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dr weber
first: the lab volunteers will get a beer during happy hr from dr weber 
:)
second: he's soliciting suggestions for something to do besides pathology 
this afternoon. well, the suggestions all sucked so we're stuck here.

GRANULOMATOUS INFLAMMATION

this is not synonymous w/chronic inflammation
it is a specific subtype of chronic inflammation with very specific 
histological characteristics.

causes of granulomatous inflammation 
two categories:
immune and non immune granulomatous inflammation

NON IMMUNE:
you usually get a granulomatous inflammation within tissue due to an 
agent that can't be properly phagocytosed and you have to think primarily 
in terms of foreign bodies - eg, suture material is too large to 
phagocytize, won't disintegrate, so causes granuloma. also metal or wood 
embedded in tissue can cause granuloma. so that's pretty easy to 
visualize...any agent in tissue that can't be phagocytosed - too large, 
or whatever. this is non immune or foreign body granuloma

IMMUNE
most granulomas in animals are due to pathogenic organisms that have 
evolved to evaded host defense mechanisms (phagocytosis). some of these 
are physically very large, some have big cell walls that won't degrade, 
etc etc. you expect that when they induce an inflammatory response, the 
immune system becomes involved...think of mycobacteria, fungi, parasites 
eg migrating nematode larvae, etc. these all provoke a granulomatous 
response.

development of granuloma in lung secondary to mycobacterium TB:

if you take a rabbit and expose to aerosolized mycobacterium TB...
the TB gets into the alveoli. first thing body does is to have a 
neutrophil response. the PMNs will phagocytize the TB but can't digest 
them or kill them. in 24-48 hrs, the PMNs die of course, and they release 
the viable TB organisms into the tissue. as this is going on, within 
first 24-48 hrs of infxn, you start having mphages come in also. the 
mphages are accompanied by lymphocytes (T cells) also coming to the area. 
you have a scattering of some dying PMNs, but by 48-72 hrs you mostly 
have mphages and lymphs. the mphages also phagocytize the TB organisms, 
but can't kill or digest them. many mphages will phagocytize the TB, then 
wander off through lymphatic system and assist in spread of TB to 
regional lymph nodes or even to bone marrow or spleen in this way. 
delayed hypersensitivity starts to develop after about 7-10 days. then, 
the macrophages are activated - they start to look different - they 
become "epitheliod" cells. the most characteristic histological finding 
of a granuloma is the epitheliod cell, which is a macrophage which has 
changed morphologically into a cell that looks more like an epitheliod 
cell. the normal mphage has clear cytoplasmic borders. but the 
epithelioid cells have very nondescript cytoplasmic borders. you see a 
very large nucleus which you shouldn't confuse with the cell itself. the 
epithelioid cell has a lot of interdigitating membranes...so it kind of 
washes out the cytoplasmic borders.  while these cells are developing, 
another change occurs. you often see giant cells. giant cells don't have 
to be present in every granuloma, sometimes they are there, sometimes 
not. they are fusions of macrophages. you see a "giant" cell with a dozen 
or more nuclei all within one cytoplasmic outline.  giant cells can be 
"foreign body type" with nuclei clumped in middle of cell, or "Langhans 
type" giant cell, with ring of nuclei around the outside, and this kind 
was first seen with TB and may be indicative of TB. but neither one of 
these types of giant cells is, on its own, diagnostic of a particular 
kind of granulomatous response. you can see both types. so, mainly, so 
far, granuloma is a focal collection of mononuclear cells, predominantly 
of the epithelioid type. now, also, we start seeing fibroblasts getting 
activated and starting to lay down collagen. we get a lot of collagen 
production and you see prominent nuclei of the fibroblasts. this walls 
off the granuloma. so usually a granuloma is a focal lesion - eg 1-2 mm - 
but can get very very large. once granuloma starts getting large, it can 
start to look like a tumor! but as long as the lesion is focal and you 
just have a few spots, they're easily noted as focal, small, grey-yellow 
granulomas. but they can get bigger, you can have fusion of multiple 
granulomas and formation of these tumor like masses.

in TB, we call this a "tubercle" - a granuloma that's walled off by 
fibroblasts/collagen, containing giant cells, epitheliod cells, other 
mononuclear cells, etc. as hypersensitivity develops, a peculiar thing 
happens inside the tubercle (this is specific to TB) - the center part of 
the granuloma will undergo caseous necrosis. this is particularly 
indicative of TB infection. this occurs probably due to delayed 
hypersensitivity causeing cytokine release from activated mphages and 
intense tissue destruction locally, in the presence of lipid, causing 
caseous necrosis. this is diagnostic of TB, often. also, when this 
occurs, you can have subsequent mineralization or calcification of the 
central area of the granuloma...so you can recognize it on a radiograph 
as a discrete lesion, opaque, usually a good diagnostic indicator of 
calcified granuloma.

so, reminder: talking about immune granulomas, remember what happens 
w/cytokines and cell types...
initially a mphage presents the TB Ag to T cells,right? what kind of T 
cells are involved in DTH rxns? well, mphage uses MHCII to present Ag to 
the CD4+TH1 cell (remember mphage makes IL12 which drives T cells to the 
TH1 path). the TH1 cells are activated and clone out after being 
presented w/Ag. so they proliferate in the area of the infxn, and they 
produce gamma interferon, which in turn will activate more 
macrophages...so, with activation of macrophages, mphages are better at 
phagocytizing, killing, and digesting TB organisms. also keeps mphages 
from wandering away any more.

always think of the role of immune system and how it helps development of 
inflammatory response. does immune system respond to inhalation of plant 
fiber? no. you may get a granuloma, but immune system doesn't play a role 
in this, because cellulose doesn't provoke an immune response. now, if 
plant was contaminated with fungi or something, you may see an 
immunological response. what about to a wood splinter? a wood splinter in 
the dermis will cause an abcess - then you lance the abcess - and the 
splinter will come out with the fluid. so you won't get a granuloma from 
that. always think- what is contaminating substance? is it acting like a 
foreign body or infectious agent or is it contaminated with a pathogen, 
or what?

another cell type to consider is eosinophils. if granuloma is caused by a 
parasite or immune complexes, you will see eosinophils in the granuloma.

ok.
what is the main difference between a granulomatous inflammation and a 
plain chronic inflammation? well...

grossly, the granuloma is more focal, localized, is usually quite 
discrete. granuloma usually small but not always. is grey-yellow with 
discrete outline. 
histologically, granuloma primarily mononuclear cells with epitheliod 
cells and macrophages predominating. also lymphocytes, giant cells, 
fibroblasts.

chronic inflammation grossly causes contraction of the organ, distortion 
of organ, causes organ to become more grey-white from fibroblast 
proliferation and collagen. organ is firmer. there is massive organ 
dysfunction as well.  overall, the organ is involved more uniformly than 
with the granuloma. you don't see cirrhosis of ONE liver lobe, for 
example. histologically, the main difference is that you see loss of 
normal architecture, proliferation of fibroblasts, deposition of 
collagen, and some lymphocytes, plasma cells, macrophages...NO 
epithelioid cells or giant cells would be seen.

we consider the granulomatous inflammatory rxn a TYPE of chronic 
inflammation, ok? not synonyms.

now a bunch of slides:

corn cob foreign body in lumen of bowel - will NOT cause granuloma. is in 
the lumen, not in the tissue. could cause obstruction and necrosis of 
intestinal wall, though. then, it could induce a granulomatous response 
at point of contact with inside of tissue wall. 

slide: mountain, slightly sloping pasture with multifocal horses. 

slide: rhesus monkey organs. liver is completely covered with multifocal 
discrete yellowish granulomas, about 1-3 mm.also the lung appears very 
swollen. we are told it is very firm. the lung is enlarged and firm 
because the entire lobe IS a granuloma. the granulomas have coalesced 
into one. this causes actual enlargement of the lung. no normal tissue is 
left here.

slide: sectioned granuloma showing caseous necrosis within.

monkeys are very susceptible to human TB, usually die pretty fast from 
it.

slide: histological prep of TB affected lung. many alveoli show edema - 
eosinophilic stuff inside them. large area of caseous necrosis - just a 
pink spot. then, a basophilic outer area just outside that - almost all 
the cells in it are epithelioid cells. there is one langhans type giant 
cell. note, the epithelioid cells have very vague cytoplasmic borders. 
there are also a few lymphocytes.

slide: another one of same lung. can see a giant cell of foreign body 
type. still a lot of epithelioid cells and more lymphocytes than before.

remember once you get activation of macrophage, after start of DTH 
reaction, you also start seeing development of giant cells.

TNF is very important for granuloma formation. granulomas do not develop 
in the absence of tumor necrosis factor..

slide: omentum and rumen of cow. the omentum is covered with multifocal 
nodules 1mm-10 cm pinpoint to coalescing multinodular masses. these are 
multiple granulomas on omentum of cow w/TB. each of the nodules has very 
discrete subdivisions into very fine, focal yellow centers. these 
represent caseous necrosis. looks almost like tumor, or other 
proliferative mass. very ugly.

last year on exam dr weber had beautiful granulomatous inflammation of 
lung specimen, and two slides, and 80% of class called it a tumor b/c 
they ignored or didn't understand the slides.

slide: intestine of cow - two sections. left: more normal looking. has 
some enlargement of rugal folds of small intestine on one edge but mostly 
normal. right: extremely swollen rugal folds all over entire thing. this 
is due to Johne's dz, caused by a mycobacterium. 

histo slide of Johne's dz: macrophages are full of the pink organisms. 
they can't kill'em, just eat'em up and hold them. so in the mucosa we see 
a chronic granulomatous type of inflammation.

slide: cow maxilla with massive swelling with discrete focal areas of 
yellow with irregular centers. there is massive erosion of bone. why? 
this is a fungal infection - actinomycosis - and you see the bone erosion 
not from the fungus removing the bone, but the inflammatory rxn causes a 
lot of vascularity in periosteum, and stimulates osteoclasts to remove 
bone, and you could see tooth loss and stuff secondary to this.


organism too big for phagocytosis. histologically we see a small abcess 
developing around the organism, and superimposed on that is granulomatous 
inflammatory rxn. this is a pyogranuloma - a granulomatous infl rxn that 
has a high infiltration of neutrophils and abcessation associated with 
it. so, in the first slide, the yellow things are the abcessed area, and 
the main granuloma is the giant swelling all around it.

FIP can cause pyogranulomatous inflammation as well.

close up of histo slide of cow thing - accumulation of fungus. 
epithelioid cells surrounding this.

slide from the lab practical: showing lots of abnormal stuff - branching 
structures that look kinda like yeast or fungus or something to me. this 
is invasion of tissue by foreign organism. one of the slides was stained 
with special stain and it shows black squiggly lines and dots that are 
not normal, and are probably fungus.

last slide before going to lab: from a horse. this horse had multiple 
nodular skin eruptions. they were hairless. the main cell type we see is 
eosinophils. this is an eosinophilic granuloma. could have been due to a 
parasite introduced by flies or something. most likely some kind of 
parasite is involved.  very intense and almost exclusive eosinophilic 
infiltration.

in lab, we need a volunteer to discuss liver. also, he's going to lead us 
through the granuloma slides.

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