In this picture, with phagocytosis I want you to understand
what's going on in great detail. I want you to begin
with the inset picture on the left, and that is a neutrophil.
Where are you right now in terms of acute inflammation?
The neutrophil has left the blood vessel. It has now approached
the bacteria in my interstitium which you call an exudate
and we are about to engulf our bacteria. I have taken this
neutrophil the inset and we blown it up in this picture,
completely blown it up. I've given you a little area here in
the middle where we are going to swallow and engulf the bacteria.
If you take a look at that green pellet, it says bacteria. You are
going to take this up, and when you do this is where we begin.
Your first enzyme you see there is NADPH oxidase. I repeat
NADPH, not NADH. Is that understood from biochemistry.
You tell me where NADPH is produced in biochemistry.
You've heard of HMP shunt or the hexose monophosphate shunt
or pentose phosphate pathway. Lot of P's huh. Can you picture
that. Would you tell me what the rate limiting enzyme is
in your HMP shunt. Good. Glucose-6-phosphate dehydrogenase or G6PD.
You must have NADPH so that you can properly form NADPH oxidase.
So you can take the oxygen. Once again would you tell me what
cell this is. A phagocytic cell, good. And perfectly normal
for a phagocytic cell to create free radicals. I am walking
you through this very methodically because now
we actually are going to inject pathologies and you may or
may not have seen this pathologies. So there is going to be
new information here that you want to be very clear about. Up until
now I have been really quick with the information.
Now we have created the most important free radical at this point.
This is called a superoxide. You see that superoxide.
So you have created it. How did you create it? With the help of
NADPH oxidase. Let's stop here for one second. I said pathology.
What if you have a patient that is deficient of NADPH oxidase.
And you have a child that has recurrent infections.
Recurrent infections especially to catalase positive organism.
Welcome to chronic granulomatous disease. Right. At some point
I will walk you through a table where I am going to go through
the details of some of these diseases. Let's continue.
So now you have formed a superoxide. Now you have a next
enzyme. It's called a superoxide dismutase. Perfect.
And you are going to create another very important component.
That's called H2O2. What's another name for H2O2?
Hydrogen peroxide. Very important that you know about hydrogen
peroxide. Let's talk about a few things here. See that iron, Fe,
can you tell me a condition in which iron might be overloaded?
Haemochromatosis. What does iron damage? Oh my goodness
everything in the body. Skin, heart, pancreas, gonads,
everything. How is it causing such damage? You have heard of
Fenton reaction. What does that mean? Iron or maybe perhaps
copper may then take the hydrogen peroxide
it may create a free radical. And if this free radical is found
outside the neutrophil in excess it's going to cause massive
damage to normal tissue. Are we clear about Fenton reaction.
Let's continue. So now we have formed a hydrogen peroxide.
In a neutrophil, you take this one step further and you must know
the enzyme MPO, myeloperoxidase. That myeloperoxide will form
a very important type of free radical in which it cause ultimate
destruction of this bacteria. Welcome to bleach, amazing huh.
The inner body, we produce bleach. Unbelieveable. Hypochlorous
acid. This takes care of the bacteria, myeloperoxidase.
Okay in the meantime, so you have engulfment of a bacteria,
picture that. Just because you engulf something,
does it mean that you kill the bacteria? No. Would you tell me
in a neutrophil, it's origin, is called a granulocyte is'nt it.
What does the granule contain in a neutrophil? These enzymes,
these hydrolytic enzymes. You see them. NADPH oxidase,
the myeloperoxidase, okay. So you have taken out the bacteria
but then you have the granule that has to make it's way.
And then it combines with phagosome and then you form a
phagolysosome. It's only when you have proper fusion
of the granule containing the enzyme and this phagosome
containing the bacteria. Kind of like a video game. They combine
and once they do, destruction of the bacteria. Simple enough. I know
I was being silly there but it works I hope. Give you another pathology.
What if the lysosome, the granule does'nt properly make it's
way over to the phagosome. And you don't kill your bacteria.
What's the name of that disease? Good, that's Chediak Higashi. Two
diseases here right off the bat. NADPH oxidase deficiency,
chronic granulomatous disease or don't properly migrate your
lysosome over this then results in Chediak Higashi disease.
Spend a little bit time. Not to worry I will give you further
details. In the meantime, I want you to take a look at something
else here. There is my hydrogen peroxide and by that I mean take
a look at the right side. There is my hydrogen peroxide
and with that hydrogen peroxide you will notice that you
have glutathione taking care of that hydrogen peroxide.
How do you form reduced glutathione, that GSH? You need NADPH. How do
you form that NADPH? The G6PD. Glucose-6-phosphate dehydrogenase.
I want us to stop here. I am going to give you a third pathology.
From henceforth, every single time that you hear about NADPH
you should be thinking biochemistry, has to be G6PD. Good. And
what if you're deficient of that enzyme. Who's your patient
most likely in G6PD deficiency. Well, maybe African. And really
it's an X-linked recessive, right, X-linked recessive.
So you need to have proper amounts of G6PD so that you can
then create the NADPH so that you can have proper reduction
of your glutathione. So you can protect yourself against
the free radicals. Alright, okay. Now, is it possible
with G6PD deficiency, usually when you think about G6PD
deficiency may I ask you; Are you going to be dealing
with this cell. What is this cell? A neutrophil. No. Usually
right you think G6PD deficiency Dr. Raj that is hemolytic anemia.
That is an RBC. Why are you even talking about it here? Because
when you have a patient and you're reading a stem of a question.
You are reading a chart of a patient. And they have hemolytic
anemia and they are susceptible to catalase positive organims.
This patient has G6PD deficiency. Okay, Dr. Raj I understand
that the patient ate fava beans and they ended up developing
hemolytic anemia, I get that. Because now the RBC cannot
protect itself. But why is the patient susceptible to catalase
positive organisms? What's the name of that enzyme that we just
talked about that's responsible for creating superoxide?
Take a look. NADPH oxidase. In G6PD deficiency, you cannot
produce any NADPH. If you can't produce NADPH, how can you
form NADPH oxidase. Is that clear. You can't. Two cells that
are damaged in G6PD deficiency; RBC's, neutrophils.
No other condition is going to give you such a recurrent type
of behavior. So what about in chronic granulomatous disease,
what did you learn about that in Immunology. Only a patient
that is susceptible to catalase positive organism.
There is no such thing as NADPH oxidase and RBC to protect the
RBC. Only the neutrophil. Three pathologies from this diagram
and more information that I've given you here Fenton reaction
and myeloperoxidase. Spend time here, make sure that you're
completely comfortable with everything that I've talked to
you about with enzymes and the biochemistry. The last little
point that I want you to make. I want you to go to the right
top. See the bacteria there. It's covered by chocolate. What?
No, I'm being serious but it's covered by C3b. What am I
referring to? I'm not a huge fan of strawberries, okay.
But you put that strawberry in chocolate, I cannot get
enough. So, what is it that you're taking the bacteria
think of it as being a strawberry. In all seriousness, you
are taking the bacteria, you are dipping it into chocolate
making it mighty tasty for the neutrophil. It's called an
opsonin. You see the bacteria. The chocolate is the C3b.
It's an opsonin also IgG. You are making it really really
tasty for the neutrophil to then bring about phagocytosis.
Is that clear? If it is, good. If it's a little bit too much,
digest this accordingly. Lot of good information.
All of this that I've talked about is high yield at any point in
time. In Pathology, Biochemistry, Immunology, questions will arise.