Tuberculosis pathology is hard!!


by sameeralord
Tags: pathology, tuberculosis
sameeralord
sameeralord is offline
#1
May5-12, 02:06 PM
P: 635
Hello,

I'm reading tuberculosis pathology and I'm finding it hard to understand because my general poor knowledge in pathology. This is what I gathered from the reading.

1. Tubercle bacilli reach alveoli of lung and ingested by macrophages.
2. Then macrophages call other macrophages and T cells to wall off the bacilli in lung(forming a tubercle). Now my question is phagosome-lysosome fusion is inhibited by these bacilli, how can macrophages kill these bacilli. Now what is the difference between this tubercle and a granuloma. In a granuloma is it only macrophages that wall off the foreign substance or T cells as well.
3. After few weeks macrophages die releasing bacilli and forming caseous necrotic centre. Why does this cause caseous necrosis, is any necrosis in lung causes cheesy like appearance which is called caseous, is caseous necrosis always covered by granuloma.
4. Now when the tubercle/granuloma ruptures how do cavities form in lungs, and how does this allow for the infection to spread in lung?
6.Why is this a type IV hypesensitivity reaction?
5. What on earth is Ghon's complex?

Thanks!!
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mishrashubham
mishrashubham is offline
#2
May15-12, 01:18 PM
P: 605
Quote Quote by sameeralord View Post
1. Tubercle bacilli reach alveoli of lung and ingested by macrophages.
2. Then macrophages call other macrophages and T cells to wall off the bacilli in lung(forming a tubercle). Now my question is phagosome-lysosome fusion is inhibited by these bacilli, how can macrophages kill these bacilli.
Initially they can't because phagosome-lysosome fusion is inhibited. However the macrophages also display the pathogen antigens which cause T Helper cells to release γ-interferons which activate the macrophages so that they can overpower the inhibition and destroy the pathogen.


Quote Quote by sameeralord View Post
Now what is the difference between this tubercle and a granuloma.
Tubercle is simply a hard round structure and the term granuloma indicates that it is formed of macrophages. So it is both a tubercle and a granuloma.


Quote Quote by sameeralord View Post
3. After few weeks macrophages die releasing bacilli and forming caseous necrotic centre. Why does this cause caseous necrosis, is any necrosis in lung causes cheesy like appearance which is called caseous, is caseous necrosis always covered by granuloma.
The type of necrosis depends on the agent that has caused the necrosis. So every lesion in the lung would not necessarily be caseous. I'm not sure about other cases but in the case of tuberculosis, the caseous necrosis always occurs at the centre of granuloma.

Quote Quote by sameeralord View Post
1. Tubercle bacilli reach alveoli of lung and ingested by macrophages.
2. Then macrophages call other macrophages and T cells to wall off the bacilli in lung(forming a tubercle). Now my question is phagosome-lysosome fusion is inhibited by these bacilli, how can macrophages kill these bacilli.
Initially they can't because phagosome-lysosome fusion is inhibited. However the macrophages also display the pathogen antigens which cause T Helper cells to release γ-interferons which activate the macrophages so that they can overpower the inhibition and destroy the pathogen.


Quote Quote by sameeralord View Post
Now what is the difference between this tubercle and a granuloma.
Tubercle is simply a hard round structure and the term granuloma indicates that it is formed of macrophages. So it is both a tubercle and a granuloma.


Quote Quote by sameeralord View Post
3. After few weeks macrophages die releasing bacilli and forming caseous necrotic centre. Why does this cause caseous necrosis, is any necrosis in lung causes cheesy like appearance which is called caseous, is caseous necrosis always covered by granuloma.
The type of necrosis depends on the agent that has caused the necrosis. So every lesion in the lung would bot necessarily be caseous. I'm not sure about other cases but in the case of tuberculosis, the caseous necrosis always occurs at the centre of granuloma.

Quote Quote by sameeralord View Post
4. Now when the tubercle/granuloma ruptures how do cavities form in lungs, and how does this allow for the infection to spread in lung?
When the granuloma ruptures it releases substances meant for the pathogen to the nearby alveolar tissue. This causes extensive cell damage via necrosis in the surrounding tissue. Also the tubercle naturally occupies some space during its formation. When this drains out after the rupture, it leaves behind that empty space. This leads to cavity formation.

Also since the MTB cells are no longer contained in closed structures, they can enter the bloodstream or other parts of the lung.

Quote Quote by sameeralord View Post
6.Why is this a type IV hypesensitivity reaction?
It is a type IV hypersensitive reaction because it consists of everything that characterize type IV hypersensitivity, namely a cell mediated immune response involving marcrophages presenting antigens which are recognized by T Helper cells, which then go on to produce interferons and interleukins followed by activation of macrophages that produce lytic enzymes that destroy the pathogen.

Quote Quote by sameeralord View Post
5. What on earth is Ghon's complex?
http://en.wikipedia.org/wiki/Ghon's_complex I think that explains it nicely
bobze
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#3
May17-12, 12:57 PM
Sci Advisor
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Quote Quote by sameeralord View Post
6.Why is this a type IV hypesensitivity reaction?

Quote Quote by mishrashubham View Post
It is a type IV hypersensitive reaction because it consists of everything that characterize type IV hypersensitivity, namely a cell mediated immune response involving marcrophages presenting antigens which are recognized by T Helper cells, which then go on to produce interferons and interleukins followed by activation of macrophages that produce lytic enzymes that destroy the pathogen.

Thanks!!

Just to clarify this isn't a type IV hypersensitivity reaction. A hypersensitivity reaction is an undesired/unfavorable response by the immune system. Granulomas (walling off by epitheliod macrophages) and abscesses (walling off by fibrosis and epithelialization) are looked at as a "success" by your body. That is to say, its the desired outcome by the immune system because the body cannot do anything to what is contained within (note, that is why we have to drain abscesses--Your body is all like "good work immune system, well just leave this here forever now").

TB infections and granulomas are an example of cell mediated immunity, aka the Th1 response. If you don't get a good Th1 response (like say your genetics predisposes you to a Th2 response) you get miliary TB (or if we're talking about leprosy you get lepromatous).


I think where you are confused Sameer is associating TB with TIVHS--The TB skin test (PPD) is a TIVHS--or "delayed hypersensitivity". Which happens because you have presensitized (read memory) T-cells that induce a Th1 response to antigen and start dumping acute phase reactants + IFNy at the site of injection that leads to local inflammation and tissue damage (from macrophage and PMNs little toxic war they wage against the antigens).

FYI Sameer if you are studying for the US medical licensing exam you should really have First Aid for step 1 (all this is in there). When do you take your test? I go june 12th which is why I havent been around much :)

mishrashubham
mishrashubham is offline
#4
May29-12, 10:15 PM
P: 605

Tuberculosis pathology is hard!!


Quote Quote by bobze View Post
Just to clarify this isn't a type IV hypersensitivity reaction. A hypersensitivity reaction is an undesired/unfavorable response by the immune system. Granulomas (walling off by epitheliod macrophages) and abscesses (walling off by fibrosis and epithelialization) are looked at as a "success" by your body. That is to say, its the desired outcome by the immune system because the body cannot do anything to what is contained within (note, that is why we have to drain abscesses--Your body is all like "good work immune system, well just leave this here forever now").
You're right the infection itself is not a hypersensitivity reaction since pre-sentization is required.

But I'm confused with what you said about the response being favourable and non-favourable; sure granulomas are great for blocking, but eventually the macrophages are lysed, leading to necrosis and spilling of MTB. This is definitely bad news isn't it? Though unintentional, it is still the work of immune response itself. Or am I missing something?
bobze
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#5
May31-12, 08:31 AM
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Quote Quote by mishrashubham View Post
You're right the infection itself is not a hypersensitivity reaction since pre-sentization is required.

But I'm confused with what you said about the response being favourable and non-favourable; sure granulomas are great for blocking, but eventually the macrophages are lysed, leading to necrosis and spilling of MTB. This is definitely bad news isn't it? Though unintentional, it is still the work of immune response itself. Or am I missing something?
When you have a granuloma of infectious origin (sarcoid and some others don't fit nicely here), its like your bodies police department's way of saying "we have you surrounded".

In your body's eyes, merging a bunch of macrophages and having them "sit tight" with infectious things is much better than letting those infectious things escape and run loose in the body. The macrophages will stimulate other cell types like fibroblasts to quickly proliferate and help lay down extracellular matrix to help keep the "bad guys surrounded". This gives the body's cell-mediated immunity specialists (Th1 cells) time to proliferate and move in to help. Ideally, as your unactivated macrophages sit there and wait full of TB they will get stimulated by IFNy secreted from Th1 cells. This "activates" macrophages and causes them to start fusing their phagosomes with lysosomes that ultimately kill the bacteria. We call this primary type of lesion the Ghon focus and these lesions usually heal up (unless as mentioned before you have some type of immune problem with generating the Th1 response).

You are correct though about the eventual problem. TB is great at surviving intracellularly in macrophages. So macrophages that escape the area unactivated or don't get enough stimuli from Th1 cells simply harbor the bugs. Eventually your body thinks the job is done after resolution of the granulomas. Little does it realize that some macrophages remained unactivated and/or escaped the area transporting TB with it. The TB can lay dormant in the macrophages for years (which can have a very long life themselves). The problem then becomes when you are immunologically stressed. At such a point the TB goes back into "active mode" and can actually replicate in the macrophages (remember they don't mind hanging out in phagosomes).This time you're likely to get a poor response for whatever reason immunologically stressed you out. We call that secondary or reactivation TB. As the TB replicate and spill out of the macrophages they "migrate" toward the apexes of lungs where O2 content is higher and start replicating in the lung interstitium.

You go through the whole cycle of "make granuloma to wall off infection" again, but for whatever reason you were immunologically stressed you're not likely to generate as strong a Th1 response. So now you have granulomas with TB replicating at the center destroying tissue (and blood vessels the life line to those tissues) along with macrophages giving it a poor showing for intracellular killing. The mac's get giddy and in a "last ditch" kind of effort dump toxic substances into the tissues too hoping to stem the tide of replicating TB. These things lead to local necrosis in the tissue, a special type of necrosis we call casesous necrosis, because it looks like "cheese" (happens with TB and some fungi)--pathologists are so gross!

When the immune system is very bad (like if you had HIV) the problem gets worse, because as the granulomas casseate, your body looses the ability to keep the infection in one place. This leads to TB organisms hitching rides in blood vessels, lymphatics etc and disseminating to other areas of the body (a famous place to head from the lungs is to the vertebrae--classically we call this Pott's disease), which generally is the prelude to the death of the patient.


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