FINAL EXAM Pathology D2 Fall Flashcards
The etiology of most diseases is ____________
multifactorial
Hypertrophy
Increase in cell SIZE (we want a BIG “trophy”)
physiologic or pathologic
caused by increased workload (functional demand) or by stimulation of trophic hormones
increased production of cellular proteins
Nondividing cell increased tissue mass
Hyperplasia
increase in cell NUMBER
physiologic or pathologic
happens in labile cells (cells that are capable of division)
Physiologic hyperplasia can be hormonal (increase in order to gain function) or compensatory (in order to fix damage)
Pathologic hyperplasia is caused by excess hormones or growth factors– may be at higher risk of malignant transformation (ex. enlargement of the prostate)
Metaplasia
Change in cell PHENOTYPE
One differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
Necrosis is always __________, whereas apoptosis can be _________ OR _____________
Necrosis is always PATHOLOGIC, whereas apoptosis can be pathologic OR physiologic
Necrosis
different types described in other cards
If damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, resulting in necrosis
- LYSOSOMAL ENZYME RELEASE IS IRREVERSIBLE
Apoptosis
caspases and endonucleases degrade DNA and proteins… cells break into fragments (apoptotic bodies)…
phagocytosis of cell fragments
DNA damage is characteristic of APOPTOSIS but NOT necrosis
apoptosis is NOT a cell adaptation to stress (cell adaptations are reversible.. like hyperplasia)
Characterized by:
- nuclear dissolution
- fragmentation of the cell without complete loss of membrane integrity
- rapid removal of cellular disease
Reversible injury is characterized as cellular ___________ or ________ change
Reversible injury: cellular swelling or fatty change
Cellular swelling due to failure of energy-dependent ion pumps, loss of fluid homeostasis
Fatty change– occurs in hypoxic injury or toxic and metabolic injury. Seen in cells dependent on fat metabolism (hepatocytes and myocardial cells)
First manifestation of all forms of injury?
cellular swelling
Depletion of ATP
ATP depletion caused by reduced oxygen and nutrient supply, mitochondrial damage, and the actions of some toxins.
Decreased ATP causes:
- failure of energy dependent sodium pump– there is influx of calcium and osmotic gain of water– cell swells
- increased glycolysis
- failure of calcium pump
- ribosomes detach from rEr… decreased protein synthesis
Mitochondrial Damage
results in apoptosis OR necrosis
apoptosis occurs through the release of pro-apoptotic proteins (like Cytochrome C)
mitochondrial damage causes:
- decreased ATP
- increased ROS
- apoptosis or necrosis
Necrosis occurs with the formation of the mitochondrial permeability transition pore (depletes ATP)
Influx of Ca and loss of Ca2+ homeostasis
usually Ca inside cell is LOW
Ischemia and certain toxins cause Ca inside cell to be released, and later calcium influxes through plasma membrane
Calcium activates enzymes, including phospholipase, proteases, endonucleases, and ATPases
Induces apoptosis by activating cascades or increasing mitochondrial permeability
Accumulation of Oxygen-derived Free Radicals
Reactive oxygen species (ROS)– single unpaired electron in outer orbit
- lipid peroxidation in membranes– attach double bond of unsaturated fatty acids of cell membrane
- oxidative modification of proteins– alters activity
- lesions in DNA– free radicals can cause single and double strand breaks in DNA
failure of sodium and calcium pumps does NOT HAPPEN with ROS
ROS inactivated by antioxidants
- intracellular: superoxide dismutase, catalase, glutathione peroxidase
- extracellular: vitamins A, C, and E
Hypoxia
Reduced oxygen
Energy production may continue by anaerobic means (hypoxia can continue glycolysis)
Ischemia
secondary to reduced blood flow
reversible if oxygen is restored, but irreversible injury and necrosis can occur if ischemia continues
Delivery of substrates for glycolysis is compromised– ATP production STOPPED
Loss of ox phos– sodium pump fails, potassium is lost and water enters cell– cell swelling
loss of surface microvilli and blebs develop on the surface
mitochondria are swollen and ER are dilated
Irreversible Cell Damage… “Which would cause the most damage?”
- irreversible mitochondrial dysfunction
- disturbances in membrane function
leakage of intracellular enzymes and other proteins into the blood may provide an indication of cell death (like in myocardial infarction)
Cellular changes in necrosis
- cell swelling
- cytoplasm is glass, homogenous, and pink and may have vacuoles
- nuclear changes (karyolysis, pyknosis, karyorrhexis)
- cells die and release cytoplasm contents– induce inflammation and repair
Name the 6 types of necrosis
- coagulative
- liquefactive
- caseous
- fat
- fibroid
- gangrene (only a description word)
Coagulative necrosis
intact cellular membrane with NO NUCLEUS
most commonly associated with ischemic injury (irreversible ischemia)
localized area of coagulative necrosis is called an infarct
Liquefactive necrosis
enzymatic digestion until tissue is gone and only pus remains
due to release of lysosomal enzymes
major causes are bacterial infections and cerebral infarcts
- cerebral infarcts present similar to wet gangrene
Caseous necrosis
associated with M. tuberculosis (mycobacterial infection)
tissue appears white and “cheesy”
morphologically defined by caseating granulomatous inflammation
Fat necrosis
common in trauma to breast or pancreatitis
Adipose has chalky white-yellow appearance
dead adipocytes look like “soap bubbles”
Fibroid necrosis
associated with autoimmune disease affecting blood vessels
- ex. Lupus erythematosis
neither fibrous or fibrinous
like fibrin but is NOT fibrin– associated with immunoglobulin deposition and necrotic material within blood vessles
Gangrene
CLINICAL TERM (description word, not a technical necrosis type)
black necrotic tissue
Wet gangrene: liquefactive necrosis and bacterial infection
Dry gangrene: ischemia and coagulative necrosis (diabetics)
Anti-Apoptotic Proteins
BCL2
prevents apoptosis
BLC2 antagonists inhibit the apoptosis prevention… so pro-apoptotic proteins can destroy the cell
Pro-Apoptotic Proteins
BAX and BAK
promote outer mitochondrial membrane proteins
Types of Intracellular Accumulations (4 general… not specific substances)
- normal endogenous substance produced at a higher rate, but the metabolism isn’t high enough to remove it
- abnormal endogenous (usually because of mutated gene) accumulates because the body has no enzymes to degrade it)
- normal endogenous when there is an enzyme defect, so body can’t degrade it
- abnormal exogenous because the cell doesn’t know how to deal with it
Steatosis
Lipid accumulation (fatty change)
Abnormal triglyceride accumulation in parenchymal cells (normal endogenous substance at normal or increased rate, but rate of metabolism is not enough)– increased lipid synthesis and reduced breakdown
liver, heart, muscle, and kidney
Cholesterol Intracellular Accumulation
can see accumulations by intracellular vacuoles
Atherosclerosis– smooth muscle and macrophages of large arteries filled with lipid vacuoles (can see cholesterol under microscope)
Xanthomas– collection of lipid-laden macrophages (foamy cells)
Cholesterolosis– cholesterol-laden macrophages in the gallbladder
Neumann-Pick Disease– lysosomal storage disease because there is an enzyme deficit in processing lipids
Hyaline Change
only a descriptive term
alteration in cells or extracellular space that gives a homogenous, glassy, pink appearance
Glycogen Accumulation
glycogen masses appear as clear vacuoles within the cytoplasm
enzymatic defects cause glycogen storage diseases (problems with glycogen or glucose metabolism)
Pigment Accumulation
can be endogenous or exogenous (coal dust and amalgam tattoo would be exogenous)
LIPOFUSCIN– wear and tear pigment, polymer of lipids and phospholipids in complex with proteins (NORMAL CONSEQUENCE OF AGING)
- resists autophagy
- associated with free radical injury
Melanin– protective mechanism
Hemosiderin– hemoglobin derived pigment, major storage forms of iron (breakdown product of blood, plays a role in bruising)
Pathologic Calcification
Abnormal deposition of calcium salts with other small amounts of mineral salts
Dystrophic calcification– deposition occurs locally in diseased or dying tissues
Metastatic calcification– occurs in otherwise normal tissues, caused by HYPERCALCEMIA
Does apoptosis have inflammation?
NO– apoptosis does not have inflammation (no inflammatory infiltrates with apoptosis)
Necrosis, however, DOES have inflammation
Foreign bodies cause which type of inflammation?
Foreign body granulomatous inflammation/foreign body granuloma
TLRs are a “sensor for microbes”, and are located where?
TLRs are located in…
- plasma membrane
- endosomes
- cytoplasm
Inflammasomes
sense CELL DAMAGE
multiprotein cytoplasmic complex for recognition of products of dead cells
Edema vs. warmth/erythema
Edema is caused by leakage of exudate/plasma protein
Warmth/erythema (redness) is caused by increased blood flow due to dilation of microcirculation of the injured area
Vascular changes with Inflammation
increased blood flow and vasodilation (after transient vasoconstriction)
increased vascular permeability
Herpes infection is an example of ________ inflammation
Serous
Dental abcesses are an example of ___________ inflammation
Purulent
Which cell is recruited first during cell injury?
Neutrophils
Which proteins help mediate with leukocyte rolling and adhesion?
rolling– mediated by selectin family of adhesion molecules
adhesion– mediated by integrins (responsible for cytoskeletal protein interactions with ECM)
Diapedesis
extravasation of leukocytes
driven by PECAM-1 (CD31)
PECAM-1
cell adhesion molecule that drives DIAPEDESIS
What inflammatory mediators are involved in chemotaxis?
- leukotriene B4
- TNF
- C5a
(cytokines, bacterial products)
Chemotaxis is NOT mediated by kinins
Process of microcirculation events mediated by resident inflammatory cells?
- transient constriction
- dilation
- increased permeability
- leaving of exudate
- increase in blood viscosity and decrease in blood flow (blood viscosity increases because exudate is gone)
What molecule activates macrophages?
INF-𝛾
(secreted by helper T cells)
Papillon-Lefevre Syndrome
genetic disorder
Mutation in the cathepsin C gene, involved in skin development and inflammatory response
depressed blood neutrophil chemotaxis
gingivitis, loss of attachment and alveolar bone resorption
What cell contributes to the major production of histamine?
Mast cells
histamine is stored in mast cell granules
histamine dilates arterioles and increases venule permeability
What is the most important coagulation factor?
Thrombin
What do opsonins do?
They enhance recognition and attachment of PMNs
Which mediators are in charge of fever?
IL-1
TNF
Prostaglandins
What are the principal mediators for increased vascular permeability?
Histamine and serotonin
C3a and C5a (mast cells)
Leukotrienes C4, D4, E4
Chronic inflammation is associated with what process/pathway?
Fibrosis
Macrophage Types (M1 and M2)
M1: classically activated macrophages
- phagocytosis and killing of bacteria and fungi
- inflammation
M2: alternatively activated macrophages
- tissue repair and fibrosis
- anti-inflammatory effects
Examples of diseases demonstrating granulomatous inflammation
Tuberculosis
Leprosy
Syphilis
Cat scratch disease
sarcoidosis
Crohn’s disease
Systemic Effects of Inflammation
- increased pulse and BP
- decreased sweating
- rigors (shivering)
- chills (search for warmth)
- anorexia
- somnolence
- malaise
Tissue Regeneration
100% recovery of lost or damaged tissue
proliferation of new cells to replace lost structures
ex. hematopoietic system and epithelia of the skin and GI tract renew themselves 24/7
Tissue Repair
combination of regeneration and scar formation (fibrosis)
Fibrosis
extensive deposition of collagen that occurs during repair (replacing parenchymal tissue with scar tissue)
Labile Tissue Differentiation
continuous division throughout life, replacing those that are destroyed
epithelial tissue, hematopoietic cells
Stable Tissue Differentiation
quiescent, which a low level of replication
liver, pancreas, kidney, bone, cartilage
2 examples of permanent tissues
cardiac muscle and neurons
(these are non-dividing cells)
Which stem cells have the easiest and hardest time differentiating?
embryonic stem cells have the greatest capacity to form the 3 tissue layers (easiest)
Adult stem cells have the hardest time differentiating
Integrins role in the cell cycle
integrins: interaction between cytoskeletal proteins and the ECM
the ECM then signals the division to happen and cytoskeletal proteins actually carry out the division
integrins from ECM activate transcription factors
integrins are “receptors for proliferation”
Cyclins and CDKs
progression through the cell cycle is regulated by cyclins and cyclin dependent kinases (CDK)
CDKs form interactions with cyclins in order to drive the cell cycle… CDK INHIBITORS block these interactions and therefore block the cell cycle
Epidermal growth factor (EGF) and transforming growth factor alpha (TGF⍺)
both share common EGFR receptor
mitogenic for epithelium, hepatocytes, and fibroblasts
Transforming growth factor beta (TGF-β)
considered FIBROGENIC
growth inhibitor for epithelial cells, strong anti-inflammatory effect
ECM structural proteins (3)
- proteoglycans (like GAGs)– provide lubrication and resilience
- fibrous structural proteins (collagen)
- adhesive glycoproteins that connect matrix elements
Collagen development from procollagen is dependent on __________
Vitamin C
(so collagen development is affected with a Vit. C deficiency)
Remember tensile strength comes from collagen
What things give tissues expansion and recoil capabilities?
Elastin
Fibrillin
Elastic Fibers
Name the four families of cell adhesion molecules (CAMs)
immunoglobulin family
cadherins
integrins
selectins
Name some glycosaminoglycans and proteoglycans
heparin sulfate, chondroitin/dermatan sulfate, keratin sulfate and hyaluronan
Angiogenesis
VEGF is the most important growth factor in adult tissues undergoing angiogenesis
vasodilation is response to NITRIC OXIDE produced by macrophages, endothelial cells, etc.
Proteinases are important in tissue remodeling during endothelial invasion, and they cleave extracellular proteins, releasing growth factors like VEGF and FGF-2
2 types of “intention” for cutaneous wound healing
primary intention: cell basement membrane injury are limited and wound edges are approximated by surgical sutures
secondary intention: larger tissue defects such as an abscess or ulceration (results in greater scarring)
Proliferative phase of cutaneous wound healing
formation of granulation tissue, proliferation and migration of connective tissue cells
Granulation tissue
presence of new small blood vessels and proliferation of fibroblasts
Wound contraction occurs through which type of cell
Myofibroblasts
happens during maturation stage of cutaneous wound healing
Dehiscence
rupture of a wound
can be caused by inadequate formation of granulation tissue or assembly of a scar
Keloids
hypertrophic scars
excessive formation of repair components
more common in African Americans
Exuberant Granulation
formation of excessive amounts of granulation tissue
Desmoids
exuberant proliferation of fibroblasts that may rarely occur at the site of incisional scars or traumatic injuries
dense collagenous proliferation at site of surgical scars
Contracture
exaggeration of the contraction of a wound that results in deformities of the would or surrounding tissues
commonly associated with serious burns
Fibrosis
excessive deposition of collagen and other ECM components with decreased degradation
most commonly caused by CHRONIC DISEASE
major cytokine involved in fibrosis is TGF-beta
Effusion
accumulation of fluid in body cavities (serial surface involvement)
Inflammatory vs. Noninflammatory Edema and Effusion
Inflammatory– protein rich exudates accumulation due to increased vascular permeability
Non-inflammatory: protein poor transudates accumulation
Transudate vs Exudate
transudate: only water leakage
exudate: protein AND water leakage (due to inflammation)
Name some causes of Edema
- venous obstruction
- lymphatic obstruction
- hepatic cirrhosis
- congestive heart failure
- DVT
- renal disease/failure
Edema can be indicative of underlying cardiac or renal disease
Ascites
effusion of the peritoneal cavity
malnutrition produced by severely inadequate amount of protein in the diet
pics of kids in other countries with big bellies (KWASHIORKOR)
Hyperemia
an ACTIVE process
more blood entering (erythema)
arterial dilation– increased blood flow–erythema of affected tissue
ex. student develops red race from embarrassment
Congestion
a PASSIVE process
resulting from reduced outflow– edema
cyanosis/hypoxia
Systemic (cardiac failure) or localized (venous obstruction)
Chronic Pulmonary Congestion
thickening of the septa
heart failure cells: hemosiderin- laden macrophages, found in chronic pulmonary congestion
Endothelin
transient VASOCONSTRICTOR
- does arteriolar vasoconstriction in hemostasis (blood clot formation)
Tissue plasminogen activator (t-pA)
Fibrinolysis effect
- counterregulatory to blood clot stabilization and resorption
Thromboxane A2 pathway
thromboxane A2 (TXA2) leads to platelet aggregation
ASPIRIN inhibits this pathway (so, aspirin can decrease thrombi formation in coronary arteries)
activation by thrombin and ADP
Glanzmann thrombasthenia
- deficit of fibrinogen binding to GpIIb-IIIa receptors
- platelet doesn’t change shape so it doesn’t have a good affinity for fibrinogen
Bernard-Soulier Syndrome
deficit of GpIb receptors so the platelet cannot adhere to vWF (no vWF means that GpIb has no ligand to trigger platelet adhesion)
Prothrombin time (PT) assay
Assessing the function of the proteins in EXTRINSIC pathway
(2, 5, 6, 10, fibrinogen
Partial thromboplastin time (PTT) assay
assessing the function of the proteins in INTRINSIC pathway
(2, 5, 7 ,9, 10, 11, 12, fibrinogen)
Fibrinogen into fibrin is caused by….
Thrombin
What inhibits t-pA?
Plasminogen Activator Inhibitor-1 (inhibits fibrinolysis)
t-pA activates fibrinolysis along with urokinase prourokinase
What inhibits plasmin?
Alpha 2 antiplasmin
Plasminogen deficiency
formation of excessive fibrin in the lamina propria at mucosal sites
CONJUNCTIVA: ligenous conjunctivitis
GINGIVA: ligneous gingivitis
**note: ligneous means excess fibrin
Factors for development of THROMBOSIS (3)
- endothelial injury
- alteration in normal blood flow
- hypercoagulability (aka thrombophilia)
Altered blood flow (stasis vs. turbulence conditions)
TURBULENCE:
- atherosclerotic plaque
- hyperviscosity
- deformed red blood cells
STASIS: aneurysms
Most common cause of congenital thrombophilia?
Factor V leiden
primary (genetic) point mutation in the factor V gene and prothrombin
Protein C and S deficiencies are RARE causes of thrombophilia
Patients with __________ are at a high risk for thrombosis
cancer
myocardial infarction
prolonged bed rest
Factors putting patients at low risk for thrombosis?
oral contraceptive use
smoking
sickle cell anemia
Lines of Zahn
at site of rapid blood flow that happened before death (ante mortem thrombus)
pale platelet and fibrin alternating with darker red cell-rich layers
Ante mortem thrombi
dry, friable, mottled and attached to vessel wall in which they are formed
Post mortem thrombi
not attached, gelatinous and have a dark red dependent portion where red cells have settled by gravity and yellow “chicken fat” upper portion
What is the worst possible rate of thrombosis?
Embolism
What is disseminated intravascular coagulation associated with?
SEPTIC SHOCK and DIC
complication of many conditions associated with systemic activation of thrombin–microvascular thrombi formation
Most common form of thromboembolic disease?
Pulmonary embolism
(originated from DVT), associated with pulmonary hypertension and right ventricular failure
Systemic thromboembolism– most come from what?
intracardiac mural thrombi
other origins are valvular thrombi, aortic aneurysms, or atherosclerotic plaques
Fat and Marrow Embolism
embolism in lung after fracture of long bones and liposuction (ex. player fractures femur)
Air Embolism
decompression sickness
gas bubbles in circulation lead to vascular obstruction
Amniotic Fluid Embolism– mortality and morbidity mostly due to what?
activation of coagulation factors (DIC) rather than mechanical obstruction of pulmonary vessels
Infarction
an infarct area is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage
result of embolism is infarction
Red (Hemorrhagic) Infarcts
arterial or venous occlusion under conditions permitting accumulation of blood in damaged tissue
happens in tissues with multiple blood supplies (like the lungs)
White Infarct
arterial occlusion in solid tissue with a single blood supply
could find white infarct in a coronary artery
Shock associated with systemic inflammation
activation of cytokine cascade
peripheral vasodilation and pooling of blood
Neurogenic shock
spinal cord injury and anesthetic complications
loss of sympathetic tone and peripheral pooling of blood
Anaphylactic shock
generalized IgE mediated hypersensitivity leading to systemic vasodilation and increased vascular permeability
hypotension due to increased vascular bed capacity that cannot be adequately filled
Nonprogressive stage of shock
initial stage in which reflex compensatory mechanisms (neurohumoral) are activated for maintenance of perfusion of vital organs
Which type of T cells are the most important in the immune system?
T-helper cells
What is the most important APC for initiating T-cell responses?
Dendritic cells
What do the classic and alternate/lectin complement pathways deal with?
Classic pathway:
- ADAPTIVE immunity (antibodies)
- activated by antigen/antibody complex
Alternate/lectin pathway:
- INNATE immunity
- activated by microbes
Are cytokines stored in cell vesicles?
NO– they are secreted, not stored in vesicles
CD8+ recognize antigens on which MHC class?
MHC class I
X-linked agammaglobulinemia (XLA, Bruton Disease)
Failure of pre-B cells to differentiate into B cells
Hereditary defect in Bruton tyrosine kinase (BTK) gene
normal T cell response because only B cells are affected…. treatment by replacement of antibodies
DiGeorge Syndrome
developmental malformation of the 3rd and 4th pharyngeal arches
- this IS NOT ACQUIRED
absence of thymus and parathyroids, so there is deficient T cell maturation
infants are vulnerable to viral, fungal, and protozoal infections
facial structures will be underdeveloped (common cleft lip and palate)
What attachment on HIV is necessary for CD4+ receptors?
CD4+ receptors must attach to gp120 on HIV
gp120 must also bind coreceptors CCR5 or CXCR4
p24 is NOT required
What cells are able to be infected by HIV? (4)
all cells with CD4+ receptors:
microglia
macrophages
dendritic cells
T-helpers
Type I hypersensitivity (IgE mediated)
mast cells release…
- vasoactive amines
- lipid mediators
- cytokines
ex. anaphylaxis, hay fever, food allergies
Type II hypersensitivity (IgG mediated cytotoxic)
complement-dependent opsonization
Graves disease and erythroblastosis fettles
Type III hypersensitivity (Immune complex-mediated)
antigen-antibody complexes are deposited in tissues, causing activation of complement, which attracts neutrophils
systemic lupus erythematosus and rheumatoid arthritis
Type IV hypersensitivity (cell-mediated)
Th1 cells secrete cytokines that activate macrophages and cytotoxic T cells and can cause macrophage accumulation at the site
TB test results, granuloma, contact dermatitis
- these do NOT involve antibodies
Anergy
functional inactivation of lymphocytes
type of peripheral self-tolerance
Systemic lupus erythematosus
can cause RENAL FAILURE
erythematosus rash on face in butterfly pattern (molar regions of face)
sterile endocarditis (Libman-Sacks)… vegetations develop on margins of valve
autoantibodies specific for SLE present (different card)
Autoantibodies specific for SLE? (2)
if they have either of these, they definitely have SLE
Anti-double stranded DNA
Anti-Sm (smith) antibody
only these are SPECIFIC to SLE.. SLE also has antinuclear antibodies, but they aren’t specific to the disease
Sjogren Syndrome
autoimmune affecting the salivary and lacrimal glands
40 fold increase in LYMPHOMA
parotid gland enlargement in half of cases
primary sjogrens (sicca syndrome)– sjogrens alone… secondary sjogrens is sjogrens + another autoimmune disorder
treat with DMARDs (hydroxychloroquine, methotrexate)
Sjogren Syndrome Antibodies?
Anti-SS-A (anti-Ro)– 70% positive
Anti-SS-B (anti-La)– 40% positive
rheumatoid factor and antinuclear antibodies
Schirmer test
tests the tear production levels. less than 5mm in 5 min indicative of SJOGRENS
(small strip of paper placed on lower eye… tears bleed down the paper)
Systemic sclerosis (scleroderma)
fibrosis of tissues, autoantibodies, and obliterative vascular disease
esophageal dysmotility (trouble swallowing)
Raynaud phenomenon
widening of PDL seen in panoramic radiograph
calcinosis, sclerodactyly, telangiectasia
Joint stiffness
LUNG FIBROSIS is a serious complication
skin changes noted first (thickening and tightening)
Antibodies in systemic sclerosis
antinuclear antibodies (ANAs) usually present
target normal proteins in nucleus
systemic sclerosis has antitopoisomerase antibodies… also have anticentromeric antibodies
Pemphigus (Pemphigus Vulgaris)
uncommon autoimmune blistering disorder
oral signs are most difficult to resolve.. “first to show, last to go”
Type II (antiboy mediated) hypersensitivity reaction
- IgG directed against epithelial desmosome complex (desmoglein 1 and 3)
intraepithelial cleating– loss of intercellular attachment due to IgG attaching epithelial desmosome complex
Pemphigus Vulgaris immunofluorescence
Positive direct immunofluorescence (“fishnet” pattern)
Positive indirect immunofluorescence
(note: MMP has negative indirect immunofluorescence)
Mucous membrane pemphigoid (MMP) (cicatricial)
type II hypersensitivity, antibodies attack basement membrane
may see intact BLISTERS intraorally (“4mm translucent vesicle of buccal surface”)
symblepharon– scarring of conjunctival mucosa (adhesions between inner surface of lid and eye)
MMP immunofluorescence
POSITIVE direct immunofluorescence
NEGATIVE indirect immunofluorescence
(confirm MMP biopsy with DIRECT immunofluorescence)
What type of tissue graft is LEAST likely to be rejected?
Autograft
hyperacute tissue rejection
occurs within minutes
type II hypersensitivity
antibodies bind antigens on graft and activate complement and clotting systems– ischemic necrosis of graft
How long before acute rejection happens to a transplant organ?
Days to weeks after transplant
(note: acute rejection is T-cell and antibody mediated)
Chronic rejection of transplanted organ
occurs over months-years
T cells react against graft alloantigens presented by graft APCs
refractory to most therapies (NOT preventible with immunosuppressives)
Graft-Versus Host Disease (GVHD)
associated with hematopoietic transplant (bone marrow transplant)– may show lesions and ulcers
** any time you see bone marrow transplant, it is most likely GVHD
immune cells from GRAFT TISSUE recognize the host as foreign and attack the host
Amyloidosis
deposition of amyloid into the tissue
results in tissue damage and functional compromise – pathology behind morbidity and mortality of amyloidosis is “physical damage and function dysruption”
extracellular deposition of amorphous eosinophilic material
CONGO RED staining positive
Expressivity
extent to which the inheritable trait is expressed (how “bad” it is)
some people can be diagnosed but not show disease characteristics (low expressivity)
Pleiotropy
one gene controls multiple phenotypic characteristics
mutation in a pleiotropic gene may have widespread phenotypic effects (Marfan syndrome)
Heterogeneity
production of similar phenotypic effects by 2 or more genetic loci… several different mutations may be responsible for the same disease state (breast cancer)
may present with a range of severity
ex. Tay-Sachs Disease
Single nucleotide polymorphism (SNPs)
substitution of a single nucleotide base
type of point mutation
can be silent, nonsense, or missense
How common are mendelian disorders?
RARE– only account for 1% of adult hospitalizations and 6-8% pediatric admissions
Marfan syndrome
autosomal DOMINANT
defective extracellular glycoprotein (fibrillin) encoded by genes FBN1 or FBN2– connective tissue alterations
Abraham Lincoln had this
NOT associated with mental retardation
Genetic diseases associated with mental retardation?
- Down syndrome
- Klinefelter
- Fragile X
Neurofibromatosis Type I (NF1) [Recklinghausen disease]
mutation of NF1 gene (tumor suppressor)
autosomal dominant
nearly 100% penetrance
highly variable expressivity
multiple neurofibromas
cafe-au-lait pigmentation
lisch nodules
axillary freckling (Crowe sign)
intellectual disability
**note: NF2 has bilateral acoustic neuromas, but this does NOT apply to NF1
Autosomal Recessive Diseases characteristics
must be homogenous for trait to be expressed
parents usually not affected, siblings have 25% chance
affected individual likely a product of consanguineous partnering
Cystic Fibrosis
3 nucleotide deletion in cystic fibrosis transmembran conductance regulator gene (CFTR)– disfunction of chloride ion channels
Phenylketonuria (PKU)
lack of enzyme phenylalanine hydroxylase (PAH)
normal at birth, but severe intellectual disability evident by 6 months (brain damage occurs if untreated during the first month)
seizures and other neurologic abnormalities
distinct musty body odor
autosomal recessive
patients develop hyperphenylalaninemia and phenylketonuria
dietary restriction of phenylalanine
Patients with PKU are on a dietary restriction of _______________________
phenylalanine
think of any amino acid uptake as dietary protein intake (ex. meat, eggs, and wheat all have high phenylalanine)
so PKU patients need a LOW PROTEIN DIET
X- linked disorders
almost all are RECESSIVE and therefore only expressed in males
(ex. woman carrier for color blindness… children are:
1/2 females are carriers
1/2 males are colorblind)
females may show partial expression because of Lyon hypothesis– inactivation of one X chromosome in each cell (Barr body)
examples:
- hemophilia
- red/green colorblindness
- Duchenne muscular dystrophy
- Bruton’s agammaglobulinemia
Structural abnormality– Deletions
loss of portion of chromosome
Ring chromosome: special form of deletion produced when the break occurs at both ends of a chromosome and the damaged ends fuse into a ring
Trisomy 21 (Down syndrome)
most common chromosomal disorder
caused by meiotic nondisjunction
parents are genetically normal
10 to 20 fold increase of ACUTE LEUKEMIA (AML or ALL)
neuropathology changes characteristic of Alzheimer disease in patients older than 40
Klinefelter syndrome
most patients are 47 XXY (at least 2 X chromosomes and one or more Y)
nondisjunction of sex chromosomes during meiosis
małe hypogonadism
gynecomastia
-20x increased incidence of breast cancer
oral manifestations: taurodontism (body of tooth is really big and roots are small… apically altered furcations and pulp chambers)
mild to no intelectual impairment
Turner syndrome
partial or complete monosomy of short arm of X chromosome
typically 45 X karyotype (entire X chromosome missing)
webbing of the neck (from distended lymph nodes)
lack of secondary sex characteristics
Fragile X syndrome is a ______________ _____________ mutation
triple repeat
(mutation in the FMR1 gene located on Xq27.3)
Mitochondrial genetic diseases
MATERNALLY INHERITED ONLY (mutations in mitochondrial genes ONLY passed by the mother)
primarily affects organs dependent on ox phos (brain, skeletal muscle, heart, liver, kidney)
Genomic Imprinting Diseases
disease arising from inactivation of maternal or paternal genes during gametogenesis (genomic imprinting)
imprinting means inactivation of that parent’s allele
some genes are expressed differently depending on maternal or paternal
Prader-Willi syndrome
deletion in PATERNALLY derived 15q12 region
Angelman syndrome
deletion in MATERNALLY derived 15q12 region
Malformation
primary errors of morphogenesis, usually multifactorial with a genetic basis
Disruption
secondary destruction of an organ/body region that was previously normal in development
Deformation
localized or generalized compression of the growing fetus by abnormal biomechanics forces
Most transcervical perinatal infections are ______________
BACTERIAL (ex. streptococcal infection)
there are a few caused by viruses
these are acquired in utero or during birth
Choristoma
pediatric neoplasm
microscopically normal cells/tissues in abnormal location
Hamartoma
excessive, focal overgrowth of cells/tissue native to that organ
Benign pediatric neoplasms? (3)
nevus flammeus (port wine stain)
hemangioma
lymphangioma
Nevus Flammeus
aka port wine stain
benign pediatric neoplasm
rarely fades with age
most often on face but may be anywhere on body
Hemangioma
most common tumor of infancy
rapid enlargement followed by gradual recession (likely to spontaneously regress by age 9)
Lymphangioma
benign pediatric neoplasm
proliferation of lymphatic channels
50-75% in head and neck
Malignant pediatric neoplasms? (3)
- neuroblastoma
-Wilms tumor (nephroblastoma) - retinoblastoma
Which neoplasms are more common in CHILDREN?
leukemias
CNS tumors
rhabdomyosarcoma
neuroblastoma
retinoblastoma
Sustaining proliferative signaling
one of the hallmarks of cancer
sulf-sufficiency in growth signal: cells have capacity to proliferate without external stimuli due to oncogene activation
mutation/overexpression of port-oncogenes
TP53 gene
most common tumor suppressor gene
guardian of the genome, most common target for mutations in human cancers
cell proliferation is NOT a function of p53, because it is a tumor suppressor
p53 slows or inhibits cell cycle progression (senescence.. permanent cell cycle arrest, G1 arrest is temporary)
Telomere
repeated nucleotides at the end of each chromosome
escape of cancer cells from senescence and mitotic catastrophe caused by telomere shortening (because they reactivate telomerase)
Are initiators alone enough to induce tumor growth?
NO
initiation = exposure of cells to a sufficient dose of carcinogenic agent, making it POTENTIALLY capable of giving rise to a tumor
Viruses that can cause oropharyngeal SCC
human papilloma virus (HPV… 16 and 18)
These classes of medications would be more effective when designing a drug for OSCC:
inhibit VEGF binding to receptors on endothelial cells
inhibit type IV collagenase
inhibit lymphangiogenesis
Which are classified as Paraneoplastic syndromes? (4)
Disseminated intravascular coagulation (DIC)
Cushing syndrome (endocrinopathies)
paraneoplastic autoimmune multiorgan syndrome (PAMS) (Paraneoplastic pemphigus)
acanthuses nigricans
Are tumor markers specific? Can they be used for definitive diagnosis?
Tumor markers are NOT SPECIFIC and CANNOT be used for a definite diagnosis
Examples of tumor markers?
hormones (calcitonin)
oncofetal antigens
specific proteins (prostate specific antigen, PSA)
cell-free DNA markers
Cancer prognosis… which is most important– grade, stage, or type
type > stage > grade
