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GRANULOMATOUS INFLAMMATION
08/05/05
1. Granulomatous Inflammation: is a distinctive pattern of chronic inflammatory reaction
characterized by focal accumulations of activated macrophages, which often develop an
epithelial-like (epithelioid) appearance
2. Recognition of a granulomatous pattern of inflammation is important b/c: there are
many atypical presentations of granulomas – always necessary to identify the specific
etiologic agent by special stains for organisms(acid-fast stains for tubercle bacilli),
culture methods (in TB and fungal diseases), molecular techniques (polymerase chain rxn
in TB), and serologic studies (syphilis). *the etiologic agent is not known in sarcoidosis.
3. Granuloma: is a focus of chronic inflammation consisting of a microscopic
aggregation of macrophages that are transformed into epithelium-like cells surrounded by
a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma
cells.
4. Cell elements present within a granuloma: monocytes (source of macrophages, epi
cells and giant cells), macrophages, epithelioid cells, multinucleate giant cells,
lymphocytes, plasma cells, neutrophils and eosinophils, and fibroblasts.
5. Giant Cells: Langhans – when the epi cells are arranged in a circular pattern (a ring of
nuclei)
Foreign Body – has randomly scattered nuclei in epi cells
6. Classic example of granulomatous disease: tuberculosis (an immune granuloma)
7. Other diseases that frequently produce Granulomatous inflammation:
mycobacterium tuberculosis: tuberculosis
mycobacterium leprae: leprosy
treponema pallidum: syphilis
gram-negative bacillus: cat-scratch disease
fungi (coccidioides): Valley fever
parasites- schistosoma and dirofilaria sp.
8. Characteristic feature classically seen in TB granulomas: central caseous necrosis
9. Additional diagnostic steps that must be taken to identify definitively the cause of a
granuloma:
10. Significance of cell-mediated immunity to granulomatous inflammation: T cellmediated hypersensitivity is a protective role.
- with persistent or non-degradable antigens, like TB, the initial perivascular
lymphocytic infiltrate is replaced by macrophages over 2-3 weeks
- accumulated macrophages undergo a morphologic transformation into
epithelioid cells which is usually surrounded by a collar of lymphocytes =
granuloma
- when first exposed to protein antigens of tubercle bacilli, naïve CD4+ T cells
recognize peptides derived from these antigens
- this drives the differentiation of CD4+ cells to TH1 cells – very important b/c
delayed hypersensitivity depends on the cytokines secreted by TH1 cells
- some TH1 cells enter circulation and may remain in the memory pool of T
cells for long periods
-
the TH1 cells secrete cytokines, mainly IFN-gamma which is responsible for
the expression of delayed-type hypersensitivity. The cytokines most relevant
are:
- IL-12: produced by macrophages and dendritic cells and is critical for the
induction of the TH1 cell response. IL-12 drives differentiation of CD4+ cells
intoTH1 cells and also induces INF-gamma secretion by T cells
- IFN-gamma: key mediator – activates macrophages which are then better able
of phagocytose; can present antigens better; secrete polypeptide growth
factors; they secrete TNF, IL-1 and chemokines and IL-12
- IL-2: causes autocrine and paracrine proliferation of T cells which accumulate
at sites of delayed hypersensitivity
- TNF and lymphotoxin: are 2 cytokines that exert effects on endo cells: 1.
cause increased secretion of prostacyclin which favors increased blood flow
by local vasodilation, 2. increased expression of P-E selectins, adhesion
molecules, and 3. induction and secretion of chemokines such as IL-8. All of
the above cause extravasation of lymphocytes and monocytes at the site of
delayed hyper rxn
- Chemokines: produced by the T cells and macrophages recruit more
leukocytes into the reaction site = “immune inflammation”
11. 2 main situations in which granulomas arise:
1. Foreign Body granuloma: from inert foreign bodies.
-they usually form when material such as talc (IV drug abuse), sutures, or
other fibers large enough to preclude phagocytosis by a single macrophage
and do not incite any specific inflammatory or immune response
- epithelioid and giant cells form and are apposed to the surface and encompass
the foreign body
2. Immune Granuloma: caused by insoluble particles, usually microbes, that are
capable of inducing a cell-mediated immune response
- occurs when inciting agent is poorly degradable or particulate
- macrophages engulf the foreign material and process and present some of it to
appropriate T lymphocytes
12. Examples of the following that produce Granulomatous inflammation:
Bacterial = Francisella tularensis (cat-scratch), Chlamydia trachomatis
Parasitic = Schistosoma, Dirofilaria sp.
Fungal = Coccidioides (valley fever), Histoplasma, Blastomyces, Cryptococcus sp
Inorganic material = ?sutures?
Unknown = Sarcoidosis
13. Naïve CD4+ cells differentiate into TH1 cells: from protein antigens of tubercle
bacilli
14. IFN-gamma: see #10