General Pathology Flashcards Preview

MOD1 > General Pathology > Flashcards

Flashcards in General Pathology Deck (239):


Science and study of the causes of disease.The term identifies the causes of disease



The cellular and molecular mechanisms resulting in the development of a pathologic lesion.The term identifies the mechanisms of a disease process



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

Anaerobic glycolysis
Glucose uptake
Extracellular matrix turnover
pH control


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



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

Tissue necrosis
Foreign bodies
Immune Responses/Autoimmune



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



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

Inflammation that is spread throughout the tissue

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

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



Replaces damaged tissue w/ native tissue

Depends on the regenerative capacity of tissue (3 types)


Labile tissues

Continuously cycle to regenerate tissue

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

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

Skeletal muscle


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

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



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



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



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



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



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



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



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



Fluid w/ low specific gravity, low protein content

Characteristic of edema from heart failure or other conditions w/out changes in the capillary permeability



Fluid w/ high specific gravity, high protein content & many red & white cells

Characteristic of edema resulting from increased capillary permeability (as seen in inflammation)



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



Condition characterized by purple spotson the skin & mucosae, confluent petechiae & ecchymoses



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



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



Expressed in most cells
Housekeeping functions:
Gastric cytoprotection
Renal Function

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

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



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



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)



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

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



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



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
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,

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

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


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 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