General Pathology Flashcards

1
Q

Etiology

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Pathogenesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Pathophysiology

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Causes of cell injury

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Anoxia/hypoxia: possible mechanism

A

Mediated via hypoxia-inducible factorIf we could create an HIF analog –> decrease hypoxia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Hypoxia-inducible factor: important impacts

A
Angiogenesis 
Erythropoiesis 
Anaerobic glycolysis 
Glucose uptake
Extracellular matrix turnover
pH control 
Apoptosis
Mitogenesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Cell injury and free radicals

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Free radicals: what are they

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Free radicals: effects

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Variability of cell response to injury

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Consequences of trauma

A

Strong, acute, very persistent trauma –> irreversible cell injury
Less intense/temporary trauma –> reversible cell injury
Non-excessive trauma –> cell adaptation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Cell adaptation: hypertrophy

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Cell adaptation: Atrophy

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Cell adaptation: Hyperplasia

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Relationship of hyperplasia & hypertrophy

A

Cells adapt to trauma by increasing both number (hyperplasia) and size (hypertrophy) Examples: thyroid cells of Graves’ disease, bronchial smooth muscle cells in asthma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Cell adaptation: Metaplasia

A

One adult cell type is replaced by another adult cell type (–> patch of ectopic tissue) Mechanism: stem cells undergo reprogramming

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Types of metaplasia

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Reversible Cell Injury: Hydropic change

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Reversible Cell Injury: Fatty change

A

Infiltration of fat (mainly triglycerides) inside hepatocytes, usually exceeding 5% of liver weight:

Histology: empty white spaces where lipid droplet were in vivo

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Irreversible Cell injury: types

A

Apoptosis (cell death with shrinkage, activation-induced cell death, cell suicide, programmed cell death)

Necrosis (cell death with swelling, oncosis, accidental cell death)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Ultrastructural changes of reversible injury

A

Plasma membrane: blebbing, loss of microvilli…

Mitochondria: swelling, amorphous densities

Dilation of ER

Alterations to the nucleus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Apoptosis: definition

A

Programmed cell death mediated by a tightly controlled cell program

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Apoptosis: Fate of dead cells

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Physiological apoptosis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
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)
26
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
27
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
28
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
29
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
30
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
31
Morphologic changes during apoptosis
Cell shrinkage (cytoplasm becomes denser) Chromatin condensation Formation of cytoplasmic blebs & apoptotic bodies
32
Necrotic cells: morphology
Increase eosinophila Glassy, homogenous appearance Vacuolated cytoplasm Replacement of dead cells by myelin figures
33
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
34
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
35
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
36
Caseous necrosis
Friable white appearance Collection of fragmented or lysed cells; amorphous granular debris Histology: halos surrounding cells characteristic of granulomatous inflammation
37
Fat necrosis
Focal areas of fat destruction
38
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
39
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
40
Stimuli for acute inflammation
Infections Tissue necrosis Foreign bodies Immune Responses/Autoimmune
41
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)
42
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
43
Pyronecrosis
Caspase 1 independent cell death dependent on NLP3 & ASC --> formation of the inflammasome Ex: Shigella infected macrophages --> necrotic cell death
44
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
45
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
46
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)
47
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
48
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)
49
Leukocyte migration
Vasodilation slows the blood flow which allows for margination of cells to the periphery (specifically in the post-capillary venules)
50
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
51
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
52
Leukocytes transmigration & chemotaxis
Leukocytes transmigrate across endothelium toward chemical attractants (chemotaxis) Neutrophils attracted by bacterial products, IL8, C5a, & leukotriene B4
53
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)
54
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
55
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
56
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)
57
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
58
CD4+ T cell activation
Extracellular antigen is phagocytosed, processed, & presented via MHC II Second signal: B7 on APC binds CD28 on CD4+ T cells
59
Activated CD4+ helper T cells
Secretes cytokines that help inflammation | Two subsets; Th1 & Th2
60
Th1 subset
generates IL2 (T cell growth factor & CD8+ T cell activator & IFN-gamma (macrophage activator)
61
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) ```
62
CD8+ cytotoxic T cell activation
Intracellular antigen is processed & presented on MHCI Second cell: IL2 from CD4+ Th1 cells
63
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
64
B lymphocytes
Immature B cells are produced in bone marrow Undergo Ig rearrangement to become naive B cells that express IgM & IgD
65
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)
66
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
67
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)
68
Caseating granuloma
Characterized by central necrosis Seen in TB (AFB stain for diagnosis) & fungal infection (Silver stain for diagnosis)
69
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
70
Regeneration
Replaces damaged tissue w/ native tissue Depends on the regenerative capacity of tissue (3 types)
71
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)
72
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
73
Permanent tissue
Lack significant regenerative potential & therefore they tend to undergo repair Ex: Myocardium Skeletal muscle Neurons
74
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
75
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)
76
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
77
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)
78
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
79
Dehiscence
Rupture of the wound (most commonly seen in abdominal surgery)
80
Hypertrophic scar
Excess production of scar tissue that is localized to the wound Made up of collagen type I
81
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) ```
82
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
83
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)
84
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
85
Arterial thrombi: most common locations
commonly seen in the coronaries than in the cerebral followed by iliac & lastly femoral
86
Venous thrombi: common locations
Found in deep leg veins, mostly in the calf then femoral then popliteal & least common in iliac veins
87
Consequences of thrombosis
Embolism, ischemia, infarction (MI or stroke)
88
Thrombotic microangiopathy
Occlusive microvascular thrombosis resulting in ischemia Seen in thrombocytopenic purpura (severe deficiency of ADAMTS13 that normally cleaves vWF --> microthrombi in most organs
89
Disseminated intravascular coagulation
Activation of coagulation sequence --> formation of microthrombi throughout microcirculation Pathogenesis: release of high levels of TF
90
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
91
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
92
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
93
Ischemia
Lack of blood or insufficient flow of blood
94
Ischemia: variables controlling degree
Speed of onset Extent of arterial occlusion Existence and status of collateral circulation
95
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
96
Hyperemia
Characterized by excess of blood in a particular organ
97
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
98
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
99
Edema
Abnormal excessive accumulation of fluid within tissue spaces or serous cavities Can be either localized or generalized
100
Edema: etiology
Interfere w/ the normal movement of blood, tissue fluid, & lymph Disturb the mechanism of fluid balance or cause Na & water retention
101
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
102
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
103
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)
104
Hemorrhage
Characterized by extravasation of blood It is distinguished according to the origin of the bleeding & if it is internal or external
105
Petechiae hemorrhages
Small and punctate, spot-like (less than 2 mm)
106
Ecchymosis hemorrhage
Large, diffuse hemorrhagic area caused by trauma
107
Purpura
Condition characterized by purple spotson the skin & mucosae, confluent petechiae & ecchymoses
108
Hematoma
Discrete, localized bleeding in a tissue --> causing a swelling
109
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
110
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
111
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
112
NSAIDS
ASA & non-acetylated salicylates Non-selective inhibitors (naproxen) Cox2 inhibitors
113
Leukotriene Pathway Inhibitors: examples
Inhibition of 5-lipoxygenase | Leukotriene-receptor antagonist
114
Arachidonic acid
Arachidonic acid is esterified in the membrane phosholipids Can then enter cyclooxygenase pathway or lipoxygenase
115
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
116
Effects of TXA2 & PGI2
TXA2 (made in platelets): vasoconstrictor & promotes platelet aggregation --> BAD PGI2 (made in endothelial cells): vasodilation & inhibits platelet aggregation --> GOOD
117
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
118
COX1 in Kidney
Important auto-regulatory role in renal function PGE2 & PGI2 dilate afferent artery Increase Na & H2O excretion
119
Uses of NSAIDS
``` Anti-inflammation Pain Fever Closure of the ductus arteriosus Low-dose for cardioprotection ```
120
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
121
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
122
Clinical uses of low dose Aspirin
Primary & secondary prevention of MI Unstable angina TIA & strokes
123
Toxicity of aspirin
``` Anion gap metabolic acidosis Primary respiratory alkalosis Tinnitus/hearing loss Adult respiratory distress syndrome Decreased mental status ```
124
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
125
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
126
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
127
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
128
Prevention of NSAID GI toxicity
High risk either avoid or consider COX2 inhibitor also can be on chronic PPI Eradicate H pylori if diagnosed
129
Leukotrienes
Arachidonic acid can make leukotrienes via lipoxygenase
130
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
131
Leukotriene pathway inhibitors
Inhibition of 5-lipoxygenase (Zileuton) Leukotriene-receptor antagonist (Zafirlukast, Montelukast)
132
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
133
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
134
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
135
Non-alcoholic fatty liver: mechanism
No history of alcohol consumption Associated w/ obese, DMII, hyperTAG Most common cause of liver disease in Western countries
136
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
137
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
138
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)
139
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)
140
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)
141
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
142
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
143
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.
144
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
145
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
146
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
147
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)
148
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)
149
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)
150
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.
151
Mediators from basophils
Preformed: histamine, proteases, cytokines, etc. Produced lipid mediators: LTC4 Cytokines: IL-4, IL-13, BAFF, APRIL, (IL-1b, TNF-a)
152
IgE-mast cell-mediator pathway: protective effects
Unclear but may be useful in the defense against parasitic worms & ticks
153
IgE-mast cell-mediator pathway: destructive effects
very common, are seen in a variety of allergic diseases
154
Neoplasia: definition
Purposeless, Excessive, Autonomous Growth of Abnormally Formed Tissues.
155
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.
156
Malignant neoplasms: definition
Neoplasms capable of distant metastasis, local invasion and relentless growth
157
Benign neoplasms: definition
neoplasms with localized, confined growth separate from the surrounding tissue and no preponderance for distance metastasis
158
Suffix -oma: when is it used
Used for benign tumors
159
Suffix -carcinoma: when is it used
Malignant tumors of epithelial origin
160
Suffix -sarcoma: when is it used
Malignant tumor of connective tissue origin
161
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
162
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)
163
Type II Hypersensitivity- Effect of antibody binding to desmosomes
Formation of blisters --> condition called pemphigus vulgaris
164
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)
165
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
166
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
167
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
168
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
169
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
170
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
171
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
172
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
173
Dystrophic calcification
Accumulation occurs in injured or dying tissues (normal Ca levels & metabolism) Ex: atherosclerotic plaques, aging/damaging heart valves
174
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
175
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
176
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
177
Cell injury caused by mercury
Causes disintegration of nerve cells, nerve fibers, & gliosis Lead to coagulative necrosis of the proximal renal tubules
178
Hemorrhagic infarct
Seen in areas where there is dual circulation (brain, lung, liver, & GI tract); non-occuluded vessels still dumps blood into the tissue
179
Allergy: definition
Different or changed reactivity
180
Major pathogenesis of allergy
Allergen --> IgE antibodies --> mast cells --> mediator pathways Pathway seen in allergic rhinitis, atopic dermatitis, asthma, allergic gastroenteropathy, anaphylaxis, & urticaria
181
Other pathogenesis of allergy
Immune complexes & T lymphocytes (mediate some disorders defined as allergic)
182
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)
183
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)
184
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
185
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
186
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
187
Allergic bronchial asthma: etiology
Effects 155 million worldwide Etiology: Animal proteins, insects, enzymes & plant proteins
188
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
189
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)
190
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
191
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
192
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.)
193
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
194
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
195
Causes of autoimmunity: exogeneous
PAMPS & DAMPS activate innate immune cells via specific receptors (TLR, dectins, NLRs, RLR) --> production of IL17A --> activate adaptive autoimmunity
196
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 ```
197
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
198
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
199
Systemic Lupus Erythematosus: general characteristics
Immune complexes deposited in tissues --> complement activation & acute inflammation ; occurs both in circulation & in situ
200
SLE: nuclear antigens
40-60% of pts have autoantibodies to dsDNA | 20-30% of pts have autoautobodies against soluble RNA
201
SLE: immunohistopathology
Granular immune deposits in kidneys --> glomerulonephritis (mesangial, focal, proliferative, diffuse proliferative) or membranous glomerulopathy Skin: Ig & complement at dermoepidermal junction
202
SLE: histopathology
Acute necrotizing vasculitis & small arteries & arterioles w. fibrinoid deposits Perivascular fibrosis in the spleen
203
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
204
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)
205
Autoimmune disease
Pathologic conditions in which structural and/or functional damage is produced by an autoimmune response
206
Myasthenia gravis: epidemiology & signs/symptoms
15-30 (in females) & 60-75(in males) S&S: weakness of striated muscle (extraocular, pharyngeal, arms, legs, & diaphragm)
207
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
208
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
209
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
210
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
211
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%)
212
Primary Immunodificiency disease
Hereditary | Include: B cell immunodeficiencies, T cell immunodifiencies, Severe combined immunodificiencies (SCID)
213
Secondary immunodificiency disease
Acquired diease | Include: Acquired immunodeficiency syndrome (AIDS)
214
B cell immunodificiencies: examples
X-linked agammaglobulinemia common variabel immunodeficiency Isolated IgA deficiency
215
IgA deficiency
Most common primary immunodeficiency Lack of serum & secretory IgA Pts have recurrent sinopulmonary infections Increased incidence of allergies & autoimmunce
216
T cell immunodeficiencies: examples
DiGeorge's syndrome Chronic mucocutaneous candidiasis TCR-related defects Cytokine deficiencies
217
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
218
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
219
HLA Class II deficiency
Referred to as bare lymphocyte syndrome Genetics: autosomal recessive Defect in CIITA or RFX5, RFXB, or RFXAP
220
HLA Class I deficency
Referred to as bare lymphocyte syndrome Genetics: autosomal recessive Defect in TAP1 or TAP2
221
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
222
Important receptors for HIV
CD4 (on T cells & monocytes/macrophages | CCR5 & CXCR4
223
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
224
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
225
HLA Class II deficiency
Referred to as bare lymphocyte syndrome Genetics: autosomal recessive Defect in CIITA or RFX5, RFXB, or RFXAP
226
HLA Class I deficency
Referred to as bare lymphocyte syndrome Genetics: autosomal recessive Defect in TAP1 or TAP2
227
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
228
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
229
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
230
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
231
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
232
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
233
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. ```
234
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
235
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
236
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
237
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)
238
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
239
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