Pathology I (end page 16) Flashcards
Pathway responsible for decreasing cell number
Apoptosis
Pathway responsible for decreasing cell size
Ubiquitin-Proteosome
degradation/autophagy..ubiquitin is a tag, proteosome is they degradation powerhouse
vauoles - lysosomes - hydrolytic enzymes
Metaplasia
induced by stress
metaplastic cells are better able to handle stress
classic example - barrets esophagus - due to acid reflux
Barrets Esophagus
metaplastic change from nonkeratinized squamous (which is able to handle friction of food bolus) to squamous non ciliated mucin producing cells (better able to tolerate acid)
Is Metaplasia reversible?
yes if stressor is removed in time e.g. treating GERD
however, if it persists, can progress to dysplasia, e.g. barrets progressing to adenocarcinoma
Apocrine Metaplasia of The Breast
metaplasia induced, however even if persistent, carries no increased risk of cancer
Vitamin A Metaplasia
ketaomalacia of the conjunctiva - conversion of goblet cell columnar to keratinized squamous
induced by vitamin A defeciency; vit A needed for proper differentiation of conjunctival tissue
Myositis Ossificans
connective tissue in muscle changes to bone, during healing, after trauma
Dysplasia
disordered cell growth
typically a precancerous growth
can stem from hyperplasia (endometrial hyperplasia) or metaplasia (barrets esophagus)
Aplasia
aplasia is a failure of cell production during embryogenesis
example: unilateral renal agenesis
Hyoplasia
decrease in cell production in embryogenesis
results in small organ
Streak Ovary
Turner Syndrome
example of small organ formation from hypoplasia
slow developing ischemia
e.g. renal artery atherosclerosis
results in atrophy
acute ischemia
e.g. renal artery embolus
results in injury
Final electron acceptor in oxidative phorphorylation
oxygen
hypoxia can impair pathway; impair ATP production
Causes of Ischemia
decreased arterial perfusion (atherosclerosis)
decreased venous drainage (Budd-Chiari Syndrome)
shock (generalized hypotension)
Hypoxemia
arterial pressure (o2)
Causes of Hypoxemia
high altitude (decreased barometric pressure) hypoventilation (increased pCO2 and decreased O2) Diffusion Defect - can't push as much oxygen into blood V/Q Mistmatch - blood bypasses oxygenated lung or oxygenated air cannot reach the lung
Diffusion Defect
can’t push as much oxygen into blood
e.g. pulmonary interstitial fibrosis
V/Q Mistmatch
- blood bypasses oxygenated lung (right to left shunt)
- or oxygenated air cannot reach the lung (ventilation problem; atelectasis)
Anemia
decrease in mass of RBC
saturation of oxygen and arterial oxygen pressure are NORMAL
Carbon Monoxide Poisoning
CO binds Hgb more closely than O2
classic sign - cherry red skin
early sign of exposure - headaches
Methemoglobinemia
iron in heme oxidized to 3+ instead of 2+
can’t bind oxygen as well
saturation goes down
arterial pressure remains same
Where do you see Methemoglobinemia?
oxidant stress (sulfa and nitrate drugs) or in newborns
Classical Findings of Methemoglobinemia
cyanosis
chocolate colored blood
Treatment of Methemoglobinemia
IV metheylene Blue - helps turn Fe 3+ to 2+
Hallmark of Reversible Cell Injury
cell swelling
initial phase of cell injury is reversible
Initial Phase of Cell Injury
reversible
loss of microvilli
membrane blebbing
swelling of rER - dissociation of ribosomes - decreased protein synthesis
Hallmark of Irreversible Injury
Membrane Damage **
end result of irreversible injury is cell death
Result of Membrane Damage (irreversible injury)
enzyme leakage (serum troponin) additional calcium enters the cell **
Mitochondrial Damage
loss of electron transport chain (inner mitochondrial membrane)
cytochrome c leaks into cytosol
Cytochrome C leakage
leaks into cytosol from cell damage
activates apoptosis
Morphological Hallmark of Cell death
Loss of a nucleus
Loss of Nucleus
nuclear condensation (pyknosis)
fragmentation (karyorrhexis)
dissolution (karyolysis)
2 mechanisms of cell death
- necrosis and apoptosis *
necrosis (ALWAYS PATHOLOGICAL)
followed by acute inflammation
has several gross patterns
Coagulative Necrosis
characteristic of ischemic infarcts
tissue remains firm
cell shape/organ structure preserved by coagulation of proteins
nucleus disappears
wedge shaped on gross exam; pale appearance
Characteristic of Ischemic Infarcts
Coagulative Necrosis ** (except for brain)*
Red Infarctions
occurs if blood re enters loosley organized tissue following a coagulative necrosis
e.g. pulmonary and testicular infarcts*
Liquefactive Necrosis
necrotic tissue becomes liquefied; enzymatic lysis
Liquefactive Necrosis is characteristic of:
Brain Infarction* - proteolytic enzymes from microglial cells
Abscess* - proteolytic enzymes from neutrophils
Pancreatitis* - proteolytic enzymes from pancreas liquify parenchyma
3 places you will find Liquefactive Necrosis
Abscess
Brain Infarct
Pancreatitis
Gangrenous Necrosis
- coagulative necrosis that resembles mummified tissue (dry gangrene)
- ischemia of lower limb and GI tract
- if superimposed infection then can get liquefactive necrosis on top of it (wet gangrene)
Caseous Necrosis
soft and friable necrotic tissue with cottage cheese appearance
combination of coag. and liquefactive necrosis
Ischemia of lower limb and GI tract
Gangrenous Necrosis
Wet Gangrene vs. Dry Gangrene
Wet - gangrenous necrosis with superimposed infection that precipitates liquefactive necrosis
Dry - coagulative necrosis that resembles mummified tissue
Common Places you will find Caseous Necrosis
granulmatous inflammation due to TB or fungal infection
Granulamatous inflammation due to TB or Fungal Infection
Caseous Necrosis is a common feature*
Fat Necrosis
chalky white appearance due to calcium deposition
fatty acids released from damage to fat e.g. breast or pancreatitis mediated damage of peripancreatic fat
Fat Necrosis and Saponification
Saponification - fatty acids join with calcium
- saponification is an example of dystrophic calcification in which calcium deposits on dead tissues
necrotic tissue acts as a nidus for calcification in setting of NORMAL serum calcium and phosphate
Saponification and Dystrophic Calcification
necrotic tissue acts as a nidus for calcification in setting of NORMAL serum calcium and phosphate
Fat Necrosis and Metastatic Calcification
unlike dystrophic calcification…occurs when there is HIGH serum calcium and phosphate levels
leads to calcium deposition in tissues (hyperparathyroidism leading to nephrocalcinosis)
Fibrinoid Necrosis
necrotic damage to blood vessel
leakage of fibrin
bright pink staining
malignant hypertension and vasculitis
2 common pathologies with fibrinoid necrosis
malignant HTN and Vasculitis
Apoptosis
ATP dependent Examples - endometrial shedding - removal of cells durng embryogenesis - CD8 T cell mediated killing of virally infected cells
CD8 T cell mediated killing of Virally infected cells
Apoptosis
Morphology of Apoptosis
Dying cell - shrinks, cytoplasm will become more eosinophlic (pink)
Nucleus condenses and fragments in organized manner
apoptotic bodies fall from cell and removed from macrophages
no inflammation follows
Does Inflammation Follow Apoptosis?
No
Apoptosis and Caspases
Apoptosis is mediated by Caspases that activate proteases and endonucleases
- proteases break down the cytoskeleton
- endonucleases break down DNA
Activation of Caspases
- Intrinsic Mitochondrial Pathway
- loss of Bcl2 - Extrinsic Receptor Ligand Pathway
- FAS death receptor (CD95)
- TNF - Cytotoxic CD8 T Cell Pathway
- perforins
- granyzmes
Activation of Caspases - Intrinsic Pathway
(discuss Bcl2)
- Intrinsic Mitochondrial Pathway
- cell injury, DNA damage, or decreased hormonal stimulation leads to inactivation of Bcl2
- lack of Bcl2 allows cytochrome c to leak from inner mitochondrial matrix into the cytoplasm and activate caspases
Activation of Caspases - Extrinsic Pathway
example is negative selection of thymocytes in thymus
- Extrinsic - Receptor Ligand Pathway
- FAS ligand binds FAS death receptor (CD95) on target cell activating caspases
- TNF binds tumor necrosis factor receptor on target cell activating caspases
Activation of Caspases - Cytotoxic CD8 Pathway
- Cytotoxic CD8 T Cell Pathway
- perforins secreted by CD8 T cell creates pores in membrane of target cell
- Granzyme from CD8+ T cell enters pores and activates caspases
- CD8+ T cell killing of virally infected cells is an example
PHYSIOLOGIC generation of free radicals occurs during:
oxidative phosphorylation.
- cytochrome c oxidase (complex IV) transfers electrons to O2
- partial reduction of O2 yields superoxide, H202, and OH radicals
PATHALOGIC generation of free radicals occurs during:
arises with:
- ionizing radiation - water to hydroxyl radical
- inflammation - NADPH oxidase generates superoxide during oxygen dependent killing by neutrophils
- Metals - Fe 2+ for example generates OH radicals via Fenton Reaction
- Drugs - P450 metabolizes drugs in liver, generates free radicals
Elimination of Free Radicals
- Antioxidants (Vitamins A, C, E) / Glutathione
- Enzymes
i - superoxide dismutase (mitochondria)
ii - Glutathioine Peroxidase (mitochondria)
iii - Catalase (peroxisomes) - Metal Carrier Proteins
- e.g. transferrin and ceruloplasmin
Location of Enzymes that Eliminate Free Radicals
i - Superoxide Dismutase (mitochondria)
ii - Glutathioine Peroxidase (mitochondria)
iii - Catalase (peroxisomes)
Examples of Free Radical Injury - Carbon Tetrachloride
CCl4
- dry cleaning industry
- converted to CCl3 free radical by P450
- cell swells - ribosomes detach - protein syn. is shot
- decreased apolipoproteins
- leads to fatty change in the liver
Examples of Free Radical Injury - Reperfusion Injury
- Return of blood to ischemic tissue results in production of Oxygen derived free radicals which further increases damage tissue
- leads to continued rise in cardiac enzymes **
- (e.g. troponin) after reperfusion to infarcted Myocardium
Basic Principles of Amyloidosis
Amyloid = misfolded protein that deposits in extracellular space, thereby damaging tissues
Multiple proteins can deposit as amyloid; shared features:
- **beta pleated sheet configuration ***
- **Congo red staining and apple green birefringence when viewed under polarized light ***
Deposition can be systemic or localized
Systemic Amyloidosis (deposition in multiple organs) (Primary)
[AL Amyloid)
- Primary
- deposition of AL Amyloid (derived from immunoglobulin light chain)
- associated with plasma dyscrasias (multiple myeloma)
Systemic Amyloidosis (deposition in multiple organs) (Secondary)
[AA Amyloid)
- Secondary
- deposition of AA amyloid which is derived from serum amyloid associated protein (SAA)
- SAA is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean Fever (FMF)
FMF (Familial Mediterranean Fever)
- FMF is due to a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Med. Origin
- Presents with episodes of fever and acute serosal inflammation (can mimic appendicits, arthritis, or MI)
- High SAA during attacks deposits as AA amyloid in tissue
Classic Clinical Findings of Systemic Amyloidosis*
- Nephrotic Syndrome - kidney is most commonly involved organ
- Restrictive Cardiomyopathy or Arryhtmia
- Tongue Enlargement, malabsorption, hepatosplenomegaly
Diagnosis of Systemic Amyloidosis
needs tissue biopsy
abdominal fat pad and rectum easily accessible targets
Organ Damage From Systemic Amyloidosis
organs must be transplanted because you cannot remove amyloid*
Localized Amyloidosis
confined to a single organ
Senile Cardiac Amyloidosis
Familial Amyloid Cardiomyopathy
Non Insulin Dependent Diabetes Mellitus
Alzheimers
Dialysis-associated amyloidosis
Medullary Carcinoma of Thyroid
Senile Cardiac Amyloidosis
NON-mutated form of serum transerythrin deposits in the heart
usually asymptomatic - present in 25% of ppl over 80
Familial Amyloid Cardiomyopathy
MUTATED serum transerythretin deposits in the heart leading to restrictive cardiomyopathy
5% of African-Americans carry the mutated gene
Non Insulin Dependent Diabetes Mellitus
Amylin (derived from insulin) deposits in the islets of pancreas
Alzheimers
alpha beta amyloid derived from beta amyloid precursor protein, deposits in the brain
gene for beta - APP is on chromosome 21
- therefore, most individuals with Down’s syndrome develop Alzheimer disease by age 40 (early onset)
Dialysis-associated amyloidosis
beta 2 microglobulin deposits in joints
Medullary Carcinoma of Thyroid
calcitonin deposits witin tumor
“tumor cells in an amyloid background”
Acute Inflammation
edema and neutrophils **
innate resposne with limited specificity (innate immunity)
Edema and Neutrophils
hallmark of acute necrosis
Mediators of Acute Inflammation
Toll Like Receptors
Arachiadonic Acid
Mast Cells
Complement
Factor XII (Hageman Factor)
Toll Like Receptors (TLRs)
present on innate immune system cells like macrophages and dendritic cells
activated by PAMP patterns commonly shared by microbes
TLRs are present on cells of adaptive immunity
(lymphocytes) and hence play role in chronic inflammation
TLRs and PAMP
Upregulation of NF-kB
- CD14 (co receptor for TLR4) on macrophages recognizes LPS (a PAMP) on outer membrane of gram- bacteria
TLR activation leads to upregulation of NF-kB which is a transcription factor that leads to upregulation of nuclear transcription factor that activates production of immune mediators
Arachadionic Acid (AA)
released from phospholipid cell membrane by phospholipase A2 and then acted on by COX enzyme or 5-Lipoxygenase
COX produces PGs
- PGI2, PGD2, and PGE2 mediate vasodilation and permeability
- PGE2 also mediates pain and fever
5 Lipoxygenase
makes LTs
LTB4 attracts and activates neutrophils
LTC4, LTD4, LTDE4 (slow reacting substancs of anaphylaxis mediate vasoconstriction, bronchospasm, and increased cell permeability.
Mast Cells
widely distributed in connective tissue
activated by tissue trauma, C3a, C5a, cross linking of IgE by antigen
Immediate response = histamine release - vasodilation/ permeability
delayed response = production of AA and metabolites (esp LTs)
Activation of Complement (3 routes)
- classical pathway - C1 binds IgG or IgM bound by antigen
- alternate pathway - microbial products directly activate complement
- Mannose Binding Lectin (MBL) Pathway
- MBL binds to mannose on microbes and activates complement
Convergence of Complement Activation
All pathways will result in production of C3 convertase which mediates C3a and C3b production from C3
This in turn produces C5 convertase - which will yield C5a and C5b
C5b
complexes with C6-9 to form membrane attack complex (MAC)
C3a and C5a (anaphylotoxins)
trigger mast cell degranulation resulting in histamine mediated inflammation / permeability
C5a
chemotactic for neutrophils
C3b
opsonin for phagocytosis
MAC
lyses microbes (“MAC attack”
Hageman Factor (Factor XII) Activation
inactive proinflammatory protein made by liver
activated upon exposure to subendothelial tissue or tissue collagen
Activated Factor XII (Hageman Factor) in turn activates:
activates
- coagulation and fibrinolytic systems
- complement
- Kinin System - kinin cleave high molecular weight kinogen (HMWK) to bradykinin
bradykinin mediates vasodilation and pain
What are the cardinal signs of inflammation?
- Redness, Warmth (rubor, calor)
- due to vasodilation (histamine, prostaglandins, bradykinin)
- Swelling (tumor)
- leakage of post capillary venules (exudate)
- Pain (dolor)
- PGE2 and bradykinin
- Fever
- pyrogens (LPS from bacteria) cause macrophages to release IL-1 and TNF which causes COX activity to increase in perviascular cells of hypothalamus
PGE2 and Bradykinin
sensitize pain receptors
increase in PGE2 raises temperature
Fever
pyrogens (LPS from bacteria) cause macrophages to release IL-1 and TNF which causes COX activity to increase in perviascular cells of hypothalamus
increase in PGE2 raises temperature
Key Steps of Neutrophil Arrival And Function
- Margination
- Rolling
3 Adhesion
- Transmigration and Chemotaxis
- Phagocytosis
- Destruction of Phagocytosed Material
- Resolution
What is Margination
vasodilation slows blood flow in postcapillary venules
cells marginate* from the center of flow to the periphery
What is the Rolling Phase?
selectin “speed bump” upregulation on endothelial cells
P selectin release from Weibel Palade bodies is mediated by histamine
E selectin induced by TNF and IL-1
Selectins will bind sialyl Lewis X on leukocytes
interaction results in leukocytes rolling on vessel wall
What is the Adhesion phase?
cell adhesion molecules ICAM and VCAM are upregulated on endotheleium by TNF and IL-1
LTB4 and C5a upregulates integrins on leukocytes
CAM and integrins will interact
Leukocyte Adhesion Deficiency
most commonly due to autosomal recessive defect of integrins (CD18 subunit)
Clinical Features
- delayed separation of umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack pus formation
Clinical Features of Leukocyte Adhesion Deficiency
delayed separation of umbilical cord,
increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes)
recurrent bacterial infections that lack pus formation
Transmigration and Chemotaxis
leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis)
neutrophils are attracted by bacterial products
(IL-8, C5a, LTB4)
Phagocytosis
consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3b)
pseudopods extend from leukocytes to form phagosomes, internalized /merge with with lysosomes - form phagolysosomes
C3b and IgG
enhance phagocytosis
Chediak Higashi
protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation
Features
- increased risk of pyrogenic infection
- neutropenia (due to intramedullary death of neutrophils)
- giant granules in leukocytes (due to fusion of granules arising from the golgi apparatus)
- defective primary hemostasis (abnormal dense granules in platelets)
- albinism
- peripheral neuropathy
Clinical Features of Chediak Higashi
- increased risk of pyrogenic infection
- neutropenia (due to intramedullary death of neutrophils)
- giant granules in leukocytes (due to fusion of granules arising from the golgi apparatus)
- defective primary hemostasis (abnormal dense granules in platelets)
- albinism
- peripheral neuropathy
Destruction of Phagocytosed Material
- oxygen dependent killing is most effective mechanism possible
- HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes
i) oxygen converted to Oxygen radical by NADPH (oxidase) (oxidative burst)
ii) oxygen radical converted to H2O2 by superoxide dismutase (SOD)
iii) H202 is converted to HOCl (bleach) by myeloperoxidase (MPO)
Oxidative Burst
i) oxygen converted to Oxygen radical by NADPH (oxidase) (oxidative burst)
ii) oxygen radical converted to H2O2 by superoxide dismutase (SOD)
iii) H202 is converted to HOCl (bleach) by myeloperoxidase (MPO)
Chronic Granulmatous Disease (CGD)
characterized by poor oxygen dependent killing
NADPH oxidase defect (autosomal recessive or X linked)
recurrent infection / granuloma formation with catalase organisms
Key organisms with CGD disease*
staph aureus pseudomonas capacia settatia marcescens nocardia aspergillus
How to Screen For CGD
Nitroblue Tetrazolium
leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert oxygen to oxygen radical
will remain colorless if defective
MPO Defeciency
increases risk to Candida infection
defective conversion from H202 to HOCl
i) increased risk for candidal infections, however most patients are asymptomatic
ii) NBT is normal; respiratory burst (oxygen to H202) works normally
Resolution Step of Neutrophil Activation
neutrophils undergo apoptosis and disappear within 24 hrs after resolution of the inflammatory stimulus
Macrophages
peak 2-3d after neutrophils
derived from blood monocytes
manage next step of inflammatory process:
1. resolution and healing - IL-10 and TGF beta
- continued acute inflammation - IL-8, key feature is persistent pus formation
- abscess - fibrogenic surrounding process
- chronic inflammation - antigen presentation
IL-10 and TGF Beta
made by macrophages - anti-inflammatory cytokines
IL-8
from macrophages - recruits additional neutrophils
macrophages and abscess
acute inflammation surrounded by fibrosis
macrophages mediate fibrosis via fibrogenic growth factors and cytokines
macrophages and chronic inflammation
macrophages present antigen to activate CD4 helper cells which will secrete cytokines that promote inflammation
Chronic Inflammation
charicterized by presence of lymphocytes and plasma cells in tissue
delayed response, but more specific (adaptive immunity) than acute inflammation
stimuli:
- persistent infection (most common cause)
- infection with viruses, mycobacteria, parasites, fungi
- autoimmune disease
- foreign material
- some cancers
T Lymphocytes
produced in bone marrow as progenitor T cells
further develop in the thymus where the T cell receptor (TCR) undergoes rerrangement and progenitor cells become CD4+ helpter T cells OR CD8 cytotoxic T cells
Further Development of T Lymphocytes
rearrangement of TLR - progenitors become CD4 or CD8
T cells use TCR complex (TCR and CD4) for antigen surveillence
TCR complex recognizes antigen presented on MHC molecules
- CD4+ T cells - MHC class II
- CD8+ T cells - MHC class I
Activation of T Cells requires
1) binding of antigen/MHC complex
2) an additional second signal
CD4 Helper T cell activation
- extracellular antigen (foriegn protein) is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen presenting cells (APCs)
- B7 on APC binds CD28 on CD4 helper T cells providing the additional second signal
- Activated CD4 helper T cells secrete cytokines which help inflammation and are divided into 2 subsets
B7 on APC
Binds CD28 on CD4 helper T cells providing the additional second signal
Activated CD4 helper T cells secrete cytokines which help inflammation and are divided into 2 subsets
- TH1 subset secretes interferon gamma
- TH2 secretes IL-4, IL-5, IL-13
TH1
secretes interferon gamma
activates macrophages
promotes B cell class switching from IgM and IgG
promotes TH1 phenotype and inhibits TH2 phenotype
TH2
secretes IL-4, IL-5
IL-4: facilitates B cell class switching to IgE
IL-5: eosinophil chemotaxis and activation, and class switching to IgA
IL-13: functions similar to IL-4
CD8 Cytotoxic T Cell Activation
antigen presented on MHC class I
IL-2 from CD4 TH1 cell provides 2nd activation signal
cytotoxic T cells activated for killing
killing occurs via
- perforin and granzyme secretion
- expression of FasL, binds Fas on target cells, activating apoptosis
Mechanism of Killing via Cytotoxic T Cells
perforin and granyzme secretion
expression of FasL which binds Fas on the target, activating apoptosis
B Lymphocytes
Immature B cell made in bone marrow and undergo immunoglobulin rearrangment to become native B cells that express IgM or IgD
B cell activation
- antigen binding by surface IgM or IgD resulting in maturation to IgM or IgD secreting plasma cells
- B cell antigen presentation to CD4 helper T cells via MHC class II
i) CD40 receptor on B cell binds CD40L on helper T cell, providing 2nd activation signal
ii) Helper T cell then secretes IL-4 and IL-5 (mediates B cell isotype swithing, hypermutation, and maturation plasma cells)
Granulomatous Inflammation is a subtype of:
chronic inflammation
Granulmatous Inflammation is charicterized by:
granulomas
- collection of epitheloid histiocytes (macrophages w/ abundant pink cytoplasm) usually surrounded by giant cells and a rim of lymphocytes
divided into caseating and non caseating subtypes
Non Caseating vs. Caseating
Ceaseating
- these granulomas exhibit central necrosis and are charicteristic of fungal and TB infections
Non Caseating
- lack central necrosis
Common Etiologies of Non-Caseating Granulomas
remember that NON caseating is NON central necrosis
rxn to foriegn material
sarcoidosis
beryllium exposure
crohn’s disease
cat scratch fever
Granuloma Formation
- Macrophages process and present antigen via MHC Class II to CD4 helper T cells
- Interaction leads macrophages to secrete IL-12, inducing CD4 helper T cells to differentiate into TH1 subtypes
- TH1 cells secrete IFN gamma, which converts macrophages to epitheloid histiocytes and giant cells
Granulomas and IFN-gamma
TH1 cells secrete IFN gamma, which converts macrophages to epitheloid histiocytes and giant cells
