive immune system.

The virus can also hide out latently in resting memory T cells, creating a persistent reservoir that's very hard to eliminate.

And this life cycle is where the drugs work?

Precisely.

Anti -retroviral drugs target different steps, blocking attachment or fusion, inhibiting reverse transcriptase, blocking integrase, or inhibiting protease.

Using combinations of these drugs is the key to effective therapy.

How does HIV infection progress to AIDS clinically?

Figure 8 .13 gives a typical timeline for untreated infection.

There's often an initial acute HIV syndrome shortly after infection, maybe like a flu or mono.

Then, a long period of clinical latency, which can last for years.

During this time, the person might feel fine, but the virus is actively replicating.

And CD4 plus T cell counts are gradually declining.

And eventually the counts get too low.

Right.

Eventually, the CD4 plus T cell count drops below a critical level, typically defined as less than 200 cells per cubic millimeter.

At this point, the immune system is severely compromised and the person is diagnosed with AIDS.

They become highly susceptible to opportunistic infections and certain cancers that a healthy immune system would normally control.

What kind of opportunistic infections are common in AIDS?

Box 8 .2 lists some.

Yes.

Box 8 .2 lists many AIDS -defining conditions.

These include protozoal infections like pneumocystis pneumonia, PCP, toxoplasmosis, fungal infections like widespread candidiasis thrush, cryptococcosis, bacterial infections like recurrent pneumonia, mycobacterium tuberculosis, mycobacterium avium complex, AMAC,

and viral infections like cytomegalovirus, CMV disease, progressive multifocal leukoencephalopathy, PML.

Certain cancers are also AIDS -defining, like Kaposi's sarcoma and certain lymphomas.

And figure 8 .43 shows some visible signs.

Yes.

Figure 8 .13 depicts some potential clinical symptoms like severe weight loss, wasting syndrome, the characteristic purplish lesions of Kaposi's sarcoma, severe herpes simplex infections, or signs of CMV retinitis which can cause blindness.

How is HIV diagnosed and monitored?

Current recommendations suggest routine screening for everyone age 13 -64.

Diagnosis usually involves tests that detect both HIV antibodies and the P24 antigen, the viral RNA or DNA.

Once diagnosed, viral load, amount of virus in the blood, and CD4 plus T cell count are monitored regularly.

And the treatment standard is ART?

Yes, antiretroviral therapy, usually a combination of three or more drugs from different classes.

The specific regimen is tailored to the individual.

ART has been incredibly successful at suppressing viral replication,

allowing CD4 plus T cell counts to recover, and dramatically reducing AIDS -related illness and death.

But it's not a cure, right?

Correct.

Because HIV integrates into the host's DNA and persists in latent reservoirs, ART cannot eradicate the virus.

It requires lifelong adherence to keep the virus suppressed.

Challenges include developing drug resistance, managing long -term side effects like increased risk of cardiovascular or metabolic problems, and the persistence of the virus in sanctuary sites like the central nervous system.

I saw a note about a newer drug, Ibalizumab.

Ah yes, Ibalizumab weak, trogarzo.

It's a monoclonal antibody, a newer approach approved for patients with multidrug -resistant HIV.

It works differently,

it binds to the CD4 molecule itself at Domain 2, and blocks HIV entry without actually suppressing the immune system directly.

An interesting potential side effect, though, is Immune Reconstitution Inflammatory Syndrome – IRS – where the recovering immune system suddenly reacts strongly to previously hidden infections.

What about kids with HIV?

Pediatric aids, usually acquired from the mother, can be particularly devastating.

Diagnosis is trickier in infants due to maternal antibodies.

The disease often progresses faster, and central nervous system involvement, HIV, encephalopathy is more common, leading to developmental delays or aggression.

Early diagnosis and immediate initiation of ART are critical for infants.

Wow, that covers a huge amount of ground from overreactions to self -attacks to outright failure of the immune system.

It really shows how complex and, frankly, delicate the immune system is.

When it works well, it's incredible.

But when it goes wrong, the consequences can be profound.

So recapping the big takeaways,

we saw hypersensitivity reactions come in those four types, driven by different mechanisms, leading to everything from allergies to tissue destruction.

Right.

And we distinguished between allergy reacting to harmless external stuff, autoimmunity reacting to self, and alloy immunity reacting to tissues from others, like transplants or transfusions.

Then we looked at immune deficiencies primary, the genetic ones, and secondary, the acquired ones like those caused by illness or treatments.

Both lead to increased infection risk.

And HIVAID serves as that stark example of an acquired deficiency,

specifically targeting the crucial CD4 plus T cells and requiring lifelong management, highlighting just how central these cells are.

It really makes you think if the balance of our immune system is this intricate and its malfunctions can manifest in so many different, sometimes devastating ways.

What does that tell us about the incredibly complex interplay between our own biology, our genes, the environment we live in, and even the microbes we encounter every day?

It's a constant dynamic dance.

A really powerful thought to end on.

Thank you so much for walking us through all of that.

My pleasure.

It's crucial information.

And thank you, Deep Divers, for joining us.

We hope this breakdown helps you understand these alterations in immunity a bit better.

Until next time.