General Pathology Flashcards
Etiology
Science and study of the causes of disease.The term identifies the causes of disease
Pathogenesis
The cellular and molecular mechanisms resulting in the development of a pathologic lesion.The term identifies the mechanisms of a disease process
Pathophysiology
Derangement of function seen in diseaseThe term emphasizes the alterations in function resulting from the structural changes occurring in cells, tissues and organs during a disease process
Causes of cell injury
Ischemia (decreased blood flow) /anoxia-hypoxia (suboptimal or lack of O2 supply) (most common cause)Physical agents Chemicals Microorganisms Immune reactions Nutritional imbalance Genetic changes
Anoxia/hypoxia: possible mechanism
Mediated via hypoxia-inducible factorIf we could create an HIF analog –> decrease hypoxia
Hypoxia-inducible factor: important impacts
Angiogenesis Erythropoiesis Anaerobic glycolysis Glucose uptake Extracellular matrix turnover pH control Apoptosis Mitogenesis
Cell injury and free radicals
Most causes of cell injury act through the generation of free radicals May increase membrane permeability, inhibit cation pumps, deplete ATP and increase cytosolic free calcium
Free radicals: what are they
Oxygen-derived (reactive oxygen species = ROS) are produced by neutrophils and macrophages. Important ROS are superoxide anion (O2-·) and peroxide ion (O2-) ROS are generated during the reduction of molecular oxygen (O2) to water.Nitric oxide (NO) is a free radical gas produced by a variety of cells (macrophages, Kupffer cells and vascular endothelium)
Free radicals: effects
Cause peroxidation of lipids (in membranes, mitochondria and in circulation) Cause peroxidation of proteins (especially thiol-containing proteins, e.g., Ca-ATPase and Na-K ATPases of plasma membranes) Interact with DNA, causing strand breaks and inducing the enzyme poly(ADP-ribose) polymerase Alter the redox activity of the cell, with profoundeffects on enzyme systems sensitive to redox potential
Variability of cell response to injury
Intensity, duration and type of traumatic event (striated muscle can be ischemic for hours vs heart only 20-30 mins)Differences in cell type Production of cytokines/growth factors Expression of cell receptors
Consequences of trauma
Strong, acute, very persistent trauma –> irreversible cell injury
Less intense/temporary trauma –> reversible cell injury
Non-excessive trauma –> cell adaptation
Cell adaptation: hypertrophy
A reversible adaptive response characterized by an increase in cell size (cells do not divide but become larger) –> occurs in cardiac muscle, skeletal muscle, & nerve)
Occurs when there is an increase in protein synthesis, structural components, and organelles
Normal: Increased exercise –> increased muscle hypertrophy
Pathological hypertrophy:
Cardiac hypertrophy in: systemic hypertension restricted aortic outflow(aortic valve stenosis)
Cell adaptation: Atrophy
Decrease in cell size due to decrease in structural components of the cell (mitochondria, myofilamentsand endoplasmic reticulum)
Pathologic atrophy:
Reduced functional activity and/or prolonged pressure Loss of innervation
Reduced blood supply
Insufficient nutrition
Loss of hormones and/or cytokines/growth factors
Cell adaptation: Hyperplasia
A reversible adaptive response characterized by an increase in the number of cells (cells divide more)
Pathologic hyperplasia
Hormonal: Cushing’s syndrome, nodular prostatic hyperplasia Autoimmune: psoriasis vulgaris, Graves’ disease
Viral: warts
Inflammation and wound healing:keloids
Relationship of hyperplasia & hypertrophy
Cells adapt to trauma by increasing both number (hyperplasia) and size (hypertrophy) Examples: thyroid cells of Graves’ disease, bronchial smooth muscle cells in asthma
Cell adaptation: Metaplasia
One adult cell type is replaced by another adult cell type (–> patch of ectopic tissue) Mechanism: stem cells undergo reprogramming
Types of metaplasia
Change from one cell type to another
Squamous, Glandular, Connective tissue (named by what the new cell type is)
Most common: columnar –> squamous
Persistent –> increase likelihood of malignant transformation
Pathologic metaplasia:
Trachea and bronchi of cigarette smokers
Barrett’s esophagus
myositis ossificans (bone formation in muscle after intramuscular hemorrhage
Keratomalacia (vitA deficiency: Retinoic acid needed for proper stem cell differentiation)
Reversible Cell Injury: Hydropic change
Cell is incapable of maintaining ionic and fluid homeostasis due to failure of energy driven pumps
Na/K ATPase
More Na in the cell –> increased water drawn into organ
Reversible Cell Injury: Fatty change
Infiltration of fat (mainly triglycerides) inside hepatocytes, usually exceeding 5% of liver weight:
Histology: empty white spaces where lipid droplet were in vivo
Irreversible Cell injury: types
Apoptosis (cell death with shrinkage, activation-induced cell death, cell suicide, programmed cell death)
Necrosis (cell death with swelling, oncosis, accidental cell death)
Ultrastructural changes of reversible injury
Plasma membrane: blebbing, loss of microvilli…
Mitochondria: swelling, amorphous densities
Dilation of ER
Alterations to the nucleus
Apoptosis: definition
Programmed cell death mediated by a tightly controlled cell program
Apoptosis: Fate of dead cells
Apoptotic cells breakdown into fragments and the plasma membrane of dead cells are marked to signal their phagocytosis
Phagocytosis is usually VERY rapid –> USUALLY there is NO inflammation
Physiological apoptosis
Occurs during:
programmed cell death during embryogenesis
involution of hormone-dependent tissues once the hormone is removed
Elimination of potentially harmful self-reactive lymphocytes
Death of cells that have already served their purpose (neutrophils after immune response)
Cell loss in proliferating cell populations
Inflammation is NOT present
Pathologic apoptosis
Elimination of cells that are injured beyond repair, occurs in:
DNA damage
Accumulation of mis-folded proteins
Cell death in certain infections (HIV)
Detection of apoptosis
Light microscopy: difficult (difficult due to rapid phagocytosis), best seen at high power
DNA electrophoresis (DNA ladders): apoptotic cells don’t have/decrease DNA steps
TUNEL (terminal deoxyribonucleotidyl transferase-dependent dUTP-biotin nick end labeling): staining (brown)
Electron microscopy: best image of apoptosis, characteristic crescent chromatin
Final events of apoptosis
Activation of endonuclease which produce DNA fragments
Induction of transglutaminase activity –> cross-linking of Lys & Glu of cytoplasmic proteins –> thick shell under plasma membrane –> changes in cell volume & shape
Intrinsic pathway of apoptosis
Cells are deprived of survivor signals, increased ER stress, or DNA damage –> inactivation of Bcl2(anti-apoptotic factors) –>
pro-apoptotic sensors BIM, BID, & BAD(also from the Bcl protein family) activate –> activation of effector proteins BAX & BAK –>
form oligomers that insert in the mitochondria forming channels –> increased permeability of mitochondria –>
release of pro-apoptotic molecules (e.g. cytochrome c) into the cytoplasm –> binds to Apaf-1 to form apoptosome –>
binds procaspase 9 then cleaves it –> activation of caspase 3 & 7 –> release of apoptotic substrates –> CELL DEATH
Meanwhile, other proteins (Smac & DIABLO) are released by the mitochondria –> bind to inhibitors of apoptosis in the cytoplasm
Extrinsic pathway of apoptosis
FasL (found on the surface of T cells & some cytotoxic T cells) binds to Fas (found on target cell that will die) –> Fas molecules come together and an adapter protein binds (FADD) –>
provides a binding site for various procaspase 8 –> these caspase 8 will cleave each other to form caspase 8 –> promotes apoptotic substances (transglutaminases & endonucleases)
Other interactions leading to apoptosis: TNF-alpha w/ TNFR
Cytotoxic T cell mediated apoptosis
CD8+ T cells secrete perforins –> pores form in target cells –>
Granzyme enters target cell via these pores –> activation of caspases –> promotes apoptotic substances
Morphologic changes during apoptosis
Cell shrinkage (cytoplasm becomes denser)
Chromatin condensation
Formation of cytoplasmic blebs & apoptotic bodies
Necrotic cells: morphology
Increase eosinophila
Glassy, homogenous appearance
Vacuolated cytoplasm
Replacement of dead cells by myelin figures
Necrotic cells: patterns of nuclear changes
3 patterns:
karyolysis: Fading of basophila of chromatin (due to loss of DNA)
pyknosis: nuclear shrinkage, increased basophila
karyorhexis: fragmented nucleus
Coagulative necrosis
Architecture of dead tissue is maintained, and have firm texture
Denatures structural proteins & enzymes –> prevents proteolysis
Caused by ischemia to the specific tissue by occulsion of a blood vessel;
localized areas of coagulative necrosis –> infarct
Looks ghosty
Liquefactive necrosis
Characterized by the digestion of dead cells –> transformation of tissue into liquid viscous mass
Appears creamy yellow –> due to dead leukocytes (pus)
Seen in focal bacterial infections & fungal infections
Infarcts in the CNS present this type of necrosis
Caseous necrosis
Friable white appearance
Collection of fragmented or lysed cells; amorphous granular debris
Histology: halos surrounding cells
characteristic of granulomatous inflammation
Fat necrosis
Focal areas of fat destruction
Components of acute inflammation
Alterations of vascular caliber –> increase blood flow
Micro-vasculature change structural to allow proteins & leukocytes to leave circulation
Accumulation & activation of leukocytes at site of injury
Necroptosis
Regulated necrotic cell death w/out caspase activation
Induced by stimulation of Fas/TNFR family of death domain receptors; dependent on RIPK1 & RIPK3 kinase activity
Different receptors lead to the formation of different complexes (i.e. necrosome or ripoptosome
Stimuli for acute inflammation
Infections
Tissue necrosis
Foreign bodies
Immune Responses/Autoimmune
Pyroptosis
Regulated necrotic-like cell death that depends on caspase 1 activation –> results in release of IL-1beta & IL-18
Characterized by: nuclear condensation, oligonucleosomal DNA fragmentation, & apoptosis (not apoptosis b/c formation of membrane pores, cytoplasmic swelling, & osmotic lysis)
Acute inflammation: vasodilation
Earliest sign of inflammation is vasodilation to increase blood flow to the site of injury (causes the typical redness and heat seen)
Induced by relaxation of vascular smooth muscle by histamine & NO
Pyronecrosis
Caspase 1 independent cell death dependent on NLP3 & ASC –>
formation of the inflammasome
Ex: Shigella infected macrophages –> necrotic cell death
Acute inflammation: consequences of increased vascular permeability
Following vasodilation, microvasculature becomes more permeable –> increased protein-rich exudate in extravascular tissue –> edema
These lead to stasis (more viscous blood that is moving slower) –> localized redness
Pathogenesis of accidental necrosis
Loss of selective permeability of plasma membrane (damage by ROS, decreased synthesis or increased breakdown of phospholipids, cytoskeleton alterations)
Loss of Ca homeostasis (increased intracellular Ca)
Mitochondrial damage (formation of mitochondrial permeability transition pores: MPTP)
Depletion of cellular ATP (caused by reduced supply of O2 & nutrients
Acute inflammation: mechanisms of increased vascular permeability
Contraction of endothelial cells –> increased intraendothelial spaces (most common); induced by leukotrienes, histamine, bradykinin, & substance P
Endothelial injury resulting in cell necrosis & detachment
Increased transcytosis of proteins & fluid
Induced by VEGF (increases number & size of channels)
Regulated necrosis: overview & types
Various forms that are mediated by various mechanisms including:
activation of death receptors, PAMPs, DAMPs, & and activation of NLPs
Final stages have same characteristics as accidental necrosis
Types: necroptosis, pyronecrosis, pyroptosis
Acute inflammation: impact on lymphathic vessels
Lymph flow is increased to attempt to drain edema
fluid, leukocytes, cell debris, & microbes enter lymph fluid
May cause secondarily inflamed lymphatics & inflamed lymph nodes (by hyperplasia)
Leukocyte migration
Vasodilation slows the blood flow which allows for margination of cells to the periphery (specifically in the post-capillary venules)
Leukocyte rolling
Endothelial cells up regulation of selectins
P-selectin release is mediate by histamine (released from Weibel-Palade)
E-selectin induced by TNF & IL1
Selectins bind weakly to sialyl Lewis X on leukocytes –> rolling of the leukocytes along the vessel wall
Leukocyte adhesion
THF & IL1 begin to upregulate ICAM & VCAM on endothelium
Integrins are upregulated on leukocytes by C5a & leukotriene B4
CAM & integrins form strong adhesion between vessel and leukocytes
Leukocytes transmigration & chemotaxis
Leukocytes transmigrate across endothelium toward chemical attractants (chemotaxis)
Neutrophils attracted by bacterial products, IL8, C5a, & leukotriene B4
Leukocyte phagocytosis
Pseudopods extend from leukocytes to form phagosomes which are then internalized & merge w/ lysomsomes to make phagolysosome
Phagocytosis is enhanced by opsonins (IgG & C3a)
Leukocytes: destruction of phagocytosed material & resolution
O2 dependent killing
Generation of HOCl by oxidative burst (O2 –> free oxygen radicals by NADPH oxidase, formation of H2O2 by superoxide dismutase, & finally formation of HOCl by myeloperoxidase)
Neutrophils undergo apoptosis & disappear within 24 hrs
Chronic inflammation: characteristics
Characterized by the presence of macrophages, lymphocytes & plasma cells (nucleus off to one side w/ visible cytoplasm)
Delayed response but more specific than acute inflammation
Stimulated if acute inflammation has not been able to resolve infection
Types of chronic inflammation
Diffuse:
Inflammation that is spread throughout the tissue
Granulomatous:
Frequently in the form of foreign bodies (inflammation localized to a small region)
T cells
Made in bone marrow, then thymus to undergo TCR rearrangement (to become CD4+ or CD8+)
CD4+: recognize antigen presented on MHC class II CD8+ recognize antigen presented on MHC class I
Also requires secondary signal for activation
CD4+ T cell activation
Extracellular antigen is phagocytosed, processed, & presented via MHC II
Second signal: B7 on APC binds CD28 on CD4+ T cells
Activated CD4+ helper T cells
Secretes cytokines that help inflammation
Two subsets; Th1 & Th2
Th1 subset
generates IL2 (T cell growth factor & CD8+ T cell activator & IFN-gamma (macrophage activator)
Th2 subset
Generates: IL4 (promotes class switching to IgE & IgG) IL5 (eosinophil chemotaxis & activation, maturation of B cells --> plasma cells, IgA class switching) IL10: inhibits Th1 phenotype (shut down inflammatory response)
CD8+ cytotoxic T cell activation
Intracellular antigen is processed & presented on MHCI
Second cell: IL2 from CD4+ Th1 cells
Cytotoxic killing by CD8+ T cells
Secretion of perforins & granzyme –> induce apoptosis in target cell
Expression of FasL, binds to Fas on target –> apoptosis
Caspases activation is what leads apoptosis in both cases
B lymphocytes
Immature B cells are produced in bone marrow
Undergo Ig rearrangement to become naive B cells that express IgM & IgD
B cell activation
1) Antigen binding by surface IgM or IgD –> becomes plasma cells secreting antigen
2) B cell antigen presentation to CD4+ helper T cells via MHC II
CD40 receptor binds to CD40L (on T helper cells) providing 2nd signal –> helper T cell can then secrete IL4 & IL5 –> help mediate B cell isotype switching, hypermutation, & maturation to plasma cells that can secrete IgG, IgA, IgE)
Granulomatous inflammation
Characterized by the presence of a granuloma
Key cell: epitheloid histiocytes (a macrophages w/ abundant pink cytoplasm)
Other cells that may be seen, but not necessary: giant cells & a rim of lymphcytes
Divided into noncaseating & caseating subtypes
Noncaseating granulomas
Lack central necrosis (nucleus is present in cells)
React to foreign material (breast cancer pt w/ breast implants)
Crohns disease (noncaseating granuloma is a hallmark sign)
Caseating granuloma
Characterized by central necrosis
Seen in TB (AFB stain for diagnosis) & fungal infection (Silver stain for diagnosis)
Formation of granuloma
Mechanism for both caseating & non-caseating granulomas
Macrophages present antigen via MHC II to CD4+ helper T cells
Macrophages secrete –> IL12 –> induce CD4+ helper cells differentiate into Th1
Th1 cells –> secretion IFN-gamma –> converts macrophages to epithelioid histiocytes & giant cells
Regeneration
Replaces damaged tissue w/ native tissue
Depends on the regenerative capacity of tissue (3 types)
Labile tissues
Continuously cycle to regenerate tissue
Ex:
Small & large bowel (stem cells in mucosal crypts)
Skin (stem cells in the basal layer)
Bone marrow (hematopoietic stem cells, marked by CD34+)
Lung (type 11 pneumocytes)
Stable tissues
Quiescent, but can reenter the cell cycle –> undergo regeneration
Ex:
Regeneration of liver by compensatory hyperplasia after partial resection
Hepatocyte produced additional cells & then reenters quiescence
Proximal tubule of kidney
Permanent tissue
Lack significant regenerative potential & therefore they tend to undergo repair
Ex:
Myocardium
Skeletal muscle
Neurons
Tissue repair
Replaces damaged tissue w/ fibrous scar
Occurs when tissue has lost stem cells (occurs in skin if the cut is very deep damaging the basal layer) or does not have a regenerative capacity
Phases of repair
Granulation tissue Consists of: fibroblasts (deposits type III collagen) Capillaries (provide nutrients) Myofibroblasts (contract wound)
Scar formation:
Type III collagen is replaced w/ type I collagen (replaced by collagenase which requires Zn as cofactor)
Mechanism of regeneration & repaire
Mediated by paracrine signaling via growth factor
Ex:
TGF-alpha (epithelial & fibroblast growth factor)
TGF-beta (important fibroblast growth factor, inhibits inflammation)
PDGF: help endothelium & smooth muscle to regrow, fibroblast growth factor
FGF: angiogenesis, skeletal development
VEGF: angiogenesis
Cutaneous healing mechanism
Primary intention: wound edges brought together, minimal scar formation
Secondary intention: edges are not approximated, the wound has a big scar but smaller in size: this is accomplished b/c granulation tissue fills defect (which contains myofibroblasts)
Delayed wound healing
Infection is most common cause
Vitamin C deficiency (important for hydroxylation of procollagen that is needed for collagen cross-linking)
Cooper deficiency (lysyl oxidase requires cross-linking collagen)
Other cause: foreign body, ischemia, diabetes, & malnutrition
Dehiscence
Rupture of the wound (most commonly seen in abdominal surgery)
Hypertrophic scar
Excess production of scar tissue that is localized to the wound
Made up of collagen type I
Keloid
Excess production of scar tissue that is out of proportion to the wound Characterized by type III collagen Genetic predisposition (more commonly seen in african americans)
Thrombosis: definition
a thrombus is a solid or semisolid mass composed of platelets, erythrocytes, & leukocytes bound together by fibrin
Caused by coagulation of blood within the vascular system during life
Virchow’s triad
Abnormalities of vascular endothelium
Alterations in rate, force or direction of blood flow (turbulence & stasis)
Hypercoagulability (increased prothrombin, factor Va, homocysteine, vWF, TF)
Characteristics of thrombi
White (mostly platelets & fibrin mostly in arteries), red (RBCs & fibrin in veins)
Mixed: most common include all components and show lines of Zahn (layers of these factors in a thrombi)
Major characteristic: thrombi are attached to vessel wall
Arterial thrombi: most common locations
commonly seen in the coronaries than in the cerebral followed by iliac & lastly femoral
Venous thrombi: common locations
Found in deep leg veins, mostly in the calf then femoral then popliteal & least common in iliac veins
Consequences of thrombosis
Embolism, ischemia, infarction (MI or stroke)
Thrombotic microangiopathy
Occlusive microvascular thrombosis resulting in ischemia
Seen in thrombocytopenic purpura (severe deficiency of ADAMTS13 that normally cleaves vWF –> microthrombi in most organs
Disseminated intravascular coagulation
Activation of coagulation sequence –> formation of microthrombi throughout microcirculation
Pathogenesis: release of high levels of TF
Embolism
Occlusion of some part of the vascular system caused by the impaction of material brought there by the circulation
Material blocking the vessel is called an embolus
Emboli: types
Divided into solid, liquid, and gaseous; not attached like thrombus
Most emboli are solid, but liquids & air can also act as an emboli
Pathogenesis of emboli
Arise mostly within veins & commonly stop in the lungs (from deep veins of the legs)
Emboli that arise from the portal system will travel to the liver
Emboli in the arteries will travel peripherally & get stuck in the arterial bed
Paradoxical embolus: rare, crossing over of the embolus, requires a septal defect
Ischemia
Lack of blood or insufficient flow of blood
Ischemia: variables controlling degree
Speed of onset
Extent of arterial occlusion
Existence and status of collateral circulation
Infarction
Localized area of cell death due to impaired supply of blood and/or oxygen
Necrosis of parenchymal cells: usually coagulative, cells become amorphous, acidophilic, loss of nuclei, & preserved cellular outline
Edema & hemorrhage in the area
Hyperemia
Characterized by excess of blood in a particular organ
Active hyperemia
Characterized by increased blood flow to the affected area
Inflammation is the most common cause
Response to increased demands for blood
Neurogenic (vasodilator stimuli occurring during fever)
Local irritation by trauma
Paralysis of vasoconstrictor nerves
Passive hyperemia
Characterized by decreased flow away from the affected organ
Caused by impaired venous return, either mechanical, hydrostatic pressure, dilatation of capillaries & venules in which the blood slows down
Edema
Abnormal excessive accumulation of fluid within tissue spaces or serous cavities
Can be either localized or generalized
Edema: etiology
Interfere w/ the normal movement of blood, tissue fluid, & lymph
Disturb the mechanism of fluid balance or cause Na & water retention
Edema: pathogenesis
One or more alterations in Starling forces –> increased flow of fluid from the vascular system into the interstitium or into a body cavity
Damage to capillary endothelium, increasing its permeability –> transfer of protein to the interstitium
Reduced effective arterial volume –> dysregulation of salt & water
Reduced cardiac output –> increased systemic venous pressure
Diminished renal blood flow —> RAAS –> salt & water retention
Transudate
Fluid w/ low specific gravity, low protein content
Characteristic of edema from heart failure or other conditions w/out changes in the capillary permeability
Exudate
Fluid w/ high specific gravity, high protein content & many red & white cells
Characteristic of edema resulting from increased capillary permeability (as seen in inflammation)
Hemorrhage
Characterized by extravasation of blood
It is distinguished according to the origin of the bleeding & if it is internal or external
Petechiae hemorrhages
Small and punctate, spot-like (less than 2 mm)
Ecchymosis hemorrhage
Large, diffuse hemorrhagic area caused by trauma
Purpura
Condition characterized by purple spotson the skin & mucosae, confluent petechiae & ecchymoses
Hematoma
Discrete, localized bleeding in a tissue –> causing a swelling
Examples of sudden nontraumatic hemorrhage
Rupture of arterial aneurysm: localized saccular or fusiform dilatation bounded by arterial wall components
Rupture of aortic dissection: lesion characterized by the formation of blood-filled channel w/in the aortic wall
Hypovolemic shock
Most common form of shock
Caused by hemorrhage, fluid loss from severe burns, trauma
Pathology: failure of multiple organ systems due to ischemic lesions in brain, heart, kidneys, adrenals
Cardiogenic shock
Caused by sudden myocardial pump failure
Complication of acute MI, severe arrhythmias, cardiac tamponade, pulmonary embolism
Characterized by low cardiac output, decreased peripheral perfusion, pulmonary congestion & elevation of systemic vascular resistance
NSAIDS
ASA & non-acetylated salicylates
Non-selective inhibitors (naproxen)
Cox2 inhibitors
Leukotriene Pathway Inhibitors: examples
Inhibition of 5-lipoxygenase
Leukotriene-receptor antagonist
Arachidonic acid
Arachidonic acid is esterified in the membrane phosholipids
Can then enter cyclooxygenase pathway or lipoxygenase
Cyclooxygenases
COX1: Expressed in most cells Housekeeping functions: Gastric cytoprotection Platelets Renal Function
COX2:
Inducible, expression is stimulated by macrophages, primary source of vascular prostacyclin, expressed in kidney
Effects of TXA2 & PGI2
TXA2 (made in platelets): vasoconstrictor & promotes platelet aggregation –> BAD
PGI2 (made in endothelial cells): vasodilation & inhibits platelet aggregation –> GOOD
COX1 in GI system
PGE2 provides cytoprotection
Stimulation of mucin secretion by epithelial cells
Stimulation of HCO3 by epithelial cells
Enhancement of mucosal blood flow & O2 delivery to epithelial cells
COX1 in Kidney
Important auto-regulatory role in renal function
PGE2 & PGI2 dilate afferent artery
Increase Na & H2O excretion
Uses of NSAIDS
Anti-inflammation Pain Fever Closure of the ductus arteriosus Low-dose for cardioprotection
Anti-inflammatory effects of NSAIDS
Decrease sensitivity of vessels to bradykinin & histamine
Inhibit effect of COX2 on human T lymphocytes production of IL2 & TNFalpha
Inhibition of apoptosis
Inhibition of inducible NO
All NSAIDS (except COX2 & non-acetylated salicylates) reversibly inhibit platelet aggregation
Aspirin
Low dose: inhibits COX1 –> decreases TXA2, does not get into circulation and DOES NOT inhibit prostacyclin
Irreversibly inhibits platelet COX1 –> decreased platelet function & prolongs bleeding time
Clinical uses of low dose Aspirin
Primary & secondary prevention of MI
Unstable angina
TIA & strokes
Toxicity of aspirin
Anion gap metabolic acidosis Primary respiratory alkalosis Tinnitus/hearing loss Adult respiratory distress syndrome Decreased mental status
Non-acetylated salicylates
Rarely used
Anti-inflammatory by:
Inhibition chemotaxis, inhibit neutrophil aggregation, decreased pro-inflammatory cytokines
Not used due to low potency, no effect on platelet aggregation & no GI side effects
Toxicity of NSAIDS: Cardiovascular
Increase risk of cardiovascular events b/c imbalance between inhibition of PGI2 & TXA2
Avoid in pts w/ known CV disease
Hypertension is secondary to Na retention & loss of vasodilation from PGI2
Causes Na retention (due to loss of PGI2) –> DO NOT GIVE TO PTs w/ CHF
Toxicity of NSAIDS: Renal
Decrease renal fx in patients w/ decrease effective circulating volume (loss of PGE2 vasodilating effect on afferent artery leading to unopposed vasoconstriction –> decreased renal function)
Decreased renal function in pts w/ preexisting renal disease
Rarely: chronic interstitial nephritis & papillary necrosis
Toxicity of NSAIDS: GI
Dyspepsia may be seen w/out ulceration
GI bleeds 50-60% have no symptoms
NSAIDs decrease blood flow, mucus & HCO3 secretion, & decreased cellular regeneration
Risk factors for bleeds:
age >60, high dose NSAIDs, concurrent glucocorticoids or anticoagulant use
Prevention of NSAID GI toxicity
High risk either avoid or consider COX2 inhibitor also can be on chronic PPI
Eradicate H pylori if diagnosed
Leukotrienes
Arachidonic acid can make leukotrienes via lipoxygenase
Effects of leukotrienes
Blood cells & inflammation:
Chemoattractant for PMNs, eosinophlils, & monocytes
Eosinophil adherence, degranulation, & oxygen radical formation
Implicated in pathogenesis of inflammation
In airways, potent bronchoconstrictors & increased microvascular permeability, plasma exudation, & mucus secretion
Leukotriene pathway inhibitors
Inhibition of 5-lipoxygenase (Zileuton)
Leukotriene-receptor antagonist (Zafirlukast, Montelukast)
Uses of leukotriene pathway inhibitors
Asthma: due to effect on airway caliber, bronchial reactivity and airway inflammation
Reduce exacerbations
Allergic rhinitis/sinusitis: usually used after nasal steroids & antihistimines
Fatty change in the heart
2 patterns:
Prolonged moderate hypoxia –> yellowish striping (coeur tigre)
Move severe hypoxia –> most cells have lipid deposit –> eventual cell death
Alcohol fatty liver: mechanism
Excessive alcohol consumption –> increased enzymes involved in conversion of fatty acids to TAGs
Decrease in TAG utilization, FA oxidation, & lipoprotein excretion
Non-alcoholic fatty liver: mechanism
No history of alcohol consumption
Associated w/ obese, DMII, hyperTAG
Most common cause of liver disease in Western countries
Amyloidosis: defined & types
Extracellular deposition of insoluble abnormal fibrils derived from aggregation of mis-folded, normally soluble, proteins
Types: AL (Ig light chain), AA (amyloid associated), AF (amyloid, mutations in transthyretin), Abeta (found in the brain of pts w/ Alzheimer disease)
Can be either localized, systemic, acquired (complication of existing disease), hereditary
AL amyloidosis
Most common type of systemic amyloidosis in NA
Onset after 40, rapidly progressive & fatal
Associated w/ myeloma & B cell disorders
Widespread deposit of Ig light chains in most organs/tissue
Common presentation:
Macroglossia, easy bruising (ecchymoses), proteinuria, heart dysfunction, hepatosplenomegaly
Clinical testing for amyloidosis
Tissue biopsy (congo red staining of abdominal fat or other tissue)
If positive, immunohistochemical staining of biopsy looking for:
Kappa or lambda light chain (AL)
Amyloid A protein (AA)
Transthyretin (ATTR)
Iron homeostasis: review
Dietary ferric ion reduced to ferrous (Fe2+) –> cross brush border via divalent metal transporter (DMT1) –> exported into circulation via exporter ferroportin & Fe oxidase (hephaestin)
Circulating Fe is bound to transferrin –> stored in macrophages & hepatocytes –> used for hemoglobin synthesis is the bone marrow
Hepcidin regulates Fe by binding to ferroportin leading to its degradation; it responds to changes in Fe via HFE, TfR2, & hemojuvelin (mutations in these lead to decreased hepcidin release –> increased Fe reabsorption)
Hemochromatosis
Intracellular accumulation of endogenous pigment hemosiderin (hemoglobin derived pigment composed of ferritin aggregates)
Caused by overload of Fe (from localized hemorrhage, increased dietary Fe, hemolytic anemias, repeated transfusion, genetic disorders –> excessive Fe absorption)
Hypersensitivity Reaction Types
Type I: Anaphylactic immediate hypersensitivity
Type II: Antibody-dependent cytotoxic hypersensitivity
Type III: Immune complex-mediated hypersensitivity
Type IV: Cell-mediated/delayed-type hypersensitivity
Type I hypersensitivity reaction: important players
Allergen (antigen causing allergy)
IgE (antibodies to allergen)
Mast cells and basophils (with receptors for IgE) and their mediators
Allergens: definition & examples
Any non-infectious environmental substance capable of inducing IgE production
Most common allergens are proteins: pollens, molds, mites, various foods, hair and saliva of dogs, cats, horses
chemicals can also be allergens (as haptens): pharmaceuticals (penicillins, sulfonamides, etc.), paints, dyes, metals, etc.
Allergens: characteristics
Belong to very few protein families
Allergen families contain similar components and/or share epitopes for IgE and T cells (molecular mimicry)
Have structural features favoring stability (repetitive structures and aggregation)
Interact with cell membranes and other lipids
What makes an antigen an allergen
Ability to activate the innate immune system (and induce a Th2 environment)
Allergens contain lipid and/or carbohydrate ligands that activate a variety of pattern recognition receptor (PRRs) pathways
The activation of TLR4 and C-type lectin receptors on innate immune cells drives Th2-mediated immune responses
1st encounter with allergen
Innate immune responses (production of IL-25 = IL-17E, IL-33, TSLP, IL-4)
Adaptive immune responses to allergen epitopes
Production of IgE antibodies to allergen
Control by allergen-specific regulatory T cells
IgE: characteristics
IgE does not bind complement
does not transfer through the placenta
has relatively low binding to neutrophils and mononuclear cells
has strong binding through its Fc fragment to receptors on mast cells and basophils (binding that lasts for more than 12 weeks)
IgE receptors: characteristics
Mast cells and basophils express two different cell surface receptors for the Fc fragment of IgE:
High affinity receptor (FceRI): facilitates the survival of the basophil or mast cells
Low affinity receptor (FceRII or CD23)
There is also a co-receptor for CD23 (CD21)
2nd encounter to allergen
Antigen must bind to 2 IgE receptors on mast cells/basophils to allow for cross linking –> release of preformed (result in the acute reaction) & newly formed mediators (released if it is chronic)
Mediators from mast cells
Preformed: histamine (–> vasodilation, etc.) heparin, proteases, cytokines
Produced lipid mediators: prostaglandins (PGE2, LTC4, etc.)
Cytokines: TNFa, TGFb, IL-1b, IFNs, IL-4, IL-5, IL-6, IL-8, IL-13,etc.
Mediators from basophils
Preformed: histamine, proteases, cytokines, etc.
Produced lipid mediators: LTC4
Cytokines: IL-4, IL-13, BAFF, APRIL, (IL-1b, TNF-a)
IgE-mast cell-mediator pathway: protective effects
Unclear but may be useful in the defense against parasitic worms & ticks
IgE-mast cell-mediator pathway: destructive effects
very common, are seen in a variety of allergic diseases
Neoplasia: definition
Purposeless, Excessive, Autonomous Growth of Abnormally Formed Tissues.
Reactive process
it is characterized by a reaction to a primary process and may mimic a neoplasm.
However, it is not autonomous and its fate follows the fate of the primary process.
Ex: abscess is a reaction to bacterial infection and its fate will follow the fate of the infection.
Malignant neoplasms: definition
Neoplasms capable of distant metastasis, local invasion and relentless growth
Benign neoplasms: definition
neoplasms with localized, confined growth separate from the surrounding tissue and no preponderance for distance metastasis
Suffix -oma: when is it used
Used for benign tumors
Suffix -carcinoma: when is it used
Malignant tumors of epithelial origin
Suffix -sarcoma: when is it used
Malignant tumor of connective tissue origin
Type II Hypersensitivity- Effects of antibodies to cellular epitopes: overview
Cell death w/out inflammation (by opsonization & phagocytosis, & activation of the complement sequence)
Changes in cell function
Neutralization of block of hormones, enzymes, & cytokines
Activation of enzymes
Type II Hypersensitivity- Effects of antibody binding to basement membrane epitopes
Non-collagenous domain of alpha-3 chain of collagen IV –> activation of complement –> inflammation –> cell injury in kidney & lungs (called Goodpasture’s syndrome)
Type II Hypersensitivity- Effect of antibody binding to desmosomes
Formation of blisters –> condition called pemphigus vulgaris
Type II Hypersensitivity- Effect of antibodies to cell surface receptors
Antibodies to receptors cause changes in cell function
Ex: antibodies to TSH receptors –> stimulate thyroid cell function (Graves’ disease)
antibodies to ACh receptors: inhibit striated muscle function (myasthenia gravis)
Detection of circulating antibodies
In vitro:
ELISA (Enzyme linked immunosorbent assay)
Immunoblotting (Western blotting)
In vivo:
Agglutination of red cells (antihuman globulin test)
Direct immunofluorescence (DIF) of tissue biopsies- FITC-labeled antibodies to bind to human immunoglobulins and then look under fluorescence microscope
Type III Hypersensitivity: types of immune complexes
Circulating immune complexes, formed in the blood & then trapped in the tissues
In situ immune complexes, sequential binding of antigen, antibody & complement at the level of the basement membrane
Type II Hypersensitivity: formation of circulating immune complex
Form when there is specific antibody meets antigen & then binds complement
Normally removed from circulation by the reticuloendothelial system (circulating immune complexes contain C3b that bind to RBCs, travel to liver & spleen –> phagocytized; large complexes are more rapidly cleared than smaller ones
Type III Hypersensitivity: circulating immune complex persistence & deposition
Occurs during persistent infection, repeated inhalation of antigens, & autoimmune responses
Circulating immune complexes persist & are passively trapped in the kidneys & other tissues
Conditions that favor deposition:
Increased vascular permeability, sites of turbulence & high BP, affinity of antigen to particular sites, size of complexes, Ig class
Type III Hypersensitivity: in situ immune complexes
Formation occurs when an antibody specifically binds to soluble antigens (i.e. DNA) that have become localized within tissues b/c of their electrostatic change
Effect of immune complex on type of damage
Localization of immune complexes impacts the type of damage
Ex:
Immune complexes localized in mesangial or subendothelial sites in the kidney attract PMNs –> inflammation –> glomerulonephritis
Immune complexes localized in renal subepithelial sites cannot attract PMNs –> no inflammation –> membranous nephropathy w/ damage caused by MAC
Pathophysiology of immune complex-mediated cell injury
Explain by:
Serum sickness- circulating immune complexes –> bind complement (generate C3a & C5a) –> stimulation basophils to release vasoactive amines (histamine –> causes endothelial cell retraction & increase vascular permeability
Arthus reaction- animal is immunized w/ an antigen to obtain a specific antigen; once antibodies are in the circulation, same antigen is injected into skin –> specific antibodies bind to antigen –> localized inflammation
Hereditary Hemochromatosis
Most common in ppl of Western European descent
Mutations in the HFE gene –> low hepatic secretion of hepcidin –> elevated serum transferrin-iron saturation & high Fe levels
Treatment: iron depletion via phlebotomy
Dystrophic calcification
Accumulation occurs in injured or dying tissues (normal Ca levels & metabolism)
Ex: atherosclerotic plaques, aging/damaging heart valves
Metastatic calcification
Accumulation of Ca in normal tissue; levels of serum Ca are elevated b/c of alterations in Ca metabolism
Ex: Ca deposition in renal tubular BM
Asbestosis
Inhaled asbestos are captured by alveolar macrophages (may play important role in pathogenesis)
Asbestos fibers stimulate collagen production
Pathophysiology: pulmonary fibrosis –> dyspnea –> pulmonary hypertension –> R ventricular hypertrophy
Predisposes pts to bronchogenic adenocarcinoma & malignant mesothelioma
Wernicke-Korsakoff syndrome
Thiamine deficiency; absence of thiamine pyrophosphate decreases the ATP available to neurons
Leads to: memory deficits, ocular dysfunction, ataxia
Seen in pts w/ chronic alcoholism, poor diet, gastritis, old age
Occurs in alcholics that have a sudden infusion of glucose w/out thiamine pre-treatment
Cell injury caused by mercury
Causes disintegration of nerve cells, nerve fibers, & gliosis
Lead to coagulative necrosis of the proximal renal tubules
Hemorrhagic infarct
Seen in areas where there is dual circulation (brain, lung, liver, & GI tract); non-occuluded vessels still dumps blood into the tissue
Allergy: definition
Different or changed reactivity
Major pathogenesis of allergy
Allergen –> IgE antibodies –> mast cells –> mediator pathways
Pathway seen in allergic rhinitis, atopic dermatitis, asthma, allergic gastroenteropathy, anaphylaxis, & urticaria
Other pathogenesis of allergy
Immune complexes & T lymphocytes (mediate some disorders defined as allergic)
Atopic allergy
Inherited predisposition to allergic response
Usually develop early in life & characterized by high levels of IgE antibodies
Reactions are targeted to skin, eyes, URT, GI
In infancy, Atopic march (starts w/ atopic dermatitis –> 1/2 will develop asthma & 2/3 develop allergic rhinitis)
Genetics of atopic allergy
When both parents are allergic –> 50% chance of child developing allergy
Linked w/ certain HLA haplotypes (HLA-B8 & HLA-DR2) and/or FceRI-beta (linkage is characterized by maternal pattern)
Atopic dermatitis
Acute: often in children; presents w/ pruritic erythematous papules, excoriation, & serous exudate (mostly on face, scalp, & extensor surfaces)
Chronic: often in adults; presents w/ lichenification, papules & excoriations, dry lackluster skin
Allergic rhinitis/sinusitis
20% of the US population affected at some point in their life
Common symptoms: sneezing, rhinorrhea, pruritus & nasal obstruction
Seen often when there is a family history
Allergic conjunctivitis
Affects 25% of people
Characterized by conjunctival infiltration w/ inflammatory cells
Occurs when allergens cause degranulation of ocular mast cells –> local release of inflammatory mediators
Allergic bronchial asthma: etiology
Effects 155 million worldwide
Etiology: Animal proteins, insects, enzymes & plant proteins
Monoallergy
Differ from atopic disease b/c: lack genetic predisposition develop at any time in life characterized by response to a single allergen results in systemic effects
Examples: latex allergy –> Systemic anaphylaxis, urticaria, angioedema
Immune complex mediated allergic disease: example
Example: allergic bronchopulmonary aspergillosis (early phase)
Pathogenesis: Deposition of immune complexes of allergen + IgG or IgM complexes of allergen + IgG or IgM antibodies to the allergen + complement, with activation of the complement cascade and inflammation in the lung (early phase)
T cell mediated allergic disease: examples
Examples: allergic contact dermatitis, hypersensitivity pneumonitis
Etiology of allergic contact dermatitis: metals (nickel), dyes, various drugs, poison oak and poison ivy (urushiol)
Etiology of hypersensitivity pneumonitis (example: allergic bronchopulmonary aspergillosis, late phase): inhaled bacteria,fungi and animal products
Available allergy tests
Skin testing: patch test, intradermal injection
Total serum IgE levels: ELISA
Allergen-specific IgE antibody levels: Radioallergosorbent test
(RAST)
Allergen-specific IgG antibody levels: ELISA
Treatment of allergic disease
Anti-inflammatory/immunosuppressive agents
Hyposensitization therapy (Immunotherapy with recombinant allergens or derived synthetic peptides)
Anti-cytokine-directed therapies (Anti-TNF-a, anti-IFN-gamma,
etc.)
Anti-IgE (mAb, etc.)
Celiac disease: clinical features
Malabsorption of many nutrients –> diarrhea, streatorrhea, weight loss, & anemia
Biopsy: villus atrophy w/ chronic inflammatory infiltrates
Development of circulating autoantibodies to the enzyme transglutaminase 2
Celiac disease: pathogenesis
Innate autoimmune response:
gliadin toxic peptides –> secretion of IL15 –> upregulation of NKG2D by CD8+ cells; upregulation of MICA (stress-induced MHC I polypeptide-related molecule) –> direct epithelial damage
Adaptive autoimmune response:
Gluten peptides bind to DQ2 or DQ8 on APC –> gluten-reactive T cells controls formation of autoantibodies to TG2
There are also gluten-reactive CD4+ T cells –> increase IFN-gamma, IL21 –> mucosal damage
Causes of autoimmunity: exogeneous
PAMPS & DAMPS activate innate immune cells via specific receptors (TLR, dectins, NLRs, RLR) –> production of IL17A –> activate adaptive autoimmunity
X-linked immune dysregulation polyendocrinopathy & enteropathy syndrome (IPEX)
Mutations of FOXP3 resulting in nonfunctional CD4, CD25, T reg
Primary T cell immunodeficiency w/ autoimmune phenotype (enteropathy, DMI, thyroiditis, hemolytic anemia, thrombocytopenia Allergic phenotype: atopic dermatitis
Pemphigus vulgaris (PV): general characteristics
autoantibodies bind to skin epitopes –> cause damage by intracellular signaling pathways, skin cell cell apoptosis & detachment
Clincial features: acantholysis & blister formation in the skin & mucous membrane
Pemphigus vulgaris (PV):pathogenesis & diagnosis
Autoantibodies react w/ epitopes of desmogleins 3 & 1 (important mediators of squamous cell adhesion)
Dsg3 autoantibodies –> intracellular signaling pathways that lead to apoptosis & cell detachment
Diagnostic test: indirect & direct IF & ELISA
Systemic Lupus Erythematosus: general characteristics
Immune complexes deposited in tissues –> complement activation & acute inflammation ; occurs both in circulation & in situ
SLE: nuclear antigens
40-60% of pts have autoantibodies to dsDNA
20-30% of pts have autoautobodies against soluble RNA
SLE: immunohistopathology
Granular immune deposits in kidneys –> glomerulonephritis (mesangial, focal, proliferative, diffuse proliferative) or membranous glomerulopathy
Skin: Ig & complement at dermoepidermal junction
SLE: histopathology
Acute necrotizing vasculitis & small arteries & arterioles w. fibrinoid deposits
Perivascular fibrosis in the spleen
Hasimoto’s: general features
Damage caused by cellular mechanisms:
Cytotoxic T lymphocytes & cytokines (IFN-gamma, TNF-alpha, IL17)
Chronic inflammation & parenchymal damge of the thyroid
Thyroid goiter or nodules in some pts
There are circulating autoantibodies to thyroid peroxidase, thyroglobulin
Hasimoto’s: cellular mechanisms
CD4+(delayed) & CD8+(cytolysis) T lymphocytes
Production of cytokines –> inflammation and/or cell death
CD8+ kills cells directly
(Mechanism also occurs in MS, DMI)
Autoimmune disease
Pathologic conditions in which structural and/or functional damage is produced by an autoimmune response
Myasthenia gravis: epidemiology & signs/symptoms
15-30 (in females) & 60-75(in males)
S&S: weakness of striated muscle (extraocular, pharyngeal, arms, legs, & diaphragm)
Myasthenia gravis: pathogenesis
Autoantibodies to AChR block binding of ACh to receptors & decrease AChR –> effects of ACh inhibition
T lymphocytes play an important role; they are capable of reacting with epitopes of AChR
Rheumatoid Arthritis (RA): clinical features
Increased risk w/ HLA-DRB1
Chronic systemic inflammatory process in several joints, skin, blood vessels
Features: morning stiffness, involvement of hand joint, rheumatoid nodules, symmetric arthritis
Rheumatoid arthritis: histopathology
Joints: heave infiltration of CD4+ T cells, B cells, plasma cells, & macrophages in synovial stroma; vasodilation, angiogenesis, organized fibrin, osteoclastic activity, formation of pannus (synovium, inflammatory cells, & fibroblasts) over the cartilage
Skin: nodules (central fibrinoid necrosis surrounded by lymphocytes, plasma cells, & macrophages)
Blood vessels: vasculitis of medium/small arteries
Rheumatoid arthritis: pathogenesis
Abnormal amounts of serum rhematoid factors (RF: IgM autoantibodies to Fc portion of IgG)
Serum autoantibodies to citrullinated autoantigens (anti-CP: directed against self-proteins post-translationally modified by the enzymatic conversion of arginine to citrulline)
Increased productione of IL-17, IL6, IL1, TNFalpha
Sjögren’s syndrome
Chronic inflammatory process of salivary & lachrymal glands –>
sicca (dry eyes –> keratoconjunctivitis) & xerostomia (dry mouth)
Have antibodies to antigens of salivary & lachrymal glands; also have rheumatoid factors & antibodies to ribonucleoproteins (SS-A(Ro) in 70-95%, SS-B(La) 60-90%)
Primary Immunodificiency disease
Hereditary
Include: B cell immunodeficiencies, T cell immunodifiencies, Severe combined immunodificiencies (SCID)
Secondary immunodificiency disease
Acquired diease
Include: Acquired immunodeficiency syndrome (AIDS)
B cell immunodificiencies: examples
X-linked agammaglobulinemia
common variabel immunodeficiency
Isolated IgA deficiency
IgA deficiency
Most common primary immunodeficiency
Lack of serum & secretory IgA
Pts have recurrent sinopulmonary infections
Increased incidence of allergies & autoimmunce
T cell immunodeficiencies: examples
DiGeorge’s syndrome
Chronic mucocutaneous candidiasis
TCR-related defects
Cytokine deficiencies
Severe combined immunodeficiencies (SCID)
Most severe forms of primary immunodeficiencies
Characterized by lymphopenia & various defects in T & B cell functions
Ex: Alymphocytosis, X-linked SCID, Non-X-linked form of SCID, Adenosine desaminase deficiency
Wiskott-Aldrich syndrome
X linked mutations in the WASP gene (WASP protein involved in cytoskeleton-dependent responses important for platelets & T cells
Symptoms: recurrent sinopulmonary infections (IgM deficiency)
Eczema & thrombocytopenia
HLA Class II deficiency
Referred to as bare lymphocyte syndrome
Genetics: autosomal recessive
Defect in CIITA or RFX5, RFXB, or RFXAP
HLA Class I deficency
Referred to as bare lymphocyte syndrome
Genetics: autosomal recessive
Defect in TAP1 or TAP2
AIDS: transmission
Occurs through blood or semen from infected person
A person needs to be exposed to intact free virus or immune cells infected with the virus
Important receptors for HIV
CD4 (on T cells & monocytes/macrophages
CCR5 & CXCR4
Severe combined immunodeficiencies (SCID)
Most severe forms of primary immunodeficiencies
Characterized by lymphopenia & various defects in T & B cell functions
Ex: Alymphocytosis, X-linked SCID, Non-X-linked form of SCID, Adenosine desaminase deficiency
Wiskott-Aldrich syndrome
X linked mutations in the WASP gene (WASP protein involved in cytoskeleton-dependent responses important for platelets & T cells
Symptoms: recurrent sinopulmonary infections (IgM deficiency)
Eczema & thrombocytopenia
HLA Class II deficiency
Referred to as bare lymphocyte syndrome
Genetics: autosomal recessive
Defect in CIITA or RFX5, RFXB, or RFXAP
HLA Class I deficency
Referred to as bare lymphocyte syndrome
Genetics: autosomal recessive
Defect in TAP1 or TAP2
AIDS: transmission
Occurs through blood or semen from infected person
A person needs to be exposed to intact free virus or immune cells infected with the virus
CCR5
CCR5 is the most important co-receptor for infection of CD4+ T cells by HIV-1
Resistance to HIV-1 is associated with recessive mutations in the extracellular domain of CCR5 (32 base pair deletion in
CCR5 gene)
Individuals that are CCR5-D32 homozygous are resistant to HIV-1 (R5) but are more susceptible to West Nile virus infection
HIV infection & dissemination
HIV infections occur via mucosal surfaces (vagina, intestine and tonsil) or blood vessels
A high percentage of memory CD4+ T cells expressing CCR5 are present in mucosal immune effector sites, where the initial limited infections is amplified –> the infection then disseminates throughout the body
Target of HIV infection
CD4+ T cells
Antigen-presenting cells (APC): Functions as a reservoir for the virus or they may transmit the virus to T cells
HIV impacts on immune system
Decrease in number of CD4+ T cells:
their total count may drop to less than 100/microliter
(normal > 400/microliter)
Decreased T cell functions (in vivo and in vitro)
Polyclonal B cell activation
Altered macrophage functions
Pathological consequences of AIDS: Changes in lymphatic tissues
Most common presentations of HIV infection is enlargement of lymph nodes (persistent generalized lymphadenopathy)
Initially follicular hyperplasia and increased cellularity in the paracortical areas
At a later point, follicular dendritic cells begin to die and there is involution of the germinal center as a result of loss of dendritic cells and CD4+ T lymphocytes: “burned out” fibrotic node
Pathological consequences of AIDS: Widespread opportunistic infections
Mycobacterial disease (both M. avium and M. tuberculosis) Pneumocystis carinii pneumonia (PCP) Candidiasis Cytomegalovirus (CMV) infection Toxoplasmosis, histoplasmosis, cryptococcosis, etc.
Pathological consequences of AIDS: CNS lesions
Before HAART some develop HIV-associated dementia (HAD)
After HAART few patients develop HAD, but have a more subtle form of CNS dysfunction = minor cognitive motor disorder (MCMD)
More susceptible to: Meningitis, Encephalitis, Myelopathy, Neuropathy
Pathological consequences of AIDS: Kaposi sarcoma
Different forms: classic, endemic, iatrogenic and AIDS-associated
Its incidence in HIV-infected patients is steadily decreasing (from an initial 35-40% to less than 14% of reported cases)
Histopathology: vascular and lymphatic proliferation, spindle cell formation (KS cells) and mononuclear cell infiltration
It is NOT a sarcoma
Pathological consequences of AIDS: Lymphoid tumors
B-cell lymphomas: systemic, primary central nervous system and body cavity-based lymphomas
Increased incidence of squamous cell carcinomas of uterine cervix and rectum
Pathological consequences of AIDS: CNS cells
CNS perivascular macrophages and microglia express CD4 and CCR5, are HIV susceptible and capable of productive infection
Astrocytes, oligodendrocytes and neurons do not express CD4
Astrocytes express chemokine receptors and may be HIV susceptible
Multinucleated giant cells (a histopathologic hallmark of HIV encephalopathy): result from fusion of infected and non-infected perivascular macrophages and microglia
MNGCs contain HIV (as shown by immunostaining of HIV antigens)
Indirect pathway for allorecognition & rejection
MHC antigens are presented to host APCs
Generates CD4+ T cells –> enter graft & recognize graft antigens –> delayed hypersensitivity
Seen in more chronic rejection situations
Direct pathway for allorecognition & rejection
Recipient T cells recognize donor MHC molecules on donor dendritic cells –> initiate antigraft response
Dendritic cells express both MHC Class I & II –> both CD4+ & CD8+ become active –> tissue damage
Seen in more acute rejection situations
