Pathoma Ch 1-3 Flashcards
1. Growth Adaptations, Cellular Injury, Cell Death 2: Inflammation, Inflammatory D/o, Wound Healing 3. Principles of Neoplasia
X-linked agammaglobulinemia
(a) Mutation
(b) Age of presentation
X-linked agammaglobulinemia
(a) Mutation in bruton tyrosine kinase, signaling molecule needed for B cell maturation
(b) Presents around 6 mo of age once maternal Ig wear off
Protooncogene mutated/translocated (activated) in the following cancers
(a) Astrocytoma
(b) Certain breast cancers
(c) GI stromal tumors
(d) Mantle cell lymphoma
Protooncogene associated w/
(a) Astrocytoma = PDGF-1 (plt derived growth factor)
(b) HER2neu receptor
(c) GIST = KIT
(d) Mantle cell lymphoma = cyclin D1- cyclin that allows cell to move from G1 into S in the cell cycle
Would the scar be larger in primary or secondary intention healed wounds
(a) Key feature in secondary intention
Primary intention healing (ex: stitched up) is when the edges are reapproximated- get a smaller scar
Secondary intention healing: edges are not approximated so more granulation tissue develops (larger scar) and tissue contracts
-contraction*** of granulation tissue/scar by myofibroblasts
What is fibrinoid necrosis?
(a) Typical histological appearance
Fibrinoid necrosis = necrotic damage to BV wall
(a) Proteins leak into the vessel wall => bright pink stain on histo
Seen in malignant HTN and vasculitis
Mast cells: immediate vs. delayed/late response
(a) Fxn of delayed response
Mast cells: immediate response is release of pre-formed histamine granules
-then histamine => vasodilation of arterioles and increased permeability of post-capillaries venules
Delayed response = release of leukotrienes
(a) To maintain the acute inflammatory response
What amyloid is deposited in Alzheimer disease?
Amyloid deposition = general term for misfolded protein deposited in extracellular space, generally around blood vessels
In Alzheimer is is Abeta-amyloid that is deposited, which is derived from a beta-amyloid precursor protein
-beta-amyloid precursor protein is encoded for gene on chromosome 21 (hence link to Trisomy 21 = Downs)
Deficiency in which complement proteins result in an increased risk of Neisseria infections
Deficiency in any proteins that make up the MAC (membrane attack complex) = increase Neisseria risk
MAC made up by C5,6,7,8,9 (C5-C9)
What is the histologic hallmark of UC vs. Crohns
UC = crypt abscess Crohns = noncaseating granulomas
Explain the mechanism of reperfusion injury
Dead tissue now gets return of O2 and inflammatory cells (in blood)
- setting up for free radical tissue injury! (b/c no enzymes in cells to oxidize free radicals)
- then free radicals create continued tissue damage
Classic ex: continual rise of trops after cath lab
Enzyme deficiency resulting in SCID
Adenose deaminase deficiency = 2nd MC cause of SCID, MC enzyme defect cause
Adenosine deaminase needed in purine synthesis => necessary for the very mitotically active cells of the immune system
So w/o adenose deaminase => no B or T cells (hence combined immunodeficiency)
MC cause of Budd Chiari
MC cause of Budd Chiari = polycythemia vera = overproduction of RBC = increased viscosity of blood
Name the two things necessary for B cell activation
B cell activation requires two signals
- B cell presenting antigen on MHCII bound to matching antibody on CD4 T cell
- CD40 on B cell binds to CD40L on helper T
Name the chemical attractants for neutrophils once they undergo transmigration
Big 4 chemical attractants = general 4 signals that attract/activate neutrophils
- C5A (complement protein)
- LTB4 (leukotriene B4)
- IL-8
- Bacterial products
Differentiate hyperplasia from hypertrophy
(a) Mechanism
Growth adaptation of tissue to increase in stress
Hyperplasia = increase in number of cells
(a) Stem cells produce more of the cell type => only done in non-permanent tissues (not neurons)
Hypertrophy = increase in size of cells
(a) Increase in protein production 2/2 gene activation (make more cellular matrix) and organelles (need more mitochondria to give larger cell more energy)
Systemic amyloidosis
(a) MC affected organ
(b) Cardiac manifestation
(c) GI manifestation
Systemic amyloidosis
(a) MC affected organ = kidneys, manifests as nephrotic syndrome (proteinuria, edema)
(b) Restrictive cardiomyopathy
- amyloid deposits cause thick/stiff walls that don’t fill as well
(c) Deposition in gut wall = thickened wall = malabsorption
Differentiate central and peripheral immune tolerance
Central = thymus/bone marrow maturation (positive and negative selection if bind MHC and don’t bind self too tightly)
Peripheral = lack co-stimulatory signal => anergy or apoptosis
Describe the following step of leukocyte arrival in acute inflammation:
Marginalization 2/2 vasodilation
In general cells run in the middle of normal blood vessels because that is where the most organized, laminar flow takes place
W/ vasodilation this slows down flow and allows cells to marginalize towards the boundaries of the lumen
= first step in neutrophils and macrophages exiting from bloodstream into interstitial space
Name the 4 key molecules for neutrophil attraction and activation
Neutrophil attraction/activation
- LTB4 (leukotriene B4)
- C5A (complement 5A)
- IL-8
- Bacterial products
Leukocyte adhesion deficiency
(a) Inheritance
(b) Defect
(c) First clinical sign
(d) Serum abnormality
(e) Ongoing clinical sign
Leukocyte adhesion deficiency- neutrophils and macrophages cannot adhere properly to endothelial surface 2/2
(a) Autosomal recessive
(b) Defect in integrins (binding protein for cellular adhesion molecules) on leukocyte
(c) Hallmark sign = delayed separation of umbilical cord
(d) Increase in circulating neutrophils (b/c less adhered down in lungs specifically)
(e) Recurrent bacterial infections w/o pus
- pus = dead neutrophils, so if neutrophils can’t leave BVs you’re not making pus!!!
Name the two ways in which free radicals damage cells
Free radical tissue damage 2/2
- peroxidation of lipids (damages cell membranes)
- oxidation of DNA (ummm oncogenic) and proteins
2 inorganic minerals necessary for scar formation
Copper needed for collagen cross linking
Zinc needed to replace collagen III (granulation tissue = first step of scar formation) w/ collagen I (strong tough scar)
Name 3 types of infections pts w/ X-linked agammaglobulinemia are susceptible to
X-linked agammaglobulinemia = low Ig of all subtypes 2/2 mutation in signaling molecule necessary for B cell maturation into plasma cells
No IgG => can’t opsonize => bacterial infections
No IgA => can’t protect mucosal surfaces => enteroviral and Giardia infections
So no/low Igs = increased risk of bacterial, enteroviral, and Giardia infections
Type of necrosis seen in
(a) testicular torsion
(b) vasculitis
Type of necrosis
(a) Testicular torsion = red infarction (not white infarction) b/c blood re-enters a loosely organized dead tissue
- torsion constricts vein before artery => ischemia due to venous obstruction but blood still flowing in (hence red)
(b) Vasculitis = Fibrinoid necrosis (damage to BV wall)
What is caseous necrosis?
(a) Differentiate gross appearance of caseous and fat necrosis
Caseous necrosis = soft friable tissue, 2/2 granulomatous Tb or fungal infxn
(a) Caseous necrosis ‘cottage cheese’ appearance (think lung Tb granulomas)
Fat necrosis ‘white chalky’ appearance’- think benign calcification on mammogram
How to diagnose systemic amyloidosis
(a) 2 histological findings
Diagnose systemic amyloid w/ fat pad biopsy- usually of abdominal fat pad or rectum
(a) Amyloid picks up congo red stain- so see red extracellular accumulation around blood vessels
Amyloid exhibits apple-green birefingence under polarized light
What is the defining feature of granulomas?
Granulomas defining features = epitheliod histiocytes
= macrophages w/ abundant pink cytoplasm
So granulomas are aggregates of epitheliod histiocytes, usually surrounded by giant cells and a rim of lymphocytes
Then can be +/- caseation (central necrosis)
Differentiate the route of spread for carcinomas vs. sarcomas
In general:
- carcinomas spread via lymphatics (ex: breast cancer to axillary lymph nodes)
- sarcomas spread hematogenously
2 key histologic features of acute inflammation
Acute inflammation = edema and neutrophilic infiltrate
Mechanism by which CD8+ T cell is cytotoxic
CD8+ T cells recognizes MHC I then kills the APC by activating apoptosis, CD8+ cell secretes perforin and granzyme
Perforin pokes a pore in the APC membrane, then granzyme enters the pore and activates caspases (enzymes that mediate apoptosis)
2 general categories of causes of acute inflammation
Acute inflammation is caused by either
- infection
- necrosis (neutrphils need to clear the debris)
Name the three free radicals physiologically produced during oxidative phosphorylation
Free radicals (chemical species w/ unpaired electron in outer orbit)
O2 + 1 e- –> O2- = superoxide
O2- + 1e- –> H2O2 = hydroxgen peroxide
H2O2 + 1e- –> OH- = hydroxyl free radical (most dangerous to tissues)
Then OH- + 1e- –> H2O by glutathione peroxidase
-so overall O2 + 4e- –> H2O
Histologic hallmark of cell death
Cell death histologically = loss of nuclei
anucleated cells are dead!
2 things necessary for 2 CD4+ cell activation
T cells need 2 things for activation
- binding of antigen and MHC complex
- costimulatory signal: B7 on APC binds to CD28 on CD4+ cell (28/7 = 4)
HyperIgM syndrome
(a) Mutation
(b) Explain serum findings
Hyper-IgM syndrome
(a) Mutation in part of the CD4-B cell costimulatory signal (so either CD40L on helper T cell or CD40 receptor on B cell defective) => B cells cannot be activated to class switch, so stay as immature B cells which are all IgM
(b) No costimulatory signal => helper T cells don’t secrete IL-4 and IL-5 to cause B cell class switching => B cells stay as IgM secreting cells (immature form)
What is the main molecular mediator of fever in acute inflammation?
(a)Where does this molecule act?
Fever caused by PGE2 (prostaglandin E2)
PG’E’2 f’eeeeeee’ver
(a) PGE2 acts at hypothalamus to increase set point of temp
Name two examples of dystrophic calcification
Dystrophic calcification = mechanism by which dead tissue acts a nidus for Ca2+ deposition
- Psammoma bodies- neoplastic cells outgrowth their blood supply, die, then Ca2+ deposits
- papillary thyroid carcinoma
- meningioma
- serous cystadenoma - Saponification (FFA joining w/ Ca2+) seen in fat necrosis
CO2 poisoning
(a) Caused by what exposures (classically)?
(b) First sign
(c) Classic clinical feature
CO2 poisoning
(a) smoke from fire, exhaust from cars or gas heaters
(b) Key first sign = headache
- can use this to screen pts exposure to smoke from fire, if HA present keep CO2 poisoning on the radar
(c) Classically present w/ cherry-red skin
- b/c Hb is bound (to CO2) which gives color
- ironic b/c they’re tissues are hypoxic
Explain the mechanism of rubor and calor in acute inflammation
(a) Main molecular mediator
Redness and heat are 2/2 increased blood flow to the area which is due to vasodilation
Vasodilation caused by histamine, bradykinin, and prostaglandins
(a) Mainly histamine
What is the shared mechanism of damage in hemochromatosis and Wilson’s disease
Excess metals (Fe and Cu respectively) deposit in tissues and are not bound => produce free radicals
So mechanism of tissue damage in metal storage d/o is by free radicals
Differentiate necrosis and apoptosis
(a) Key aftermath of necrosis
(b) Distribution of death
Necrosis = always pathologic, think of this as homicide
(a) Followed (always) by acute inflammation
(b) Death to a large group of cells
Apoptosis = think of this more as cell suicide
(a) NOT followed by acute inflammation b/c apoptotic bodies are removed by macrophages
(b) Death of a single cell or small group of cells
Type of necrosis seen in
(a) abscess
(b) eclampsia
Type of necrosis seen in
(a) Abscess => liquefactive b/c neutrophils contain lytic enzymes
(b) Eclampsia = a form of malignant HTN => Fibrinoid necrosis where intracellular proteins leak into wall of BV
Type of necrosis seen in ischemia of the lower limb
(a) If this gets infected?
(b) Wet vs. dry gangrene
Ischemia of the lower limb (think diabetic food) => gangrene necrosis- basically coagulative necrosis w/ gross appearance of mummification (ew…)
(b) W/o infection = dry gangrene
(a) W/ infection you get superimposed liquefactive necrosis = (b) wet gangrene (wet like all the pus…even more ew)
How to differentiate chronic granulomatous disease and MPO deficiency
Both are defects in O2-dependent killing after phagocytosis:
O2 –> (NADPH oxidase) –> O2- –> H2O2 –> (MPO) –> HOCl-
NBT test detects O2- production during oxidative burst (catalyzed by NADPH oxidase)
=> NBT test abnormal in CGD (NADPH oxidase defect), while normal in MPO deficiency
Buzzword: delayed separation of umbilical cord
Dx?
Dx = leukocyte adhesion deficiency = autosomal recessive defect in integrin on neutrophil/macrophage surface that inhibits cells from binding to endothelial surface => neutrophils/macrophages can’t exit blood vessels into tissue in response to acute inflammation
Name an exception to the concept that pathologic hyperplasia can increase risk of cancer
Pathologic hyperplasia = increase in cell size due to an underlying process
-almost always leads to increased risk of cancer (metaplasia –> dysplasia –> carcinoma)
Exception = BPH = benign prostatic hyperplasia
-no increase in prostate cancer
Triad of features of Wiskott-Aldrich Syndrome
(a) Mode of inheritance
Wiskott-Aldrich syndrome
(a) X-linked recessive mutation in Wiskott-Aldrich gene
Triad:
- thrombocytopenia
- eczema
- recurrent infections
Name two mechanisms by which cytotoxic T cells kill targets
Cytotoxic T cells kill by inducing apoptosis in their targets by
- Secretes perforins (pokes hole in membrane) then granzymes that enters hole and activates caspases
- extrinsic receptor-ligand pathway: FASligand on T cell binds Fas death receptor on target cell to activate caspases
In general what are amyloid disorders?
(a) Systemic vs. localized
Amyloid d/o = deposition of misfolded proteins in the extracellular space, especially around blood vessels
(a) can be systemic (in multiple body systems) or localized deposition in a single organ
Key distinguishing feature of dysplasia vs. carcinoma
Dysplasia can be reversible w/ removal of the stressor
Then if the stress persists long enough and carcinoma develops it is irreversible
Give 3 Ddx for enlarged LN
(a) Dx if biopsy shows proliferation of lymphocytes in 20:1 ratio
Ddx for enlarged LN is 3-fold
- Hyperplasia 2/2 response to infection
- Lymphoma
- Mets
(a) Cancer is monoclonal => 20:1 ratio is 2/2 lymphoma
Ddx for caseating granulomas and stains
Ddx for caseating granulomas
- Tb (AFB stain)
- fungal infections (GMS stain)
Immunohistochemical stain indicative intermediate filament indicative of
(a) Epithelial cell
(b) Mesenchyme
(c) Neuroendocrine cell
(a) Epithelial cell = keratin stain
(b) Mesenchymal = vimentin
(c) Chromgrannin stain = neuroendocrine cells
- carcinoid tumor
- small cell carcinoma
Key complement protein
(a) Activate mast cells
(b) Attract/activate neutrophils
(c) Mark stuff for phagocytosis
(d) Forming MAC
Complement proteins
(a) C3A and C5A activate mast cells (to release histamine)
(b) C5A attracts/activates neutrophils
(c) C3B opsonizes molecules for phagocytosis
(d) C5B along w/ C6-C9 form membrane attack complex to poke hole in membrane
Explain the mechanism of rubor and calor in acute inflammation
(a) Main molecular mediator
Redness and heat are 2/2 increased blood flow to the area which is due to vasodilation
Vasodilation caused by histamine, bradykinin, and prostaglandins
(a) Mainly histamine
Name 3 permanent tissues
(a) Undergo hyperplasia or hypertrophy?
3 permanent tissues = in G0, not producing more, no stem cells
- cardiac myocytes
- neurons
- skeletal muscle
(a) No stem cells => can’t undergo hyperplasia (increase in cell number), only can undergo hypertrophy
ex: dilated cardiomyopathy
ex: getting swolllllll
Compare and contrast X-linked agammaglobulinemia and CVID
Both have low numbers of all Ig subtypes
X-linked agammaglobulinemia = mutation in tyrosine kinase needed for signaling in B cell maturation
CVID = either B cell or helper T cell (no IL-4/IL-5 to activate B cell) defect
Difference = CVID carries increased risk of autoimmune disease and lymphoma
Why does infection delay wound healing?
B/c infection causes sustained inflammation, and inflammatory cells therefore take up space and prevent collagen (granulation tissue/scar) deposition
Name the 2 mechanisms by which atrophy of a tissue takes place
Atrophy takes place by
- ubiquitin-proteasome degredation: proteins are targeted (ubiquinated) for degradation in proteasome (organelle)
- autophagy of cellular components: vacuoles engulf cellular components, then fuse w/ lysosome for direct destruction
Classically, how many times does a single cell have to mutate before the earliest symptoms of cancer arise?
30 times
Role of macrophages in acute inflammation
Macrophages come in as the last part of acute inflammation (after both edema and neutrophils) to manage the next step
-can determine if inflammation needs to continue (release more IL-8 to attract more neutrophils), if healing should start (via IL-10 and TGF-beta), or if want to form abscess, chronic inflammation
Basically: mediates next step after neutrophil’s job is done
Name the key toll like receptor that recognizes lipopolysaccharide
(a) Where are LPS?
(b) Mediating molecule activated by active TLR
CD-14 = TLR on macrophage surface that recognizes LPS
- LPS = type of PAMP (pathogen associated molecular pattern)
- basically the TLR recognizes PAMPs to activate acute inflammation and say there is a foreign antigen present (part of innate immunity)
(a) LPS present on cell membrane of all gram negative bacteria
(b) Once TLR recognizes its PAMP, NF-kappaB is activated to turn on the acute inflammatory response
What is methemoglobinemia?
(a) Pharmacologic causes
(b) What age group is most susceptible?
(c) Classic clinical findings
(d) Tx
Methemoglobinemia = Iron in Hb is oxidized from Fe2+ to Fe3+
(Fe2 binds O2), so Fe3+ has much lower affinity for binding O2
(a) Sulfa drugs and nitrates are the classic drugs that cause methemoglobinemia
(b) Newborns b/c enzymes to deal w/ oxidative stress aren’t mature
(c) Cyanosis w/ chocolate-colored blood
(d) Tx = IV methylene blue- helps reduce Fe3+ to Fe2+ (provides electrons)
Explain circumstance in which troponins continue to rise after artery is opened in the cath lab
troponins = cardiac intracellular proteins that get released into blood stream 2/2 cardiac tissue damage
Pt goes to cath lab, O2 and inflammatory cells rush towards dead tissue => free radicals form and cause further tissue damage, so you get continued damage (as seen by continued trop elevation) after reperfusion
Name the two molecular mediators of pain in acute inflammation
Molecular mediators of pain in acute inflammation = PGE2 (prostaglandin E2) and bradykinin
Name 3 cancers associated w/ EBV
EBV
- nasopharyngeal carcinoma
- Burkitt lymphoma
- CNS lymphoma in AIDS
Name 2 key catalase (+) organisms
- Staph aureus (NOT STREP- catalase test can be used to distinguish staph and strep)
- Pseudomonas cepacia
-pts w/ chronic granulomatous disease (NADPH oxidase defects => defective O2-dependent killing) are at increased risk of infxn w/ catalase+ bacteria
Describe the key factors in granuloma formation
Granuloma formation: macrophages present antigen on MHCII to CD4+ causing macrophages to secrete IL-12
This IL-12 induces CD4+ T cells into Th1 subtype. Then Th1 secretes IFN-gamma
This IFN-gamma converts macrophages into epithelioid histiocytes
Distinguish the roles of histamine and bradykinin in acute inflammation
Both histamine and bradykinin cause vasodilation of arterioles and increased permeability of post-capillary venules
Then in addition bradykinin mediates pain
During wound healing, differentiate regeneration and repair
(a) Which tissues undergo each type
Tissues w/ stem cells intact can undergo regeneration (gut, skin, liver) while permanent tissues (myocardium, skeletal muscle, neurons) have no active stem cells so can only undergo repair (scar formation) after an injury
Give a classic example of location of each of the 4 types of collagen
Collagen I (strong): bone Collagen II (car'two'lige) = cartilage Collagen III (pliable): blood vessels (need to be able to stretch) Collagen IV: basement membranes
Describe molecules that must be up/down regulated for cancer cell to break thru the basement membrane
Downregulation of E-cadherin (keeps endothelial cells attached to each other) allowing the cells to attach to laminin on the basement membrane
Then the cells get a mutation encoding for a type IV collagenase (break down collagen IV on basement membrane), break thru and attach to fibronectin to spread locally
Then eventually get into blood vessels or lymphatics
Hypertrophic scar vs. keloid
Hypertrophic scar = within the boundaries of the scar and type I collagen (hard/stiff)
Keloid = excess type III collagen (pliable/mushy) way out of proportion to the wound
- much larger than the wound itself
- genetic predisposition: seen in African Americans
- classically on the earlobe
Name the 3 pathways by which apoptosis can be activated
Apoptosis (aka capsase) activation by:
- Intrinsic mitochondrial pathway
- cellular injury, DNA damage, loss of hormone stimulation to the cell - Extrinsic receptor-ligand pathway (FAS ligand)
- cancer and immune maturation
- how T cells that bind too closely to self-antigen are killed off in the thymus - Cytotoxic CD8+ T-cell pathway (perforins/granzymes)
The following chemicals increase the risk of which cancers?
(a) Aflatoxin
(b) Alkalating aents
(c) Arsenic
(d) Nitrosamines in smoked foods
(e) VInyl chloride in PVC pipes
Environmental carcinogens
(a) Aflatoxins that can infect wheat products increase risk of HCC
(b) Alkalating agents (used in chemo) increase risk of lymphoma and leukemia
(c) Arsenic: squamous cell carcinoma, lung cancer (arsenic is in cigs), angiosarcoma of liver
(d) Nitrosamines (Japanese)- stomach cancer
(e) Vinyl chloride and angiosarcoma of liver
2 general categories of causes of acute inflammation
Acute inflammation is caused by either
- infection
- necrosis (neutrphils need to clear the debris)
Contrast X-linked agammaglobulinemia and Hyper-IgM syndrome serum findings
X-linked agamma: low IgG, IgM, IgA, IgE (all low)
Hyper IgM: high IgM but low IgG, IgA, IgE -b/c immature B cells have IgM, so when B cells can't class switch they all make IgM
MC Ig deficiency
IgA deficiency
Explain which cancer vitamin A is sometimes used in the tx of
Vit A is needed to maintain specialized epithelium and is a key part in the immune system, specifically in immune cell maturation
Vit A is used in tx of PML (promyelocytic leukemia) b/c helps immune cells mature
Which physiologically produced free radical is the most dangerous to tissues?
OH- (hydroxyl ion) is the most dangerous
Ddx for noncaseating granulomas
Noncaseating granulomas found in
- reaction to foreign material (ex: leak of implant)
- sarcoidosis
- Crohns disease
- Cat scratch disease (‘stellate’ shaped granuloma)
- Beryllium exposure (similar presentation to sarcoidosis)
MC cause of SCID
MC cause of SCID = mutation in shared part of interleukin receptor = defective interleukin signaling => inability to activate immune response
IgA deficiency
a) Increased risk of what infections (x2
(b) Associated autoimmune disease
IgA deficiency
(a) Increased risk of viral and mucosal infections
(b) High association w/ Celiac disease
Explain why translocations of proto-oncogenes are often w/ a piece of chrom14
Chrom14 contains the gene for immunoglobulin heavy chain which is constitutively active => when translocation occurs this turns on the proto-oncogene
Name 4 carcinomas that spread hematogenously
Majority of carcinomas spread via lymphatics, while sarcomas (malignancy of mesenchymal tissue) spread hematogenously
4 exceptions
- renal cell carcinoma into renal vein
- hepatocellular carcinoma into hepatic vein
- Follicular carcinoma of the thyroid
- choriocarcinoma b/c it’s placental tissue and it’s placenta’s job to invade BVs
Give 2 reasons why damage to the mitochondrial membrane causes irreversible damage to the cell
Mitochondrial damage => irreversible damage b/c
- cyt C gets released into cytosol and activates caspases (initiates apoptosis)
- cell can’t survive w/o electron transport chain (which is on the inner mitochondrial membrane)
Differentiate dystrophic and metastatic calcification
Calcium isn’t normally deposited in tissues, so when it is there are 2 pathological mechanisms
- Dystrophic calficiation = when dead tissue acts as nidus upon which for calcium to deposit
ex: saponification in fat necrosis, Psammoma bodies
- normal serum Ca2+ - Metastatic calcification (not cancer…) = when serum Ca2+ is elevated so Ca2+ just deposits wherever (‘metastatically’) in tissues
Key complement protein
(a) Activate mast cells
(b) Attract/activate neutrophils
(c) Mark stuff for phagocytosis
(d) Forming MAC
Complement proteins
(a) C3A and C5A activate mast cells (to release histamine)
(b) C5A attracts/activates neutrophils
(c) C3B opsonizes molecules for phagocytosis
(d) C5B along w/ C6-C9 form membrane attack complex to poke hole in membrane
Explain the mechanism of swelling (tumor) in acute inflammation
(a) Main molecular mediator
Swelling 2/2 fluid escaping blood vessel into the intra
Cell responsible for scar contraction
Myofibroblasts
First part of scar = granulation tissue: collagen III (stretchy) b/c of deposition by myofibroblasts (‘myo’ = contractile properties)
Distinguish the roles of histamine and bradykinin in acute inflammation
Both histamine and bradykinin cause vasodilation of arterioles and increased permeability of post-capillary venules
Then in addition bradykinin mediates pain
Path report: very poorly differentiated tumor with positive chromogrannin stain
Chromogrannin stains for neuroendocrine cells: lots of possibilities, think carcinoid tumors, small cell carcinomas
Differentiate granulation tissue from scar tissue
Granulation tissue = first step of scar formation
- collagen III deposition by fibroblasts
- has contractile capability b/c of myofibroblasts (myo = contractile properties)
Scar is collagen I and does not have contractile capabilities
Differentiate primary vs. secondary systemic amyloid
Primary systemic amyloid = AL amyloid deposition, AL is derived from immunoglobulin light chains
=> associated w/ plasma cell dyscrasias (abnormalities) where plasma cells make more light chains then heavy chains, so light chains deposit in tissues
Secondary systemic amyloid = AA amyloid deposition, AA comes from SAA which is an acute phase reactant
-so seen in chronic inflammatory states: cancer, autoimmune d/o
What is the main molecular mediator of fever in acute inflammation?
(a)Where does this molecule act?
a
Describe the back and forth communication btwn CD4+ cells and
(a) CD8+ cells
(b) Macrophages
(a) CD4+ (helper T cells) secrete IL-2 to activate CD8+ cytotoxic T cells
(b) CD4+ cells release IFN gamma to activate macrophages, macrophages release back IL-12 to induce CD4 –> Th1
Name the key toll like receptor that recognizes lipopolysaccharide
(a) Where are LPS?
(b) Mediating molecule activated by active TLR
CD-14 = TLR on macrophage surface that recognizes LPS
- LPS = type of PAMP (pathogen associated molecular pattern)
- basically the TLR recognizes PAMPs to activate acute inflammation and say there is a foreign antigen present (part of innate immunity)
(a) LPS present on cell membrane of all gram negative bacteria
(b) Once TLR recognizes its PAMP, NF-kappaB is activated to turn on the acute inflammatory response
Describe the following step of leukocyte arrival in acute inflammation:
Adhesion
After marginalization (vasodilation) and rolling (selectins) leukocytes must adhere to BV wall
Done by cellular adhesion molecules (CAM) on endothelial cells binding to integrins on neutrophils
- CAMs upregulated by TNF and IL-1
- Integrins upregaulted by C5a and LTB4 (leukotriene B4)
Key = CAMs binding to integrins
Type of necrosis seen in
(a) Tb
(b) Myocardial infarction
(c) Brain infarction
Type of necrosis seen in
(a) Tb => caseating- combo of coagulative and liquefactive- ‘cottage-cheese’ appearance
(b) MI => coagulative necrosis- cell death w/ maintenance of tissue architecture
(c) Brain infarction => liquefactive necrosis b/c microglial cells (CNS macrophages) release enzymes that degrade surrounding tissue
In addition to nightblindness, name an effect of vitamin A deficiency on the eye
Vitamin A is necessary for maintenance of specialized epithelium, including the cornea
W/o vit A cornea undergoes metaplasia = ketatomalacia = thickening of conjunctiva
-can lead to blindness
Which mechanism of apoptosis would be used to kill a cell w/
(a) Cellular injury
(b) Viral infection
Mechanism of apoptosis
(a) Cellular injury would activate intrinsic mitochondrial pathway
- cyt C leaks into cytosol and activates caspases
(b) Virally infected cell (presenting viral antigen on MHC I) would be killed off by cytotoxic CD8+ mediated apoptosis via perforin and granzymes to activate capsases
Kid presents w/ periorbital angioedema- expect which primary immune disorder
Hereditary angioedema, especially periorbital, pretty specific for C1 inhibitor deficiency
Give the 2 prototypical examples of fat necrosis
Fat necrosis
- Peripancreatic tissue in pancreatitis
- when pancreatic enzymes are activated in the pancreas instead of SI lumen - Breast tissue after trauma
- s/p surgery, or even simple trauma
- may cause lump and be confusing on mammography
Mast cells: immediate vs. delayed/late response
(a) Fxn of delayed response
Mast cells: immediate response is release of pre-formed histamine granules
-then histamine => vasodilation of arterioles and increased permeability of post-capillaries venules
Delayed response = release of leukotrienes
(a) To maintain the acute inflammatory response
Distinguish Th1 and Th2 cells
Two subtypes of CD4+ cells = Th1 and Th2
Th1 stimulate IL-2 to stimulate CD8+ cells, and IFN-gamma to activate macrophages
Th2 release IL4 and IL5 to activate B cells and initiate class switching
Common mechanism of all 3 apoptosis pathways
(a) 2 components of breakdown
Apoptosis mechanism = capsases (enzymes)
(a) Capsases activate
- proteases to break down cytoskeleton
- endonucleases to break down DNA
Name the hallmark finding of
(a) Reversible cell injury
(b) Irreversible cell injury
Hallmark finding of
(a) Reversible cell injury = cell swelling
- reduced ATP => reduced Na/K activity => increase in intracellular Na => water follows and cell swells
(b) Irreversible cell injury = membrane damage
- plasma membrane damage => Ca2+ gets in, cell proteins leak out
- mitochondrial membrane damage
Differentiate infections one is susceptible to when they have a defect in T cells vs. B cells
T cells- alone (as in w/ normal B cells) see increased risk for viral and fungal infections
B cells- more responsible for bacterial infections
- No IgG => pyogenic infections
- No IgA => mucosal infections (like gut mucosa, giardia)
What is myositis ossificans?
(a) MC cause
(b) How to differentiate on imaging from osteosarcoma
Myositis ossificans = metaplasia of skeletal muscle (example of how CT can undergo metaplasia)
Inflammation of skeletal muscle (a) often 2/2 trauma causes a metaplastic production of bone w/in the skeletal muscle
(b) See a distinct separation of the lesion from the bone, while osteosarcoma you’d see on Xray the lesion directly growing from the bone
Shape of amyloid depositions
Amyloid deposition = general term for misfolded proteins deposited extracellularly, takes on beta-pleated sheet configuration
Name the 4 key molecules for neutrophil attraction and activation
Neutrophil attraction/activation
- LTB4 (leukotriene B4)
- C5A (complement 5A)
- IL-8
- Bacterial products
Hallmark of carbon tetrachloride exposure
During first pass metabolism in the liver CCl4 –> CCl3- (free radical)
This free radical damages hepatocytes => decreased liver protein synthesis => decreased apolipoprotein production => fat gets trapped in liver
Fatty changes to the liver = clinical hallmark of CCl4 (laundry garment business)
Chediak-Higashi syndrome
(a) Inheritance
(b) Defect
(c) Clinical signs: ID, serum, skin pigmentation, neuro
Chediak-Higashi syndrome
(a) Autosomal recessive
(b) Protein trafficking defect that inhibits phagocytosis
- can’t destroy material if you can’t move the phagosome to meet the lysosome inside neutrophil/macrophage
(c) Clinical signs:
- recurrent pyogenic infections
- neutropenia 2/2 defect in cellular division complex (affecting bone marrow)
- albinism b/c can’t move melatonin produced by melanocytes up above keratinocytes
- peripheral neuropathy b/c distant cell bodies can’t supply distal nerves
22q11 microdeletion
(a) Name of syndrome
(b) Embryologic abnormality
(a) 22q11 microdeletion = DiGeorge syndrome 'CATCH 22' Cleft lip/palate Abnormal facies Thymic aplasia Cardiac abnormalities (esp ToF) Hypocalcemia 2/ 2 parathyroid aplasia by microdeletion on chrom 22
(b) Lack of development of the 3rd and 4th brachial pouch
Describe the following step of leukocyte arrival in acute inflammation:
Rolling
Neutrophils and macrophages, once marginalized to boundary of lumen, have to slow down by rolling along wall, done by upregulation of SELECTIN expression on endothelial cells that bind to sialyl Lewis X on leukocytes
Key = selectins on endothelial cells bind to slow down leukocytes
Explain the link btwn Alzheimer disease and Down Syndrome
Alzheimer is due to Abeta amyloid deposition, Abeta amyloid comes from beta-amyloid precusor protein that is coded for by gene on chromosome 21
So trisomy 21 (Down) by some way must increase beta-amyloid precursor protein production/deposition b/c Down’s pts get early-onset Alzheimer’s by age 40
These antibodies protect specifically against what kind of infection
(a) IgA
(b) IgG
(a) IgA are on mucosal surfaces (think nose, gut) => protect against viral and Giardia infections
(b) IgG (recall: and C3b) are the primary opsonins => protect against bacterial infections
In acute inflammation when do the following peak: fluid, macrophages, neutrophils
Fluid comes first, peaks within hours.
Then neutrophils come second, peaking at 24 hrs
Last are macrophages (enter interstitial space same way as neutrophils), peak around 2-3 days
Name a way besides hematogenously and lymphatically that a cancer can metastasize
(a) Classic example
Most sarcomas spread hematogenously, while carcinomas spread lymphatically. Cancers can also spread into body cavities
(a) Ovarian carcinoma spreading to omentum causing “omental caking”
Which mechanism of apoptosis would be used to kill a cell w/
(a) Significant DNA damage
(b) T cell in thymus that fails negative selection
Mechanism of apoptosis
(a) Significant DNA damage would activate intrinsic mitochondrial pathway
- cyt C leaks into cytosol and activates caspases
(b) Maturation of the immune system by killing off self-targeting T cells = extrinsic receptor-ligand pathway via FAS ligand
* FAS ligand*
Why are pts w/ chronic granulomatous disease not as susceptible to infxn from catalase (-) organisms
O2 dependent killing: O2 –> (NADPH oxidase) –> O2- –> H2O2 –> (MPO) –> HOCl0
In CGD the defect is in NADPH, so no H2O2 is made. However, catalase negative bacteria provide H2O2 so O2-dependent killing can still occur
-while catalase breaks down the available H2O2 => O2-dependent killing cannot occur in pt w/ CGD during infection w/ catalase (+) bacteria
Explain how the following pathologically produce free radicals
(a) Ionizing radiation
(b) Inflammation
(c) Free iron accumulation
Pathologic free radical production
(a) Ionizing radiation hits water in tissues and releases OH- (hydroxyl free radical)
(b) Inflammation: one way by which neutrophils kill tissues is w/ oxidative burst which starts w/ reduction of O2 –> O2- by NADPH
(c) Free iron (not bound to transferrin or ferritin) produced OH- by the Fentin rxn
Arachidonic acid
(a) Where does it come from?
(b) 2 important derivatives used in the acute inflammatory reaction
Arachidonic acid
(a) Cell membrane component
(b) 2 pathways
Arachidonic acid –> (cyclooxygenases) –> prostaglandins
Arachidonic acid –> (5-lipooxygenase) –> leukotrienes
Explain when repair occurs instead of regeneration
(a) Result of MI
(b) Cut w/ steak knife vs. butter knife
Repair occurs instead of regeneration when there are no stem cells- either tissue stem cells are removed (really deep skin cut) or aren’t present/active (in permanent tissues)
(a) Post-MI = fibrous scar
- myocardium is a permanent tissue, can’t undergo regeneration so after injury (ischemia), a fibrous scar is made
(b) Deep cut that cuts out stem cells in the basal layer (steak knife) will scar b/c can’t undergo regeneration
Differentiate caseating and noncaseating granulomas
Caseating = presence of central necrosis: epitheliod histiocytes in the center of the granuloma lack nuclei (are dead)
Nonceasating = no central necrosis
Arachidonic acid
(a) Where does it come from?
(b) 2 important derivatives used in the acute inflammatory reaction
Arachidonic acid
(a) Cell membrane component
(b) 2 pathways
Arachidonic acid –> (cyclooxygenases) –> prostaglandins
Arachidonic acid –> (5-lipooxygenase) –> leukotrienes
How long after an infection is cleared do neutrophils stay around?
(a) How do they get out?
(b) What comes next?
Neutrophils are gone only 24 hrs after acute inflammation
(a) They don’t get out, they die. Undergo apoptosis and form pus
(b) Then macrophages come in! Eat up the pus, get rid of all the debris etc
2 key histologic features of
(a) acute inflammation
(b) chronic inflammation
(a) Acute inflammation = edema (excess fluid in interstitial space) and neutrophilic infiltrate
(b) Chronic inflammation = lymphocytes and plasma cells
Clinical features of MPO deficiency
Myeloperoxidase = enzyme used in O2 dependent killing after phagocytosis
H2O2 –> (MPO) –> HOCl- (bleach)
Then bleach goes on to kill the bacteria
Increased risk of candida infections
Name 2 opsonins that target cells for neutrophil phagocytosis in acute inflammation
Opsonins C3b and IgG mark cells/proteins for neutrophilic phagocytosis
Mechanism of organ adaptation to
(a) Increase in stress
(b) Decrease in stress
(c) Change in type of stress
Growth adaptation
(a) Increase in stress => hyperplasia and/or hypertrophy
(b) Decrease in stress => atrophy
(c) Change in type of stress => metaplasia
Explain the mechanism of swelling (tumor) in acute inflammation
(a) Main molecular mediator
Swelling 2/2 fluid escaping blood vessel into the intravascular space
-due to increased vascular permeability of post-capillary venules
(a) Main mediator = histamine
2 tests T cells must pass to mature out of the thymus
- Positive selection- make sure they recognize MHC
2. Negative selection- make sure they don’t bind self too tightly
Which immune cell uses apoptosis as mechanism of causing cell death?
CD8+ T cells recognize antigens presented on MHCI and activated capsases to cause apoptosis
Name the two molecular mediators of pain in acute inflammation
a
Explain the mechanism of metaplasia using Barrett’s esophagus
Mechanism of metaplasia = reprogramming of stem cells to make a dif kind of cell (one that is more adapted to handle the new type of stress)
Barrett’s: stem cells go from making nonkeratinized stratified squamous ep –> intestinal epi (nonciliated columnar ep w/ goblet cells) to better deal w/ acid
What is coagulative necrosis?
(a) Differentiate from liquefactive necrosis
Coagulative necrosis = cell death where tissue architecture is maintained due to coagulation of proteins
-so tissue shape and structure is maintained, but cells are anucleated (aka dead)
(a) While liquefactive necrosis is destruction of architecture (literally liquifying the tissue)
- enzymatic degradation of the cells and proteins
