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Robbins General AP
Notes from reading big robbins
88
Pathology
Post-Graduate
08/01/2011

Additional Pathology Flashcards

 


 

Cards

Term

CH 1 CHEMICAL INJURY

Effect on cell to induce injury:

Mercuric chloride

 

Cyanide

 

Carbon tetrachloride (CCl4)

Definition

Mercury: binds sulfhydryl groups of cell membrane and other proteins, increases membrane permeability, and inhibits ATPase-dependent transport.  Particularly GI tract, kidney

 

Cyanide: effects mitochondrial cytochrome oxidase and blocks oxidative phosphorylation

 

CCl4 (and many other chemicals): conversion by cytochrome P-450 to highly reactive toxic free radicals.  Produce auto-oxidation of polyenic fatty acids in membranes (leads to rapid severe fatty liver)

Term

 CH 1 REVERSIBLE CELL INJURY

Two patterns of reversible cell injury

 

the four main ultrastructural changes in reversible cell injury

Definition

(1) Cellular swelling- incapable of ionic and fluid homeostasis, also called hydropic change

(2) fatty change- due to hypoxic or toxic damage

 

Ultrastructural: (a) plasma membrane alterations- blebbing, blunting, distortion of microvilli, myelin figures, loosening of intercellular attachments; (b) mitochondrial changes- swelling, rarefaction, amorphous densities; (c) dilation of endoplasmic reticulum- detachment and disaggregation of polysomes; (d) nuclear alterations- disaggregation of granular and fibrillar elements

Term

 CH 1 APOPTOSIS

 

Biochemical features

Definition

(1) Protein cleavage- protein hydrolysis, by a family of cysteine proteases= caspases; predominantly responsible for cleavage of nuclear scaffold and cytoskeletal proteins

(2) Protein cross-linking- increased transglutaminase activation- covalently links proteins leading to shells that break into apoptotic bodies

(3) DNA breakdown- into large 50 -300kB  pieces (by large DNAses), then further internucleosomal cleavage into 180-200 bp frags by endonucleases

(4) Phagocytic recognition- express phosphatidylserine on outer plasma membranes (and sometimes thrombospondin), signal adjacent cells to recognize as dead.

Term

CH 1 APOPTOSIS- Mechanisms

 

The four components of apoptosis and specific examples

Definition

(1) Signaling pathways- a. transmembrane (hormones, growth factors and cytokines)- either positive or negative signals.  Most important= activator of apoptosis, thru plasma membrane receptors of the TNF-R superfamily.  b. intracellular- ir glucocorticoids binding to nuclear receptors; or physiochemical agents (ie heat, radiation, viruses)

 

(2) Control and Integration- proteins that connect death signals to execution mechanisms and either allow or abort the death signal.  Thru 2 pathways: (a) adapter proteins- Fas-Fas ligand; (b) regulating mitochondrial function- thru Bcl2 family of proteins

 

(3) Execution phase- the final proteolytic cascade, from which several signaling and regulatory mechanisms converge.  Highly conserved across several species, proteases - of the caspase family (unique ability to cleave after aspartic acid residues).  Exist as zymogens and must undergo proteolytic cleavage for activation  which sets off a cascade of initiator and execution caspases

 

(4) removal of dead cells- thru specific apoptotic markers on the cell fragments, adjacent cells or phagocytes will remove the fragments.

Term

CH 1 APOPTOSIS

 

Bcl2 and mitochondrial function

Definition

Apoptotic events affect mitochondria in two ways:

(1) increased mitochondrial membrane permeability leads to swelling

 

(2) increased permeability of the outer membrane leaks an apoptotic trigger molecule- cytochrome c (which normally resides between the outer and inner mitochondrial membranes).  

 

the most important proteins responsible for increased mitochondrial membrane permeability are of the Bcl2 family (the mammalian homolog of the anti-apoptotic ced-9.  And other members of the Bcl2 family regulate the activity of Bcl2.  thus mitochondrial permeability is determined by ratio of pro-apoptotic (e.g. Bax, Bad) and anti-apoptotic (e.g. Bcl-XL) members of the Bcl2 family

 

Bcl2 can also inhibit apoptosis by binding other proteins and sequestering them.  Most notable is the pro-apoptotic protease activating factor (Apaf-1).

 

When released, Apaf-1 binds with cytochrome c, gets activated and initiated the caspase cascade.

Term

 CH 1 APOPTOSIS- Specific examples

 

TNF-R signaling

Definition

Two methods of cell death:

(1) Fas-Fas ligand mediated apoptosis- cell surface receptor, Fas (CD95) on T cells binds to either membrane bound or soluble Fas ligand (FasL or CD95L) produced by immune cells.  Important for elimination of activated lymphocytes, and limiting host response

 

(2) TNF-induced: TNF-R binds cytokine TNF, and induces apoptosis thru the adapter protein TRADD (TNFR-adapter protein with a death domain)--> binds to FADD (like in Fas-Fas ligand method) and initiates caspases.

Term

CH 1 APOPTOSIS- specific examples

 

Cytotoxic T-lymphocyte stimulated apoptosis

Definition

thru 2 methods:

(1) Foreign antigens presented on infected host cells, express Fas ligand and kill target cells by Fas-Fas Ligand method

 

(2) secretion of perforin- a transmembrane pore-forming molecule and release of cytotoxic granules into target cells- most importantly granzyme B- can directly activate caspases

Term

CH 1 APOPTOSIS- specific examples

 

Apoptosis after growth factor deprivation

 

DNA-damage mediated

Definition

(1) main example of death after growth factor deprivation- neurons require nerve growth factors for support.  withdrawal--> pro-apoptotic proteins of the Bcl2 family binds to Bcl2 and increases mitochondrial membrane permeability

 

(2) genotoxic stress, as seen in radiation or chemotherapeutic agents.  thru accumulation of p53- which will stimulate apoptosis if repair of damaged DNA does not occur

Term

CH 1 SUBCELLULAR RESPONSES TO CELL INJURY

 

(1) Lysosomes

 

(2) Smooth Endoplasmic Reticulum

 

(3) Mitochondria

 

(4) Cytoskeletal 

Definition

(1) lysosomes- though most proteins and carbs can be digested by lysosomal enzymes easily, some lipids remain undigested- which may then be either extruded from the cell or remain in the cell as residual bodies, ie. lipofuscin pigment is undigested material from lipid peroxidation (other materials that cannot be digested such as certain inhaled carbon particles or tattoo pigment will remain in the same residual bodies)

- also in hereditary lysosomal storage disorders- will result in abnormal accumulation of macromolecules when the lysosome is deficient in a particular enzyme

-and some drugs effect lysosomes- ie chloroquine (antimalarial)- increases pH and inactivates the lysosomal enzymes; and amiodarone (antiarrhythmic) binds phospholipids and prevents breakdown.

 

(2) Hypertrophy of the SER- most notably of hepatocytes in response to drugs (ie Barbiturates)- which are metabolized by the P-450 system.  increasing amounts of the drug leads to synthesis of more enzyme and more SER.

 

(3) Mitochondrial- megamitochondria (large and abnormal shapes) seen in alcoholic liver disease.  inherited metabolic diseases of skeletal muscle (mitochondrial myopathies)- have increased numbers of large mitochondria with abnormal christae and crystalloids.  certain tumors- oncocytomas (salivary gland, thyroid, parathyroid and kidneys)- cells with abundant large mitochondria

 

(4) Cytoskeleton- (a) thin filaments- cytochalasin B- prevents polymerization of actin filaments (req'd for functioning thin filaments); phalloidin (the toxin in the Amanita phalloides mushroom also binds actin filaments.  (b) Microtubules- defects lead to male sterility due to lack of sperm motility; and can immobilize cilia of the respiratory tract. Drugs effecting- colchicine (used to treat gout) bind tubulin to prevent the immune response (as microtubules are very important for leukocyte migration and phagocytosis).  And drugs targeting microtubules can be antineoplastic/antiproliferative as microtubules are important for mitotis spindle formation.  (c) Intermediate filaments- accumulation of intermediate filaments leads to cytoplasmic inclusions: ie mallory body/hyalin in alcoholic liver disease (composed of keratin filaments); neurofibrillary tangles- accumulations of neurofilaments in alzheimer's disease

Term

CH 2 INTRACELLULAR ACCUMULATIONS

Lipids

 

Steatosis (fatty change):

major organs, most common cause in industrialized nations, what is accumulated, reasons, reversible/irreversible?, morphology

Definition

fatty change is abnormal accumulation of triglycerides, most often in the liver, but also heart, muscle and kidney;most common cause in industrialized nations = ALCOHOL abuse (but may also be d/t other toxins, protein malnutrition, diabetes mellitus, obesity and anoxia.  In normal liver, free fatty acids are esterified into triglycerides which are then converted to cholesterol or phospholipids, or ketone bodies.  To release triglycerides from hepatocytes, req's association with apoproteins to form lipoproteins (defects in any of these stages can lead to accumulation of triglycerides in the tissues.   Alcohol- alters mitochondrial and microsomal fxn; CCl4 and protein malnutrition- decrease synthesis of apoproteins; anoxia- inhibits fatty acid oxidation; starvation- increases fatty acid mobilization from periphery.  Overall, steatosis is reversible (unless some vital cellular process is impaired).

Morphology- liver- begins as small liposomes (membrane-bound) closely assoc w/ endoplasmic reticulum, which coalesce to cytoplasmic vacuoles which eventually displace the nucleus peripherally.  heart- (1) prolonged moderate hypoxia (ie anemia) bands of yellow myocardium alternating with normal (tigered effect) vs (2) profound hypoxia or myocarditis- uniformly effect myocardium

Term

CH 2 INTRACELLULAR ACCUMULATIONS

Proteins

 

Examples (two types); defects in protein folding- 2 mechanisms of accumulation

Definition

Excesses due to decreased capacity to metabolize proteins or intermediates

Ex- (1) Reabsorption droplets in proximal renal tubules; (2) excess synthesis of normal secretory protein (eg plasma cells creating Ig's--> ER distended producing Russell body inclusions.

 

Defects in protein folding slow the process of transport thru the cell and lead to accumulation: 2 mechanisms of disease- (a) defective intracellular transport and secretion of critical proteins- ie a1-antitrypsin deficiency--> abnormal protein folding d/t mutation leads to decreased levels of circulating protein and causes disease (emphysema); or CF- chloride channel.  (b) Toxicity of aggregated abnormally folded proteins- most commonly a/w the neurodegenerative disease (Huntington's, Parkinson's, Alzheimers).

Term

CH 2 INTRACELLULAR ACCUMULATION

 

Pigments (endogenous)- their formation

Definition

(1) Lipofuscin: from lipid peroxidation of polyunsaturated lipids of subcellular membranes.  indicates free radical injury

 

(2) melanin- tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine

 

(3) Hemosiderin- hemoglobin-derived, how iron is stored in cells.  In cells, iron is stored in association wit apoferritin as ferritin micelles.  With local (ie bruises) or systemic (ie hemosiderosis) excess of iron is stored as hemosiderin.  varying shades of a bruise due to progressive transformation of hemoglobin: biliverdin (green-blue)--> bilirubin (red) --> hemosiderin (golden-yellow)

Term

CH 2 CALCIFICATION

 

matrix proteins req'd for normal bone calcification (and possibly lead to dystrophic Ca2+)

Definition

(1) osteopontin- high affinity for hydroapatite, which is abundant in foci of dystrophic Ca2+

 

(2) osteonectin- aka SPARC, binds minerals and inhibits cell migration in angiogenesis

 

(3) osteocalcin

 

(4) GLA-containing proteins (gamma-carboxyglutamic acid)- req's Vit K to form, binds tightly to minerals needed for bone formation

Term

CH 2 CALCIFICATIONS

 

Metastatic calcification- the four main causes; the principal tissues involved and why

Definition

Four main causes: (1) increased PTH- hyperparathyroidism d/t parathyroid tumors or ectopic secretion by malignant tumors--> bone resporption

 

(2) destruction of bone tissue- primary bone tumors- myeloma, leukemia; or metastases- breast, etc; or accelerated bone turnover- Paget's disease; or d/t immobilization

 

(3) Vit D related d/o's: Vit D intoxication, sarcoidosis (which activated a Vit D precursor in macrophages); or idiopathic hypercalcemia of infancy (Williams syndrome)- d/t abnormal sensitivity to Vit D.

 

(4) renal failure- retention of phosphate leads to secondary hyperparathyroidism

 

Principally effects- gastric mucosa, kidneys, lungs, systemic arteries and pulmonary veins- as all of these tissues lose acid creating an internal alkaline environment.

Term

CH 3 ACUTE INFLAMMATION

 

terms: exudate

vs

transudate

Definition

Exudate- extravascular fluid with high protein content, much cellular debris and specific grav >1.020.  implies abnormal endothelial permeability

 

transudate- fluid with low protein content (mostly albumin) and specific grav <1.012.  essentially an ultrafiltrate plasma and results from hydrostatic pressure imbalance.  the endothelial permeability is still normal.

Term

CH 3 LEUKOCYTE ADHESION/MIGRATION

Major endothelial cell adhesion molecules, endothelial:leukocyte pairs, how the molecules induce and propagate inflammation

Definition

(1) Selectins: bind to sialylated Lewis X which is covalently bound to mucin-like glycoproteins on leukocytes. Ex- P-selectin, E-selectin, L-selectin

Responsible for rolling (P-selectin) with some function in adhesion to activated endothelium (E-selectin)

 

(2) Immunoglobin family- ICAM-1 and VCAM-1: ICAM-1 binds β-integrins (LFA-1= CD11a/CD18; and MAC-1= CD11b/CD18), predom fxn- adhesion, arrest and transmigration.  VCAM-1 binds α4β1 and α4β7 integrins, fxn- adhesions (eos, monos, lymphs)

 

(3) the integrins (as mentioned above) are on the leukocytes and bind the endothelial adhesion molecules.

 

mechanisms of adhesion molecule activation: (a) redistribution to the cell surface= P-selectin is contained within Weibel-Palade bodies which are brought the surface in response to histamine, thrombin, plt-activating factor, etc. (within min);  (b) induction of adhesion molecules synthesis- IL-1 and TNF can induce protein synthesis of more adhesion moleules, usually delayed 1-2 hrs.  Ex- E-selectin, is not present on normal endothelium; also ICAM-1 and VCAM-1;  (c)  increased avidity of binding-  ex, LFA-1 is always present on leukocytes, but will not bind it's counterpart ICAM-1 - until chemotactic agents cause conformational change in the integrin molecule for which it will bind, increasing avidity/affinity.

Term

CH 3 PHAGOCYTOSIS

Opsonization of particles- the major opsonins, and their receptors

 

*nonopsonic phagocytosis

Definition

microorganisms are not recognized by phagocytes until they are coated by naturally occurring factors (=opsonins), which are part of innate immunity

 

Major opsonins: (1) Fc fragment of IgG, as part of a naturally occurring Ab to the particle- binds FcγR. (2) C3b (=opsonic fragment of C3), and stable form C3bi, generated by complement cascade- binds to complement receptors 1, 2, 3 (CR 1, 2, 3). and (3) collectins= lectin, carbohydrate binding proteins bind to microbial cell walls, and the receptor is C1q-Receptor

 

*nonopsonic phagocytosis- CR3 binds the opsonin C3bi.  CR3 is identical to CD11b (β2-integrin-Mac-1)- and can bind lipopolysaccharides on bacteria and lead to phagocytosis without intervention of Ab or complement.

Term

CH 3 PHAGOCYTOSIS

 

Killing mechanisms 

Definition

bacterial killing is largely accomplished by reactive oxygen species

 

the phagocyte NADPH oxidase complex- creates superoxide and then H2O2.  However, the quantities of H2O2 produced in the phagolysosome are insufficient to effectively kill bacteria.

 

The most efficient bactericidal system, is in neutorphils, is the H2O2-MPO-halide system: MPO in the presence of a halide (ie Cl-) converts H2O2 to HOCl, which effectively kills bacteria by halogenation (also effective against fungi, parasites, viruses)

 

Other leukocytes lacking MPO- can kill bacteria (slower, of course), using supoeroxide, hydroxyl radicals and singlet-oxygen

Term

CH 3 ACUTE INFLAMMATION

 

Defects in leukocyte function genetic diseases

Definition

(1) Leukocyte adhesion deficiency-1: defect= β2-integrin (β chain of CD11/CD18) --> abnormal adhesion, spreading phagocytosis and oxidation burst generation

 

(2) Leukocyte adhesion deficiency-2: defect= sialylated Lewis X (receptor for selectin), the defect is attributed to mutations in fucosyl transferase

 

(3) Chediak-Higashi syndrome- autosomal recessive, d/t defect in membrane-associated protein involved in organelle membrane docking and fusion--> neutropenia, defective granulation, and delayed killing.  the disease is also a/w- albinism, nerve defects, and bleeding disorders

 

(4) Chronic granulomatous disease: leads to decreased oxidative burst, due to defect in NADPH oxidase complex (a) X-linked- defect in membrane component; (b) autosomal recessive- cytoplasmic components

 

(5) Myeloperoxidase deficiency- absent MPO-H2O2-halide system --> delayed killing

Term

CH 3 INFLAMMATION MEDIATORS

 

Vasoactive amines

Definition

(1) Histamine: widely in tissues, but MOST is within granules of mast cells, usually present in CT adjacent to blood vessels (also in basophils and platelets

-released in response to: physical injury (heat, cold, trauma); Abs binding mast cells; anaphylatoxins (frags of complement)= C3a and C5a; histamine-releasing proteins in WBCs; substance P (and other neuropeptides); and cytokines (IL-1, IL-8)

- Causes dilation of arterioles and increased vascular permeability (via H1 receptors on microvasculature). and constricts large arteries

 

(2) Serotonin: (5-hydroxytryptamine)- also preformed, stored in platelets (as well as enterochromaffin cells).  Release is stimulated when platelets aggregate.  Results in increased in permeability

Term

CH 3 INFLAMMATION MEDIATORS

 

Complement 

(1) classic pathway

 

(2) alternative pathway

Definition

classic pathway: 

C1-activated by Ag-Ab complex (IgG or IgM)-->C1 act--> with C4 + C2 to create C4b2a (=C3 convertase) which can cleave C3 to C3a and forms C4b2a3b (=C5 convertase) which can cleave C5 to C5a. C3a and C5a- are major inflammatory mediators (which can also be generated by plasmin or lysosomal proteases)

 

Alternative pathway:  C3 ---> C3b ---with factor B and factor D--> C3bBb (=alternative pathway C3 convertase, stabilized by properdin)- which can convert C3 to C3b ---with more C3b--> creates C3bBb3b (=alternative pathway C5 convertase)- which cleaves C5 -->C5b


C5b with C6,7,8,9 (C5-9) form the membrane attack complex

 

[image]

 

 

 

Term

CH3 CHEMICAL MEDIATORS

 

Complement regulators/inhibitors

Definition

Regulators/inhibitors:  

-DAF (decay-accelerating factor)- enhances dissociation of C3 and C5 convertases;

- factor 1- proteolytic cleavage of C3b;

-C1INH (C1 inhibitor)- binds C1 and blocks immune complex binding;

-CD59 (membrane inhibitor of reactive lysis)- blocks MAC formation

 

--deficiency of C1INH= syndrome of hereditary angioneurotic edema - episodic edema in the skin and extremities, laryngeal and intestinal mucosa provoked by emotional stress or trauma

Term

CH 3 CHEMICAL MEDIATORS

 

Complement- biologic functions

Definition

biologic functions: 

(1) vascular functions- C3a, C5a (and sometimes C4a) are anaphylatoxins that increase vascular permeability and vasodilation, predominantly by releasing histamine from mast cells.  

-C5a also activates lipoxygenase pathway of arachidonic acid.

 

(2) WBC adhesion, chemotaxis and activation- C5a powerful chemotactic for neuts, monos, eos and basos

 

(3) phagocytosis- C3b and C3bi, act as opsonins and fix to bacterial wall for phagocytosis

 

Term

CH 3 CHEMICAL MEDIATORS

 

Kinin system-

major players and cascade

 

major function

 

inactivation of the system

Definition

cascade starts with Hageman factor (=fXII from clotting cascade (with exposed collagen, basement membrane and activated plts) + the cofactor- HMWK (high molecular weight kininogen)--> fXIIa (which acts on both the kinin and clotting cascade):

 

- XIIa converts prekallikrein --> kallikrein

---kallikrein: converts HMWK --> bradykinin


-Bradykinin: vasoactive peptide, potent, increases vascular permeability; also causes contraction of smooth muscle, dilation of blood vessels (and pain when injected in the skin)

 

-Kallikrein- is a potent activator of fXIIa (Hageman factor) itself, thus acts as a potent auto-amplification of the initial stimulus.  kallikrein also can directly cleave C5--> C5a, promoting chemotactic activity.  AND converts plasminogen to plasmin--> which degrades fibrin (fibrinolytic system)--> forming fibrin degradation products (fibrin split products)

 

-bradykinin activity is short-lived- quickly inactivated by kininase.  Any remaining bradykinin  in the circulation- is inactivated by ACE (angiotensin converting enzyme) in the lung

Term

CH 3 CHEMICAL MEDIATORS

 

Cytokines- 5 classes by activity and examples

Definition

(1) regulate lymphocyte function:  activation, growth and differentiation, IL-2, IL-4- favor lymphocyte growth; IL-10, TGF-β- negative regulators

 

(2) natural immunity: inflammatory cytokines, TNF-α and IL-1β; (and type I interferons- IFN-α and β; and IL-6

 

(3) activate inflammatory cells: activate macrophages in cell-mediated immunity, IFN-γ, TNF-α, TNF-β, IL-5, IL-10, IL-12

 

(4) Chemokines: chemotactic activity

 

(5) stimulate hematopoiesis- WBC growth and differentiation, IL-3, IL-7, c-kit, GM-CSF, G-CSF, M-CSF, and stem cell factor

 

 

Term

CH 3 CHEMICAL MEDIATORS

 

The two MAJOR inflammatory cytokines and all their activities

Definition

TNF-α and IL-1

 

(A) stimulate/initiate production of acute phase reactants--> fever, ↑sleep, ↓appetite, ↑APRs, hemodynamic shock (hypotension, ↑vascular resistance, ↑HR, and ↓pH); and neutrophilia

 

(B) Endothelial effects- leukocyte adherence, PGI (prostaglandin) synthesis, procoagulant, ↓anticoagulation, ↑IL-1,IL-8,IL-6,PDGF

 

(C) Fibroblast effects- ↑ proliferation, collagen synthesis, collagenase, protease, PGE synthesis

 

(D) Leukocyte effects- ↑ cytokine secretion, Priming

Term

CH 3 CHEMICAL MEDIATORS

 

Nitric Oxide-

main action, other actions, three types and expression

Definition

Main action of NO= relaxation of smooth muscle--> vascular dilation

 

acts in paracrine manor as it only last a few seconds; induces c-GMP

 

Other actions: reduces plt aggregation, inhibits mast-cell activities, regulates WBC recruitment.  Also possess antimicrobial activity (killing by reactive species).

 

Three types of synthesizing proteins: endothelial (eNOS), neuronal (nNOS) and cytokine inducible (iNOS).  eNOS and nNOS are constitutively active and activity can be rapidly increased by increasing cytoplasmic Ca2+.  iNOS is induced by activation of macrophages (esp by TNF-α and IFN-γ)

 

Term

CH 3 CHEMICAL MEDIATORS

 

Neutrophil granules

 

types, major actors in each and difference in mobilization

Definition

Specific (secondary) and azurophilic (primary) granules

 

Specific- lysozyme, collagenase, (also gelatinase, lactoferrin, plasminogen activator, histaminase, alk phos)

Azurophil- MPO, lysozyme, defensins, acid and neutral hydrolases, proteases

 

Specific- more likely to be excreted extracellularly

 

Azurophil- released into phagosomes, usually more destructive than secondary.

Term

CH 3 CHEMICAL MEDIATORS

 

α1-antitrypsin and a1AT deficiency

Definition

a1AT is the major inhibitor of neutrophilic elastase, thus deficiency leads to sustained action of elastase and other proteases

 

--leading to destruction of elasticity of the lung, causing the typical lung disease

Term

CH 4 CELLULAR GROWTH

 

3 major classes of cell surface receptors involved in signal transduction of cell growth

Definition

(1) Receptors with intrinsic kinase activity- extracellular , single transmembrane and a cytosolic domain - which usually has tyrosine-kinase (or less commonly serine/threonine) activity; usually the growth factor (ie EGF, FGF, PDGF), which have two receptor binding domains, and will bind two receptors--> dimerization.  The dimerization of the receptors leads to autophosphoylation, which creates binding site for cytolic signal protein (of the src homology 2 (SH2) family.  Examples of signal pathways- ras, PI-3-kinase, phopholipase C-γ (protein kinase C pathway), src tyrosine kinase family.

 

(2) Receptors without intrinsic catalytic activity- extracellular, single transmembrane and cytosolic domain- which associates with other cytosolic protein tyrosine kinases which phosphorylate the receptor.  Exs- most receptors in this category are of cytokines

 

(3) G-protein linked receptors- seven transmembrane loops; ligand binding activates signal transducing G protein complex which activates the efector system.  Exs- chemokines, as well as epinephrine and glucagon hormones 

Term

CH 4 CELLULAR SIGNALS

 

the 5 main signal transduction pathways in cell growth 

Definition

(1) Mitogen-Activated Protein (MAP) kinase pathway: thru receptor tyrosine kinase in autophosphorylation--> activation of Ras protein.  Ras is a GTPase, with GDP=inactive form-->GTP=active->which initiates a cascade of other kinases--> eventually leading to changes in gene expression (usually a/w increased cell proliferation). [thus, cancers with Ras mutations, have constitutive activity].  Overall, this pathway leads to stimulate quienscent cells (G0) to enter cell growth

 

(2) Phospholinositide-3-Kinase (PI-3-kinase): usual signals are a/w with cell survival; ie phosphorylation of glycogen synthase kinase 3 and ↑glycogen synthesis

 

(3) inositol lipid (IP3) pathway: activation of phospholipase Cγ; either tyrosine kinase or G-protein linked tyrosine kinase receptors. Release IP3 and increase Ca2+release from ER

 

(4) cyclic adenosine monophosphate (cAMP) pathway: coupled to G-protein (7-spanning) receptors to ↑cAMP levels--> activate series of protein kinases.  ie epinephrine and glucagon

 

(5) JAK/STAT pathway: lack intrinsic kinase activity; binding activates series of janus kinases (JAKs); mediates functional responses.

Term

CH 4 GROWTH FACTORS

 

EGF/TGF-α

Definition

EGF- binds receptor (c-erb-B1) with tyrosine kinase activity, is mitogenic for a variety of epithelial cells and fibroblasts as well as hepatic cell division

 

TGF-α: extensive homology with EGF, uses the EGF receptor and produces similar biologic effects as EGF

Term

CH 4 GROWTH FACTORS

 

PDGF

Definition
three isoforms (AA, AB, BB), two receptors-PDGF-Rα ad PDGF-Rβ.  is stored in α granules of platelets; (can be produced by several other cell types- mac's, endothelium, etc).  Causes migration and proliferation of fibroblasts, smooth muscle, and monocytes
Term

CH 4 GROWTH FACTORS

 

FGFs

Definition

FGFs - bind receptors with intrinsic tyrosine kinase activity

 

many functions: angiogenesis, wound repair, development (skeletal muscle development and lung maturation), hematopoiesis

Term

CH 4 GROWTH FACTORS

 

VEGF

Definition

three main types: VEGF, VEGF-B, VEGF-C (and placental growth factor- PIGF)

 

Promote blood vessel formation in early development (vasculogenesis), and also play a  central role in angiogenesis ( in cancer, chronic inflammatory states and healing wounds)

 

[VEGF-C- specifically lymphatic endothelial cell proliferation

 

Term

CH 4 GROWTH FACTORS

 

TGF-β

Definition

family of proteins, with wide-range of functions

 

Produced by platelets, endothelial cells, lymphocytes, macrophages

 

fxns as an inhibitor and stimulator:  TGF-β is a growth inhibitor of most epithelial cell types; in low concentrations- is mitogenic for fibroblasts, in high concentrations- is inhibitory;  stimulate fibroblast chemotaxis and inhibit collagen degradation= overall favors fibrogenesis

Term

CH 4 EXTRACELLULAR MATRIX

 

components of:

-interstitial matrix

 

-basement membrane

Definition

interstitial matrix: fibrillar (types I, III, V) and nonfibrillar collagen, elastin, fibronectin, proteoglycans, hyaluronate, others

 

BM: amorphous nonfibrillar collagen (mostly type IV), laminin, heparan sulfate, proteoglycan, and other glycoproteins

Term

CH 4 EXTRACELLULAR MATRIX

 

Collagen types and locations

-general structural info

Definition

Fibrillar types (I, II, III)/ aka interstitial types

Non-fibrillar (or amorphous) types (IV, V, VI)

 

I- bundles of fibers, in skin, bone, tendons, and most other organs

II- thin fibrils, cartilage, vitreous humor

III- thin fibrils, blood vessels, uterus, skin

IV- amorphous, all basement membranes

V- amorphous/fine fibrils, 2-5% of interstitial tissues, blood vessels

VI- amorphous, interstitial

VII-anchoring filament, dermal-epidermal junction

VIII- probably amorphous, endothelium, descemet membrane

IX- cartilage, probable role in maturation

 

collagen is synthesized and secreted as procollagen--> cleaved into collagen--> and cross-linking is essential to tensile strength.

Term

CH 5 HEMODYNAMIC D/O

 

Edema-

 

difference in characteristics between d/t hydrostatic pressure vs inflammatory edema

 

Four main causes of edema and examples

Definition

Edema from hemodynamic derangements is protein-poor transudate (sp grav <1.012); from inflammatory causes- usually due to increased vascular permeability and results protein-rich exudate (sp grav >1.020)

 

Causes of edema:

(1) Increased hydrostatic pressure:

      (a) localized- impaired venous outflow (ie DVT), edema usually restricted to area distal to obstruction

      (b) Generalized- increased venous pressure, most commonly d/t CHF (usually RV failure).  edema is perpetuated to more than just d/t increased venous pressure by the renin-angiotensin-aldosterone axis.  renal hypoperfusion leads to secondary aldosteronism (with Na and water retention) in an effort to increase renal perfusion, which only increases vascular hydrostatic pressure and edema.  Tx- with salt restriction, diuretics, or aldosterone antagonists)

 

(2) Reduced Plasma Oncotic pressure- excessive loss (proteinuria, from whatever cause) or reduced synthesis (liver dz, malnutrition).  Reduced osmotic pressure leads to increased fluid in interstitial space.  With increased edema--> renal hypoperfusion and secondary aldosteronism again perpetuates edema

 

(3)  Lymphatic Obstruction: lymphedema from blocked drainage.  Tumors, parasitic infection (ie filariasis), surgical removal of nodes for cancer, or irradiation.

 

(4) Sodium and water retention: increased salt (as a primary cause), causes of influx of water to vascular space (water follows Na) and both increases hydrostatic pressure AND decreases plasma oncotic pressure.  can occur from many renal diseases, ARF, PSGN, etc

Term

CH 5 THROMBOSIS

 

Three primary abnormalities leading to thrombosis

 

Endothelium-

roles in antithrombosis and prothrombosis 

Definition

3 main abnormalities (aka Virchow's triad): (1) endothelial injury, (2) stasis of blood; and (3) hypercoagulable state

 

ANTITHROMBOTIC

In normal/uninjured states- the endothelium is anticoagulant.  Non-activated plts do not adhere to endothelium d/t production of endothelial prostacyclin (PGI2) and NO.  they can also degrade ADP (from plt granules) by producing ADPase.

Membrane-bound (on endothelial surface)- are a. Heparin-like molecules that act as cofactors for antithrombin III (to inactivate thrombin, fXa, and others); and b. thrombomodulin- binds thrombin and converts it to anticoagulant- which activates Protein C (which when bound to Protein S- degrades fVa and fVIIIa)

Endothelial cells synthesize t-PA- promoting fibrinolysis

 

PROTHROMBOTIC

endothelial production of vWF for plt adhesion

Bacterial endotoxin or cytokines (TNF, IL-1) stimulate endothelial cells to produce tissue factor which activates the extrinsic pathway.

And endothelial cells secrete inhibitors of plasminogen activator (PAIs)- which reduce fibrinolysis

 

 

Term

CH 4 THROMBOSIS

 

Normal blood flow- describe

 

Effects of stasis and turbulence

Definition

normal blood flow is laminar, with platelets (and other cellular elements) in the center, and plasma to the periphery, separating the platelets from endothelium

 

Turbulence- can induce endothelial injury and thus activation--> procoagulant activity, WBC adhesion and disruption of laminar blood flow brings platelets into contact with endothelium.  Stasis also prevents removal of the procoagulant/activated clotting factors from the area

Term

CH 4 THROMBOSIS

 

Hypercoagulable states- primary and acquired

Definition

Primary: 

- Common: Factor V leiden (glut-->arg at 506 position) or a different mutation of fV (G1691A); Prothrombin mutation (G20210A); mild homocysteinemia (d/t 5,10-methylenetetrahydrofolate reductase homozygous mut); increased levels of factors (VIII, IX, X, fibrinogen)

-Rare: AT III deficiency, Prot C or Prot S def

-Very Rare: Fibrinolysis defects; and Homozygous homocystinuria (marked elevations in homocysteine, d/t deficiency of cystathione β-synthetase

 

Acquired:

High-risk: prolonged immobilization; MI; Afib; tissue injury (surgery, fracture, burn); cancer; prosthetic heart valve; DIC (can be from any condition a/w widespread activation of thrombin); HIT; APA syndrome

 

Low-risk: cardiomyopathy, nephrotic syndrome, hyperestrogenic states (OCPs, pregnancy, post partum), sickle cell anemia, smoking

Term

CH 5 GENETIC DISORDERS

Autosomal dominant

 

In what situation would an affected child have non-affected parents?

 

Incomplete penetrance vs variable expressivity

 

The two major categories of proteins affected in AD d/o's

 

common AD d/o's by organ system

Definition

autosomal dominant d/o's are manifested even in heterozygous state, both males and females effected and can transmit; and USUALLY at least one parent is affected; when one parent is affected, each child has a 1 in 2 (50%) chance of being affected

 

In cases in which the parents are NOT affected- the d/o is caused by new mutation in the germ line (egg or sperm), and there is no increased risk in siblings.

 

Penetrance- some individuals inherit the gene mutation, but are phenotypically normal= incomplete penetrance

Espressivity- a trait is seen in all individuals with the mutation, but is expressed differently in each individual= variable expressivity (ie. NF-1 pts- some have just cafe-au-le spots, whiel others have numerous tumors, etc)

 

Two major categories of proteins affected:

(1) Involved in regulation of complex metabolic pathways that are subject to feedback inhibition (ie. LDL receptors-->loss of LDL-R --> elevated cholesterol-->atherosclerosis)

(2) Key structural proteins, even if part of a multimer protein (will interfere with formation of a functional multimer); [ie. collagen- which forms a trimer; or cytoskeletal elements of red cell membrane (eg spectrin)]

 

-mutations in genes that encode enzymes do not manifest as AD, b/c most are heterozygotes and with enzymes, 50% loss of enzyme can be compensated for 

 

Most common d/o's: 

--Nervous: Huntington dz, neurofibromatosis, myotonic dystrophy, tuberous sclerosis

--Urinary: Polycystic kidney dz

--GI: Familial polyposis coli

--Hematopoietic: Hereditary spherocytosis, von Willebrand dz

--Skeletal: Marfan syndrome, Ehlers-Danlos syndrome, Osteogenesis imperfecta, Achondroplasia

--Metabolic: Familial hypercholesterolemia, Acute intermittent porphyria

 

 

Term

CH 5 GENETIC D/O'S

Autosomal recessive

 

Are parents affected?; Risk with each birth; expression and penetrance.

 

Type of proteins affected

 

If a mutant gene occurs with low frequency, what can be said of the relationship of the parents of an affected individual?

 

Examples of AR d/o's by organ system

Definition

AR are far more common than AD.  Dz only results when both alleles are mutated.  Parents are usually not affected; each child has a 1 in 4 chance of getting.  Expression is far more uniform than AD.  complete penetrance is common.  Onset is in early life

 

If the gene is a low frequency gene- it is highly likely the marriage is consanguineous.

 

Many of the mutated genes encode enzymes.  usually in heterozygotes- the cell can still make 50% of normal, and will still function as a normal cell.

 

Examples:

--Metabolic (nearly all inborn errors of metabolism)- Cystic fibrosis, Phenylketonuria, galactosemia, homocystinuria, Lysosomal storage dz's, α1-antitrypsin def, Wilson's dz, Hemochromatosis, Glycogen storage dzs

--Hematopoietic: Sickle cell anemia, Thalassemia

--Endocrine: Congenital adrenal hyperplasia

--Skeletal: Ehlers-Danlos syndrome, Alkaptonuria

--Nervous: Neurogenic muscular atrophia, Friedrich ataxia, Spinal muscular atrophy

Term

CH 5 GENETIC D/O's

X-linked recessive

 

Inheritance patterns (male vs female)

 

Examples by organ system

 

 

Definition

Mutant genes on the X chromosome do NOT have homologues on the Y, thus males are called hemizygous.  These diseases typically affect males.

 

The affected male does not transmit to the son, but all his daughters will be carriers (assuming the mother is not a carrier).  Sons of heterozygous females have a 1 in 2 chance of getting the gene mut.

 

The heterozygous female usually does not express the full phenotype; however sometimes will partially express the disease (due to X inactivation).  Ex- G6PD def: predisposes to red cell hemolysis in response to certain drugs.  Females may express this in some of the red cells and thus would show symptoms, but not to the same degree as the males.

 

Examples of XLR d/o's:

--Musculoskeletal: Duchenne muscular dystrophy

--Blood: Hemophilia A and B, Chronic granulomatous dz, G6PD deficiency

--Immune: Agammaglobulinemia, Wiskott-Aldrich syndrome

--Metabolic: Diabetes insipidus, Lesch-Nyhan syndrome

--Nervous: Fragile X syndrome

Term

CH 5 GENETIC D/O'S

X-linked dominant

 

inheritance pattern and example

Definition

XLD is an uncommon pattern

 

A heterozygous affected female passes it to half of her sons and daughters; an affected male transmits to all his daughters and none of his sons

 

Ex: Vitamin-D-resistant ricketts

Term

CH 5 GENETIC D/O'S

 

Mendelian disorders-

Protein examples- give the protein type/fxn and the disease caused by the mutation

  • Phenylalanine hydroxylase
  • Hexosaminidase
  • Adenosine deaminase
  • α1-Antitrypsin
  • Low-density lipoprotein receptor
  • Vitamin D receptor
  • Hemoglobin
  • Cystic fibrosis transmembrane conductance regulator
  • Collagen
  • Fibrillin
  • Dystrophin
  • Spectrin, ankyrin, or protein 4.1
  • Factor VIII
  • Rb protein
  • Neurofibromin
Definition
  • Phenylalanine hydroxylase- an enzyme--> Phenylketonuria
  • Hexosaminidase- an enzyme-->Tay-Sachs dz
  • Adenosine deaminase- an enzyme--> Severe Combined immunodeficiency
  • α1-antitrypsin- an enzyme inhibitor--> α1-antitrypsin deficiency--> emphysema and liver disease
  • Low density lipoprotein receptor- a receptor--> Familial hypercholesterolemia
  • Vitamin D receptor- a receptor--> Vitamin D-resistant rickets
  • Hemoglobin: a transport protein for oxygen--> α-Thalassemia; β-Thalassemia; Sickle cell
  • Cystic Fibrosis transmembrane conductance regulator: a transport protein for ions--> Cystic fibrosis
  • Collagen: an extracellular structural protein--> osteogenesis imperfecta; Ehlers-Danlos syndromes
  • Fibrillin: an extracellular structural protein--> Marfan syndrome
  • Dystrophin: a cell membrane structural protein--> Duchenne/Becker muscular dystrophy
  • Spectrin, ankyrin, or protein 4.1: a cell membrane structural protein--> Hereditary spherocytosis
  • Factor VIII: hemostasis--> Hemophilia A
  • Rb protein: growth regulation--> Hereditary retinoblastoma
  • Neurofibromin: growth regulation--> Neurofibromatosis type 1
Term

CH 5 GENETIC D/O'S

 

Defects in structural proteins-

Marfan Syndrome

Definition

Caused by defects in fibrillin-1 protein (d/t mutation of gene FBN1 (15q21.1), a major component of extracellular matrix (provides scaffolding for tropoelastin to form elastic fibers).  variable expressivity- explained by the large size of the gene locus and many different mutations are known, dx by DNA sequencing is not feasible.

 

Clinical manifestations:

--Skeletal abnormalities: tall with long extremities, long tapered fingers and toes; lax joint ligaments in hands and feet (double-jointed).  long-head (dolichocephalic), with frontal bossing and prominent supraorbital ridges.  may easily develop kyphosis, scoliosis, rotation or slipping of vertebrae; deformed chest (pectus excavatum)

--ocular changes: bilateral subluxation or dislocation of lens (bilateral ectopia lentis), very specific for Marfan's

--Cardiovascular: the most life-threatening features; mitral valve prolapse AND most important- ascending aortic dilation.  Both due to cystic medionecrosis.  30-40% of pts die of aortic dissection.

Term

CH 5 GENETIC D/O's

 

Defects in structural proteins-

Ehlers-Danlos Syndromes 

types, gene defects and clinical manifestations

Definition

A heterogeneous group of diseases from defect in synthesis or structure of fibrillar collagen

 

Overall features of EDS- dysfunction leads to lack of adequate tensile strength of collagen fibers; skin is hyperextensible, joints are hypermobile; and may effect several internal organs and EDS pts are prone to colon or vascular rupture, rupture of cornea or retinal detachment, diaphragmatic hernia

 

Types:

- Classical (I/II)- most commonly in the genes for collagen type V, COL5A1 and COL5A2.  AD inheritance, skin and joint hypermobility, atrophic scars, easy bruising

 

- Hypermobility (III)- AD inheritance, unknown gene defect; joint hypermobility, pain and dislocation

 

- Vascular (IV)- abnormalities of type III collagen, COL3A1, at least 3 distinct mutations; AD inheritance. blood vessels and intestines are rich in type III collagen- thus this type is a/w more severe defects- thin skin, arterial or uterine rupture, bruising, small joint hyperextendibility

 

-Kyphoscoliosis (VI)- the most common AR type, gene defect= Lysyl hydroxylase; hydroxylysine is necessary to cross-linking of collagen fibers.  Hypotonia, joint laxity, congenital scoliosis, ocular fragility

 

- Arthrochalasia (VIIa,b)- defect in conversion of procollagen to collagen, d/t mutations in COL1A1 and COL1A2.  AD inheritance; severe joint hypermobility, skin changes (mild), scoliosis, bruising.  Heterozygotes will 50% normal type I collagen, but b/c the abnormal chains affent formation of helices- the heterozygotes will manifest dz

 

- Dermatosparaxsis (VIIc)- also a defect of conversion of procollagen to collagen, d/t gene defect of Procollagen N-peptidase.  AR inheritance; severe skin fragility, cutis laxa, bruising

Term

CH 5 GENETIC D/O's

 

Lysosomal storage diseases

 

Subgroups and individual examples, with deficient enzymes and metabolite accumulated

Definition

Glycogenoses

- Type 2-Pompe disease- enz: α-1,4-Glucosidase (lysosomal glucosidase), accumulates: Glycogen

 

Sphingolipidoses

-GM1 gangliosidosis- enz: GM1 ganglioside β-galactosidase, acc: Gm1 ganglioside

- GM2gangliosidosis:

   -- Tay-Sachs disease, enz: Hexosaminidase, α subunit

   --Sandhoff dz, enz: Hexosaminidase, β subunit

   --GM2gangliosidosis, var AB


Sulfatidoses

-Krabbe dz, enz: Galactosylceramidase, acc: Galactocerebroside 

-Fabry dz, enz: α-Galactosidase A, acc: Ceramide trihexoside

-Gaucher dz, enz: Glucocerebrosidase, acc: Glucocerebroside

-Niemann-Pick dz (types A and B), enz: Sphingomyelinase, acc: sphingomyelin

-Others: metachromatic leukodystrophy, (Arylsulfatase); Multiple sulfatase deficiency (many sulfatases)


Mucopolysaccharidoses

 

Hurler (MPS I H), enz: α-L-Iduronidase

and Hunter (MPS II), enz: L-Iduronosulfate sulfatase

    --Dermatan sulfate, heparan sulfate

 

Mucolipidoses

-I-cell disease and pseudo-Hurler polydystrophy

 

Others: Fucosidosis; Mannosidosis; Aspartylglycosaminuria; Wolman dz; Acid phosphatase deficiency 

 

 

Term

CH 5 GENETIC D/O's

 

Tay Sachs disease

Definition

GM2 Gangliosidosis: Hexosaminidase  α-subunit deficiency

mutation on chr 15; especially common in Jews (of Ashkenazi origin)

 

GM2 ganglioside accumulates- in many tissues (heart, liver, spleen), BUT the clinical picture is from involvement of central and autonomic nervous systems and retina

 

Histology: neurons ballooned with cytoplasmic vacuoles (positive for fat stains).  EM: cytoplasmic inclusions, whorled within lysosomes composed of onion-skin layers.  the destruction of neurons--> proliferation of glia

[image]

[image]

[image]

Clinical fx: manifest sxs ~6mos. motor and mental deterioration (motor incoordination, mental obtundation, muscular flaccidity, blindness, dementia; w/i 1-2 yrs,  complete vegetative state, and death w/i 2-3 yrs

Term

CH 5 GENETIC D/O'S

 

Niemann Pick disease Types A and B

Definition

Lysosomal accumulation of sphingomyelin; mutation in acid sphingomyelinase gene (11p15.4)- imprinted gene (maternally expressed, paternall silenced)

Type A: severe infantile form with extensive neurologic involvement, early death w/i first 3 yol

Type B: organomegaly, no CNS involved, usually survive into adulthood

 

- sphingomyelin, a major component of lipid membranes, accumulates in many organs, particularly w/i mononuclear phagocyte cells--> foamy cytoplasm, vacuoles stain + for fat; EM: membranous cytoplasmic bodies, resembling lamellated myelin figures ("zebra" bodies)

-splenic involvement is usually massive

Term

CH 5 GENETIC D/O's

Lysosomal storage diseases

 

Gaucher Disease

Definition

AR inheritance, mutations in gene encoding glucocerebrosidase.  Is the most common lysosomal storage dz.  

[Glucocerebrosidase- normally cleaves glucose residue from ceramide].

-thus glucocerebroside accumulates (which is derived from catabolism of glycolipids in cell membranes.

-Thus- the accumulations are within the mononuclear phagocyte system, in MANY organs

[the pathologic changes are also due to activation of macrophages and secretion of cytokines (ie IL-1, IL-6, TNF)]

 

3 types:

- Type I: the most common (99%), aka chronic non-neuronopathic form.  Storage dz limited to phagocyte system throughout the body; does not involve the brain.  Splenic and skeletal fx are prominent; predilection for Jewish.  Sx's usually d/t splenomegaly and bone involvement

-Type II: acute neuronopathic, infantile acute cerebral pattern; no predilection for Jewish; virtually NO detectable glucocerebrosidase; clinical picture dominated by CNS dz--> death at early age; lipids accumulate in phagocytic cells around blood vessels in the brain

-Type III: intermediate between type I and II; systemic dz and a chronic progressive CNS involvement, beginning in adolescence or early adulthood.

 

Morphology:  massive accumulations in phagocytic cells (in all forms) = Gaucher cells: stuffed with fibrillary material, described as "crumpled tissue paper".  usually PAS+ (intensely). EM: elongated, distended lysosomes, with stored lipid in stacks of bilayers

[image]

[image]

 

 

Term

CH 5 GENETIC D/O'S

Glycogen storage diseases

(glycogenoses)-

 

The 3 main forms, and examples

Definition
  • Hepatic form: the liver is a main producer of glucose from glycogen breakdown, thus this type is a/w hypoglycemia and hepatic enlargement. Ex: von Gierke disease (type I)- d/t deficiency in Glucose-6-phosphatase, also called hepatorenal.  Hypoglycemia can be bad enough to incite convulsions; hyperlipidemia, hyperuricemia, may develop gout and skin xanthomas
  • Myopathic type: McArdle syndrome (type V), d/t deficiency of Muscle phosphorylase; effects skeletal muscle only, accumulations in subsarcolemmal location.  A/w painful cramps with strenous exercise; myoglobinuria in 50% of cases, onset in adulthood; constant elevated serum CK
  • Miscellaneous type: Pompe dz (type II), d/t deficiency of lysosomal glucosidase (acid maltase)- also a lysosomal storage disorder. mild hepatomegaly, massive cardiomegaly, and muscle hypotonia--> cardiorespiratory failure w/i 2 yrs.  Morphology- ballooning of lysosomes, lacy cytoplasmic pattern; glycogen in sarcoplasm of cardiac and skeletal muscle
[image]
Term

CH 5 GENETIC D/O'S

 

Alkaptonuria

Definition

aka Ochronosis

- AR inheritance, lack of homogentisic oxidase- which converts homogentisic acid to methylacetic acid in the tyrosine degradation pathway

   --homogentisic acid accumulates- and binds to collagen in connective tissue, giving joints and tendons a blue-black color, most evident in ears, nose and cheeks; serious sx's from joint deposits--> erosion and denudation.  A large amount is excreted--> giving a black color to the urine after oxidation

   --arthropathy does not develop until 30's

Term

CH 5 GENETIC D/O's

Down's syndrome-

 

Methods of attaining genetic defect and approx frequency; Clinical features

Definition

Down's syndrome (trisomy 21)- the most common chromosomal abnormality in live births; a major cause of mental retardation

 

The most common cause of +(21) is meiotic nondisjunction in the parental gamete- 95% of which are of maternal origin.

-4% are due to robertsonian translocation of Chr 21 with another acrocentric chr (ie 22,14)- which is usually inherited from the mother who is a carrier.

- 1% are mosaics- due to mitotic nondisjunction in early embryogenesis.

 

Clinical features- flat facial profile, down-slanting palpebral fissures, epicanthic folds; usually severe mental retardation (IQ 25-50); mosaics- may have variable and often much more mild disease.  

-~40% have congenital heart defects, typically of endocardial cushion (ostium primum, ASD, VSD, AV valve abn), + esophageal and small bowel atresias

-10-20X increased risk of developing acute leukemia, both ALL and AML (if AML, is commonly acute megaloblastic leukemia)

-Virtually all pts- develop Alzheimer's disease after age 40

-Abn immune response, more susceptible to infections, particularly lung

-and prone to thyroid autoimmunity

Term

CH 5 GENETIC D/O'S

 

Klinefelter Syndrome

Definition

- two or more X chromosomes, plus two or more Y chromosomes; with male hypogonadism; incidence- 1 in 660 live births

 

-Due to meiotic nondisjunction in parental gametes, even mixture of maternal and paternal

-90% of cases have the classic genetic pattern- 47,XXY

-15% have mosaic patterns- 46,XY/47,XXY; 47,XXY/48,XXXY

-In all cases- all but one X chr is inactivated

[So, why the clinical features- and not nl male phenotype?- apparent nonrandom X inactivation, due to the shortest CAG repeats being activated first leaves, only the X chr's with the longest CAG repeats--> hypogonadism]

 

Clinical features: one of the most common causes of hypogonadism in males.  Distinctive body habitus- long legs/elongated body; small atrophic testes, small penis, lack of secondary male sex characteristics (ie deep voice, beard, male hair patterns); +gynecomastia; overall, somewhat lower IQ than normal (but not typically MR); increased risk of T2DM and metabolic syndrome; Mitral valve prolapse (in ~50%)

-Plasma gonadotropin hormones (esp FSH) ↑, testosterone variably ↓; plasma estradiol ↑

 

Testicular histology: variable- some all atrophic tubules; some mixture of normal and atrophic, some all embryonic, never maturing.  And prominent Leydig cells.

Term

CH 5 GENETIC D/O'S

 

Turner Syndrome

Definition

-complete or partial monosomy X; defined with hypogonadism of female; incidence ~1 in 2000 live births

 

-Three karyotype patterns:

(1) 57% classic- missing an entire X chromosome, 45,X

(2) 29% mosaics: 45,X/46,XY; 45,X/47,XXX; 45,X/46XX; 45,X/46,X,i(X)(q10) [controversy- that in fact ALL Turners are at least to some degree mosaic; and that all true nonmosaics are nonviable]

(3) 14% have structural abnormalities of one X chromosome- ex. isochr (46,X,i(X)(q10)- due to loss of short arm of one X; ring chromocome (46,X,r(X)); and deletions of parts of the short or long arms (del(Xp) or del(Xq))

 

Clinical features: the most severely affected- are born with edema (hand, foot and the nape of the neck-due to lymph stasis (cystic hygroma) which when the lymph clears--> webbed neck

-congenital heart disease (commonly coarctation-preductal or bicuspid valve

-*failure to develop normal secondary sex characteristics; and TS is the single most important cause of primary amenorrhea

    --in embryogenesis, the fetal ovaries form normally, but by 2 yrs old and "menopause before menarche ensues and ovaries are reduced to "streak ovaries"- with no follicles

-short stature

-mental status is usually normal, but some visual-spacial processing abnormalities

-~50% develop thyroid autoantibodies, and develop hypothyroidism

 

Molecular: many genes involved in phenotype, but only one identified as involved and thoroughly studied- short stature homeobox (SHOX), a  Xp22.33 a critical regulator of growth

Term

CH 5 GENETIC D/O'S

 

Trinucleotide repeat disorders- genes/proteins; classified by noncoding vs coding; what repeat

  • Fragile-X syndrome
  • Friedreich ataxia
  • Myotonic dystrophy
  • Spinobulbar muscular atrophy
  • Huntington dz
  • Spinocerebellar ataxia
Definition
NON-CODING:
  • Fragile-X-syndrome: CGG repeat, in FMRI gene (Xq27.3)- FMR-1 protein; full disease with >230 repeats
  • Friedreich ataxia: GAA repeat, FXN gene (9p21.1)- Frataxin; full disease with >100 repeats
  • Myotonic dystrophy: CTG repeat, DMPK gene (19q13.3)- myotonic dystrophy protein kinase (DMPK); full dz with >100 rpts
CODING REGION:
  • Spinobulbar muscular atrophy (Kennedy dz): CAG repeat, AR gene (Xq12)- Androgen receptor protein
  • Huntington dz: CAG repeat, HTT gene (4p16.3)- huntingtin protein
  • Spinocerebellar ataxia: types 1-7, most a/w Ataxin proteins, all d/t CAG repeats
Term

CH 5 GENETIC D/O'S

 

Fragile-X Syndrome

Definition

The prototype of trinucleotide repeat d/o's; 

-Incidence: 1 in 1550 for affected males, and 1 in 8000 in affected females

-*the 2nd most common cause of MR, (2nd to Down's)

-X-linked d/o, mutation in the familial mental retardation-1 (FMR1) gene

-with lack of folate in a cell- the repeat sequence is "fragile" to breakage

 

Affected males have severe MR, with IQ's ranging from 20-60; Chx phenotype- long face, large mandible, large everted ears, large testicles (macrorchidism)- the most distinctive fx in ~90% of prepubertal males

 

Fragile-X is different than most other sex-linked diseases, for several reasons:

(1) the presence of carrier males (~20%) of molecularly proven genotype, which should show disease are phenotypically normal

(2) Affected females- 30-50% of carrier females are affected with MR

(3) Risk of phenotypic effects- risk depends on position w/i pedigree

(4) Anticipation- clinical features within a family worsen with each successive generation

Term

CH 5 GENETIC D/O'S

 

What is the prototypical disease caused by mutations in mitochondrial DNA

Definition

 

Leber hereditary optic neuropathy

-a neurodegenerative dz, with progressive bilateral loss of central vision; with eventual blindness

Term

CH 6 IMMUNE SYSTEM- NL

 

MHC molecules

Definition

(1)  MHC Class I- expressed on all nucleated cells and platelets; three gene loci (HLA-A, HLA-B, HLA-C); each Class I molecule is a heterodimer consisting of highly polymorphic α chain and the conserved β2-microglobulin; displays peptides derived from proteins, ie viral antigens--> which are presented to CD8+ T lymphs--> kill infected cell

 

(2)  Class II MHC: encoded in HLA-D region (with HLA-DP,-DQ,-DR subregions); each molecule is a heterodimer of an α and β chain, each polymorphic; class II MHC present antigens internalized into vesicles (endosomes or lysosomes)- derived from extracellular microbes and soluble proteins; class II β2 domain- binds CD4--> activated CD4+ helper T cells.  Thus, Class II MHC are expressed by cells that can be activated by/respond to CD4+ T-cells= macrophages, B lymphocytes, and dendritic cells

Term

CH 6 IMMUNE SYSTEM

 

Diseases associated with specific HLA alleles:

-Ankylosing spndylitis

-Postgonococcal arthritis

-Acute anterior uveitis

-Rhematoid arthritis

-Chronic active hepatitis

-Primary Sjogren syndrome

-Type 1 DM

 

--inflammatory diseases in general

--Autoimmune diseases in general

--Inherited errors of metabolism

Definition
  • Ankylosing spondylitis:  B27 ** 90-100-fold increased risk
  • Postgonococcal arthritis: B27
  • Acute anterior uveitis: B27
  • Rheumatoid arthritis: DR4
  • Chronic active hepatitis: DR3
  • Primary Sjogren syndrome: DR3
  • T1DM: DR3, DR4 or DR3/DR4
-- Inflammatory diseases- in general a/w B27
--Autoimmune diseases- in general a/w alleles of DR locus
--Inherited errors of metablism- genes not generally a/w immune response, but localized to HLA complex of genges (ie 21-hydroxylase deficiency- HLA-BW47) or Hereditary hemochromatosis (HLA-A)- mutated HFE gene
Term

CH 6 HYPERSENSITIVITY REACTIONS

 

Immediate/Type I hypersensitivity- cells involved, general process, major chemical mediators

Definition

-mediated by TH2 cells, IgE Ab's, and mast cells--> resulting in effects on vessels, smooth muscle and pro-inflammatory recruitment

 

-Rapid immunologic reaction occurring w/i minutes, in pts previously sensitized to the Ag.  termed allergy

 

Process:  (1) APC (ie dendritic cells at the site of Ag entry) present Ag to naive CD4+ TH cells--> differentiate into TH2 cells in response to local mediators (namely IL-4)--> TH2 cells secrete cytokines (again IL-4) acting on B-cells to stimulate switching to IgE class of Ab's; inflammation is propagated by more chemokine production from TH2 cells 

(2) Mast cells (and basophils- which are not central to Type I rxns)- express FcεRI (high affinity IgE receptors- specific for the Fc portion of IgE.  IgE binding to Ag--> release of mast cell granules --> tissue damage, vascular dilation, edema, smooth muscle contraction, mucous production, inflammation

 

 (3)  The late phase- occurring 2-24 hrs after Ag exposure, is due to recruitment of eosinophils- which secrete proteolytic enzymes, leading to tissue destruction (particularly of the epithelial cells)

Term

CH 6 HYPERSENSITIVITY REACTIONS

 

Antibody-mediated/Type II hypersensitivity rxns-

three separate process of type II rxns, and the cells/mediators involved; examples of Ab-mediated/Type II diseases

Definition

-caused by Ab's the react with Ag's on cell surfaces or in extracellular matrix

Three processes:

(1) Opsonization and phagocytosis- cells opsonized by IgG Abs- recognized by Fc receptors on phagocytic cells; OR IgG and IgM on cell surfaces, activate complement producing opsonins (esp C3b).  Clinically- this process occurs in (a) transfusion reactions- from preformed Ab in the host

   (b) hemolytic disease of the newborn- IgG Ab cross the placenta

   (c) autoimmune hemolytic anemia, agranulocytosis and thrombocytopenia

   (d) certain drug reactions- when the drug acts a hapten

 

(2) Inflammation: Ab's deposit in fixed tissues and activate complement, leading to influx of inflammation and propagation of further pro-inflammatory substances.  Ex- glomerulonephritis, vascular transplant rejections, etc

 

(3) Cellular dysfunction: Ab's may bind cell-surface receptors, and impair or cause cellular dysfunction, without causing cell injury/death or inflammation.  Ex- myasthenia gravis; or Graves' disease

 

Ex's of Ab-mediated/Type II hypersensitivity rxns-  (some repeats form above)

-Autoimmune hemolytic anemia- target, Rh blood group, I Ag

-Autoimmune thrombocytopenic purpura- GpIIb/IIIa, integrin

-Pemphigus vulgaris- intercellular jxns/e-cadherin

-Vasculitis caused by ANCA- neutrophil granule proteins

- Goodpasture syndrome: non-collagen proteins in BM of lung and kidney

-Acute Rheumatic fever- Strep cell wall Ag- cross react with myocardial ag

-Myasthenia gravis- acetylcholine receptor

-Graves disease- TSH receptor

-Insulin-resistant DM- Insulin receptor

-Pernicious anemia- intrinsic factor of parietal cells

Term

CH 6 HYPERSENSITIVITY REACTIONS

 

Type III/Immune complex hypersensitivity rxns

-basic description, overall morphology and examples with associated antigens

Definition

Antigen-Antibody complexes are deposited (or formed in situ), and cause tissue damage by eliciting inflammation.

-the majority are systemic- typically involving skin, kidneys and joints.  most complexes are deposited in vessel walls --> vasculitis

-morphology: acute necrotizing vasculitis; with neutrophilic infiltrate and fibrinoid necrosis

 

-If due to a single large exposure of Ag (ie serum sickness or post-streptococcal glomerulonephritis)- usually resolve

-If prolonged exposure to Ag (ie endogenous/autoimmunity, like SLE)- persistent disease

 

Examples:

(1) Systemic Lupus erythematosus- nuclear antigens (autoimmune)--> nephritis, skin lesions, arthritis, and more

(2) Poststreptococcal glomerulonephritis- A streptococcal cell wall Ag is "planted" in the GBM; -->Nephritis

(3)Polyarteritis nodosa- hepatitis B virus Ags in some cases; -->systemic vasculitis

(4) Reactive arthritis- Bacterial Ag's (ie yersinia, gonorrhea); -->acute arthritis

(5) Serum sickness- (now not common, used to be very common, due to frequent administration of horse anti-sera for immunization); Various proteins- ie foreign serum protein--> arthritis, vasculitis, nephritis

(5) Arthus reaction- a localized immune complex disease,  identified as an experimental model; various foreign proteins, within the skin --> cutaneous vasculitis

Term

CH 6 HYPERSENSITIVITY REACTIONS

 

Type IV/Cell-mediated hypersensitivity rxns

-two main types and cells involved; examples- with associated antigens

Definition

(A) Delayed type hypersensitivity rxn- CD4+ TH1 cells, respond to tissue antigens- secrete cytokines which stimulate inflammation and activate phagocytes; CD4+ TH17 cells recruit neutrophils and increase inflammation

  --Ex: tuberculin reaction- in the PPD test- clinical findings explained by CD4+ T cells and macrophages around venules, making perivascular cuffing.  With tubercle bacilli infection in other tissue, the macrophages become epithelioid, and granulomatous inflammation is formed

 

(B) T cell-mediated cytolysis- CD8+ cytotoxic T cells directly kill tissues- thru perforins and granzymes

  --Ex: Type 1 DM; or CTLs directed against HLA ag's-->graft versus host disease

 

Examples of Type IV HRs:

(1) Type 1 DM- Ag's of pancreactic islet β cells (insulin, glutamic acid decarboxylase, etc)--chronic inflammation in islets--> destruction of β cells

(2) Mutiple sclerosis- protein Ag's in CNS myelin (myelin basic protein, proteolipid protein)--> demyelination in CNS, with perivascular inflammation--> paralysis, ocular lesions

(3) Rheuamtoid arthritis- unknown ag in joint synvioum (possibly collagen type II)--> chronic arthritis with inflammation and destruction of articular cartilage

(4) Crohn's disease- unknown ag (possibly commensal bacteria)--> chronic intestinal inflammation and obstruction

(5) Guillain-Barre syndrome (peripheral neuropathy)- protein Ag's of peripheral nerve myelin --> neuritis, paralysis

(6) Contact dermatitis- various environmental Ag's (ie poison ivy) -->skin inflammation with blisters

Term

Ch 6 AUTOIMMUNE DZ

 

What are the four main patterns of fluorescence in ANA's and what typical targets are associated with each pattern?

Definition

(1) Diffuse/homogenous- chromatin, histones, and occ dsDNA

 

(2) Rim or peripheral- more often dsDNA

 

(3) Speckled- most common and therefore least specific pattern; non-DNA nuclear particles- ie Sm Ag, RNP, SS-A and SS-B

 

(4) Nucleolar- RNA; most often seen in pts with systemic sclerosis

Term

CH 6 AUTOIMMUNE DZ

 

SLE-

-What are the two most specific/diagnostic antibodies in SLE?

-General info- incidence, prevalence, M:F ratio, age, basic clinical info

-What are the players and how do they cause coagulation abnormalities in SLE  pts?

- General theories on etiology of SLE

Definition

Antibodies to dsDNA and the Smith (Sm) Ag- are virtually diagnostic of SLE

- Lupus is the prototype of systemic autoimmune dz- fairly common (1 in 2500 in some pops); primarily affects women, F:M ratio of 9:1.  acute onset, with chronic remitting and relapsing febrile illness with injury to many organs, but primarily the skin, joints, kidney and serosal membranes

-Chx'c clinical fx: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal dysfxn, and more

 

-Antiphospholipid Ab's, present in 40-50% of SLE pts, bind plasma proteins (ie prothrombin, annexin V, β2-glycoprotein I, Protein C and S).  In vitro- these Abs may interfere with clotting time, thus were names Lupus anticoagulant, HOWEVER- in vivo- actually cause hypercoagulable state--> venous and arterial thrombosis

[the Ab's against the phospholipid-B2Gp complex- will bind cardiolipin, thus produces the false positive syphilis tests in SLE pts]

 

Etiology- still unknown, however, genetic and environmental factors play together

- Specific alleles of the HLA-DQ locus have been linked to anti-dsDNA, anti-Sm and APA (antiphospholipid Abs)

-And inherited deficiencies in early complement components (C2, C4, C1q) have been linked to impaired removal of immune complexes and loss of B cell tolerance

Term

CH 6 AUTOIMMUNITY

 

Antinuclear antibodies--w/ associated autoimmune d/o's

-Anti-dsDNA

-Anti-Sm

-Antihistone:

-Anti-nuclear RNP:

-Anti-SS-A(Ro):

-Anti-SS-B(La):

-Anti-Scl70:

-Anticentromere:

-Anti-Jo-1:

Definition

-Anti-dsDNA and -Sm (Smith)- specific/diagnostic of SLE. 

-Anti-histone- diagnostic of drug-induced lupus; also present in 50-70% of SLE

-Anti-Nuclear RNP (U1RNP)- not dx'c of a particular dz, found in SLE (30-40%), systemic sclerosis (15%), limited scleroderma/CREST (10%)

-Anti-SS-A(Ro) and -SS-B(La):  Dx'c of Sjögren syndrome; but also seen in SLE (Ro- 30-50%; La- 10-15%)

-Anti-Scl-70: Ag=DNA topoisomerase I; present in systemic sclerosis and some Limited scleroderma (CREST)

-Anti-centromere: dx'c of Limited scleroderma (CREST); also seen in systemic sclerosis

-Anti-Jo-1: Ag= Histidyl-tRNA synthetase; not a common ANA, seen in Inflammatory myopathies (25%)

Term

CH 6 AUTOIMMUNITY

 

Sjögren syndrome

Definition

-dry mouth (keratoconjunctivitis) and dry mouth (xerostomia); due to chronic destruction of lacrimal and salivary glands

-Can occur as a primary d/o, but more commonly is associated- w/ other autoimmune- most commonly with RA; but also seen in SLE, polymyositis, scleroderma, vasculitis, MCTD, thyroiditis

 

-Likely have several Ab's, but most important are the RNPs- SS-A(Ro) and SS-B(La)

 

-Morphology: early- lymph infiltrate, periductal and perivascular-->extensive, and develop germinal centers ------->Later- atrophy of acini, fibrosis and hyalinization.

-To dx: biopsy of lip- to examine minor salivary glands

[image]

 

-Complication- a single clone may be selected in the inflammatory process, and a common sequelae is (40-fold> risk) B-cell lymphoma- usually MALT

Term

CH 6 AUTOIMMUNITY

 

Systemic sclerosis

-two types, general fx, what is CREST syndrome? 

-Morphology in major organs affected?

Definition

SS- a chronic disease w/ (a) chronic inflammation; (b) widespread damage to small blood vessels and (c) progressive interstitial and perivascular fibrosis of skin and several organs

 

Two types: 

(1) Diffuse scleroderma- widespread skin involvement, with rapid progression and early visceral involvement

 

(2) limited scleroderma- skin involved, usually confined to fingers, forearms and face; late visceral involvement

--some also develop CREST: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia; and a/w anticentromere Ab's

 

Morphology:

--Skin: diffuse sclerotic atrophy, begins in fingers--> upper arms, neck and face;  Early- edema, perivascular infiltrates of CD4+ Tcells; swelling and degeneration of collagen---> progressive fibrosis of dermis, with attachment to subQ.  Loss of blood supply can cause ulceration or atrophy.

[image]

[image]

GI tract: affected in 90% of pts; progressive atrophy and fibrotic replacement of muscularis, most severe in esophagus--> rubber hose inflexibility, with LES dysfxn

 

Musculoskeletal: synovial inflammation--> hypertrophy early--> fibrosis later (similar changes to RA), but no joint destruction in SS

 

Kidneys: most prominent= vascular lesions, interlobular arteries- intimal thickening, d/t deposition of mucinous/collagenous material and concentric proliferation of intimal cells--> lesions similar to that of malignant htn;may be assoc w/ fibrinoid necrosis

[image]

 

Lungs: affected in 50% of pts; pulm htn and interstitial fibrosis; pulm vasospasm d/t endothelial dysfxn

 

Heart: pericarditis and effusion, w/ myocardial fibrosis; thickened intramyocardial arterioles

Term

CH 6 TRANSPLANT REJECTION

 

Rejection of kidney grafts-

-cell-mediated vs humoral

-hyperacute, acute, chronic

Definition

-T-cell mediated rejection: direct- donor APCs with donr MHC molecules, present peptides to recipient T cells (CTLs and TH);  indirect- recipient/self APCs with self-MHC degrade and present graft Ags

 

-Humoral/Ab mediated rejection: hyperacute rej from preformed antidonor Ab present in recipient's serum; or may develop Ab's after transplant; *the initial target of the Abs is graft vasculature--> vasculitis

 

Morphology:

(1) Hyperacute: within minutes to hours, rapid graft cyanosis, mottling and flaccidity.  Preformed anti-donor Abs in recipient--> attack vessel wall,--> fibrin thrombi and fibrinoid necrosis, with neutrophil infiltrate

 

(2) Acute- within days, or can come on months to year later suddenly after removal of immunosuppressant

--(a) acute cellular rej- mononuclear interstitial infiltrate (T cells); CTLs may cause endothelitis.  Important to recognize b/c cellular rej, in absence of humoral rejection- responds well to tx (cyclosporine)

[image]=tubulitis, interstital infiltrate

--(b) acute humoral rej-= rejection vasculitis, antidonor Abs--> extensive necrosis of renal parenchyma; lesions mimic arteriosclerotic thickening

[image]= pmns/vasculitis; C4d in peritubular capillaries

 

(3) chronic- starting after 4-6 months; vessels- obliterative intimal fibrosis--> interstitial fibrosis, tubular atrophy and loss of parenchyma; chronic  transplant cglomerulopathy- glomeruli show scarring and reduplication of BM. 

[image]

Term

CH 6 IMMUNE SYSTEM

 

Primary immunodeficiencies-

 basic distinguishing features (ie genetic defect, immune anomaly)

 

-X-linked hypogammaglobulinemia

-Common variable immunodeficiency

-Isolated IgA deficiency

-Hyper IgM syndrome

-DiGeorge syndrome

-Severe combined immunodeficiency

-Wiskott-Aldrich syndrome

-complement deficiencies

Definition

(1) X-linked agammaglobulinemia (aka Bruton's agammaglobulinemia): failure of B-precursors to mature, so produce NO Ig's; mutations in Bruton tyrosine kinase (Btk) gene on Xq21.22.  SO males affected much more than females.  becomes apparent at >6 mos of age, after maternal Ab's are gone.  Susc to H. influezae, strep pneumo, staph aureus; as well as mucosal viruses and Giardia

 

(2) Common variable immunodeficiency: hypogammaglobulinemia, - usually all Ab classes but sometimes just IgG; B cell unable to differentiate into plasma cells, d/t intrinsic b-cell defects AND abnormal TH cell-mediated activation of B cells; not all cases have a distinct inherited pattern or defect.  some a/w abnormal cytokine receptor- BAFF; or in ICOS.

 

(3) Isolated IgA deficiency: common dz, 1 in 600 in US; extremely low levels of serum and secretory IgA; familial or acq'd after toxoplasmosis, measles, or other virus; usually asymptomatic, but risk of developing severe-to-fatal anaphylactic reactions to blood transfusions with normal IgA levels.

 

(4) Hyper IgM syndrome: make IgM, but deficient in making IgG, IgA and IgE; defect in helper T cells in activating b cells and macrophages; 70% are X-linked on Xq26 (CD40L gene); 30% AR inheritance (?CD40).  recurrent pyogenic infections; and pneumonia with pneumocystis jiroveci

 

(5) DiGeorge syndrome- thymic hypoplasia; failure of developing the 3rd and 4th pharyngeal pouches-->T-cell deficiency from thymic hypoplasia (also parathyroid, clear cells of thyroid, ultimobranchial body); defect is 22q11 deletion; poor defense against fungal and viral infections d/t lack of cell-mediated immunity

 

(6) SCID- defective humoral and cell-mediated immunity; extremely susceptible to many pathogens; typically die w/i 1 yr of life, unless have BMT.  Variable genetic abnormalities- but 50-60% are X-linked- from common γ-chain of cytokine receptors (2nd most common: AR- from Adenosine-deaminase (ADA) def); both these causes have hypoplastic thymus

 

(7)  Wiskott-Aldrich Syndrome: aka immunodeficiency with thrombocytopenia and eczema; X-linked recessive, usually ending in early death.  Progressive secondary depletion of t cells.  mutations in WASP (Wiskott Aldrich syndrome protein) on Xp11.23; low IgM, normal IgG; elevated IgA and IgE.

 

(8) Genetic complement deficiencies: most common is deficient C2- generally no increased susceptibility to infections, but increased autoimmunity (like SLE);  C3 def- susc to serious and recurrent pyogenic infections and immune-complex mediated glomerulonephritis.  def of C5-9 (MAC)- leads to defective lysis of organisms; C1 inhibitor deficiency--> hereditary angioedema

Term

CH 6 IMMUNE SYSTEM

 

HIV-AIDS

 

HIV-1 structure: virus core- proteins and genes; matrix and envelope protein

Definition

-spherical virion, with cone-shaped core, lipid envelope

 

--CORE: major capsid protein- p24; nucleocapsid protein- p7/p9; two copies of genomic RNA- consisting of gag, pol and env genes; and three enzymes- protease, reverse transcriptase and integrase.  *p24 is the most readily detectable HIV protein, thus is the basis of dx'c tests- is EIA.

 

--MATRIX- core is surrounde by the matrix consisting of p17

 

--Envelope- contains tow viral glycoproteins- gp120 and gp41

 

[+ additional accessory genes on HIV- tat, rev, vif, nef, vpr, vpu]

Term

CH 6 HIV-AIDS

 

lymph node morphology throughout HIV/AIDS

 

What are the T cell# criteria for the clinical categories of HIV

Definition

-LN morphology:

--EARLY: enlarged LNs with marked follicular hyperplasia; attenuated mantle zones and germinal centers "merge" with interfollicular area

      ---The B cell expansion- reflects the polyclonal B cell activation and hypergammaglobulinemia

      ---HIV particles predominantly in follicles- within dendritic cells

      ---Also have increased plasma cells in BM (due to B cell activation), and thus may show rouleaux in PB

 

-LATE: Follicular involution, with depletion of cells; and disrupted network of follicular dendritic cells. GC's may be hyalinized

     ---viral burden is lower in the LN's likely d/t disruption of FDCs

      --- Burnt out LNs, small and atrophic.  And many have lots of opportunistic pathogens

 

 

CDC classification/HIV categories

A- asymptomatic, primary/acute HIV infection, or persistant generalized LAD

    -- A1, A2, A3 based on # of Tcells

B- Symptomatic, (not including the conditions in A)

   -- B1, B2, B3 based on # Tcell

C- AIDS indicator conditions- infections, neoplasms, CNS dz ,etc

 

A1/B1= ≥500 cells/μL

A2/B2= 200-499 cells/μL

A3/B3= <200 cells/μL

Term

CH 6 IMMUNE SYSTEM

 

Amyloidosis

 

-what are the 3 major types of amyloid protein (and describe their origin)

 

-List other more common forms of amyloid

 

-what other minor components are present in amyloid (other than the amyloid protein)?

Definition

The 3 most common amyloid proteins:

(1) AL protein: made from Ig light chains (either complete or the amino fragments); Most commonly of the λ type (but may be κ); produced by plasma cell neoplasms secreting free lambda light chains

 

(2) AA protein: =amyloid fibril protein; 76 aa, derived from proteolysis of large serum protein =serum amyloid-associated (SAA), synthesized in the liver and circulates with HDL.  Acute phase reactant; and thus this type of amyloid is called secondary amyloidosis d/t following chronic inflammation

 

(3) Aβ protein: β-amyloid protein, 4kD; makes the core of cerebral plaques in Alzheimer's dz; and is deposited in the wall  of cerebral vessels. Derived from a large transmembrane protein - amyloid precursor protein

 

Other common amyloid proteins:

A. Transthyretin (TTR): normal serum protein transports thyroxine and retinol.  forms amyloid d/t production of mutant protein--> familial amyloid polyneuropathies.  And is deposited in hearts of elderly --> senile systemic amyloidosis

 

B. β2-microglobulin- MHC class I molecule; found in pts on long term hemodialysis

 

C. Prion proteins- in a small # of cases, misfolded prion proteins are deposited as amyloid

 

Components of the amyloid material (other than the amyloid protein)= serum amyloid P component, proteoglycans, and highly sulfated glycosaminoglycans

Term

CH 7 NEOPLASIA

 

Inherited Cancer Syndromes-

 

inherited predisposition to cancers due to autosomal dominant gene mutations

 

Name the condition/cancer a/w with each AD gene defect:

-RB

-p53

-p16/INK4A

-APC

-NF1, NF2

-BRCA1, BRCA2

-MEN1, RET

-MSH2, MLH1, MSH6

-PTCH

-PTEN

-LKB1

-VHL

Definition

 

answers:

-RB: retinoblastoma

 

-p53: Li-Fraumeni syndrome- at high risk for a wide range of malignancies and often have multiple in their lifetime

     ---Breast, brain, ST sarcomas, Acute leukemia, bone carcinoma, adrenal cortical carcinoma

 

-p16/INK4A- Melanoma

 

-APC- Familial adenomatous polyposis; and 100% risk of colon cancer

 

-NF1, NF2- Neurofibromatosis 1 (NF's, MPNST), and neurofibromatosis 2 (schwannomas, acoustic neuromas, meningiomas)

 

-BRCA1, BRCA2- breast and ovarian cancers

 

-MEN1, RET- multiple endocrine neoplasia (MEN)

  •   MEN1- pituitary, adrenals, pancreas
  •   MEN2- thyroid, parathyroid, adrenals

-MSH2, MLH1, MSH6- Hereditary nonpolyposis coli, d/t defective DNA mismatch repair; most--> colon cancer (as well as cancers of small intestine, endometrium and ovary

 

-PTCH- Nevoid basal cell carcinoma syndrome

 

-PTEN- Cowden syndrome- aka multiple hamartomas syndrome (d/t hamartomas of skin and mucosa); AND increased risk cancer of epithelium including breast, skin, thyroid, endometrial, kidney, etc

 

-LKB1- Peutz-Jegher syndrome (epithelial cancers, see above)

 

-VHL- Renal cell carcinomas

Term

CH 7 NEOPLASIA

 

Inherited autosomal recessive syndromes of defective DNA repair

Definition

-Xeroderma pigmentosum- in ability to repair defects made by UV light.  develop multiple BCC and SCC at a young age.  --> melanoma and SCC with metastases and death at early age. 

 

-Ataxia-telangiectasia- ATM gene, neurodegenerative disorder of children; increased risk of several cancers d/t defective DNA repair

 

-Bloom syndrome: BLM gene, short stature and facial rash (on sun exposure), pigmentation abnormalities, cafe-au-lait spots, telangiectasias; increased risk of all forms of cancer

 

-Fanconi anemia: get AML; usually preempted by bone marrow failure

Term

CH 7 NEOPLASIA

 

RET protein

-type of oncogene; syndromes and tumors associated with mutations

Definition

RET= a growth factor receptor, proto-oncogene; normally a tyrosine kinase receptor

 

-Fxn: receptor for glial cell-line derived neurotropic factor- promote cell survival in neural development (including and esp neural crest cells/neuroendocrine cells)= thyroid parafollicular C cells, adrenal medulla and parathyroid cells.

 

A/w:

-MEN-2A: point mutations in extracellular domain--> constitutive dimerization and activation

--medullary thyroid carcinoma

--adrenal tumors

--parathyroid tumors

 

-MEN-2B: point mutations in intracellular/cytoplasmic domain--> alter substrate specificity of tyrosine kinase

--medullary thyroid carcinoma

--adrenal tumors

---earlier onset, more severe and also a/w- ganglioneuromas (lip, tongue and colon) and musculoskeletal abnormalities

--lack involvement of parathyroid

 

-Familial medullary thyroid carcinoma: also in cytoplasmic domain

-a/w only with MTC

Term

CH 7 NEOPLASIA

 

FLT3 mutations

-type of oncogene, associated tumors

Definition

FLT3= FMS-like tyrosine kinase 3 receptor; a growth factor receptor

 

-point mutations--> constitutive signaling --> acute myeloid leukemias

 

-Amplification--> breast and ovarian cancers

Term

CH 7 NEOPLASIA

 

PDGFR 

-type of oncogene, how oncogenic activation occurs, associated tumors

Definition

PDGFR= Platelet derived growth factor receptor; a growth factor receptor proto-oncogene

 

-t(5;12)- leads to fusion product of PDGFR and ETS --> permanent dimerization of PDGFR--> chronic myelogenous leukemias

-Amplifications/overexpression of normal protein- in gliomas/GBM

 

-Gastrointestinal stromal tumors: >90% have either, constitutive activity of tyrosine kinases-  either c-KIT (stem cell factor) or PDGFR 

 

-these tumors are responsive to targeted therapy- with tyrosine kinase inhibitor = imatinib mesylate

Term

CH 7 NEOPLASIA

 

Tumors assoc with the following oncogenes:

-Growth factors:

  • PDGF-β
  • FGFs
  • TGF-α
  • HGF

-Growth factor receptors:

  • EGF-R family
  • FLT3
  • RET
  • PDGFR
  • Receptor for stem cell

-Signal Transduction proteins:

  • GTP-binding (KRAS, HRAS, NRAS)
  • ABL
  • BRAF
  • β-catenin

 

-nuclear reg proteins:

  • C-myc
  • N-Myc
  • L-Myc

-cell cycle regulators

  • cyclin D
  • Cyclin E
  • CDK4
Definition

Growth factors:

  • PDGF-β: overexpression, Astrocytoma, Osteosarcoma
  • FGFs:
    • HST1: overexpression, stomach cancer
    • INT2/FGF3= amplification, bladder, breast and melanoma
  • TGF-α: overexpression, Astrocytoma, HCC
  • HGF: overexpression, thyroid cancer

Growth factor receptors:

  • EGF receptor family:
    • ERBB1: overexpression, lung SCCa, gliomas
    • ERBB2: amplification, Breast, ovary, lung, stomach, salivary gland
  • FLT3: point mutation, Leukemia
  • RET: point mutations, MEN2A, MEN2B, familial medullary thyroid ca
  • PDGFRB: overexpression- gliomas; translocation- leukemias
  • c-KIT (receptor for stem cell factor): point mutation- GIST, seminomas, leukemias

-Signal transduction proteins:

  • GTP-binding-
    • KRAS- point mutation- colon, lung, pancreas
    • HRAS- point mutation- bladder, kidney
    • NRAS- point mutation- melanomas, hematologic malignancies
  • ABL- translocation, CML, ALL
  • BRAF- RAS pathway, point mutation- melanomas
  • β-catenin- WNT pathway, point mutation or overexpression- hepatoblastomas, HCC

-Nuclear regulatory proteins:

  • transcription activators:
    • C-myc: translocation, Burkitt lymphoma
    • N-myc: amplification, neuroblastoma, small cell carcinoma-lung
    • L-myc: amplification, small cell carcinoma-lung

-cell cycle regulators:

  • Cyclin D: translocation, mantle cell; amplification, breast and esophageal
  • cyclin E: overexpression, breast cancer
  • CDK4: amplification or point mutation, glioblastoma, melanoma, sarcoma
Term

CH 7 NEOPLASIA

 

inactive vs active RAS proteins, and downstream regulated proteins

 

-a related protein mutation that leads to the same cellular effects

Definition

inactive RAS is bound to GDP--> active RAS is bound to GTP

 

-active RAS stimulates- mitogen activated protein (MAP) kinase cascade

 

-GAPs= GTPas activating proteins- bind active RAS and regulate GTPas activity- by stopping signal transduction- so loss of function mutations in these genes leads to similar effects as RAS constitutively active mutations

-ex: NF-1 (mutation in neurofibromin 1, a GAP)

Term

CH 7 NEOPLASIA

 

the main cell cycle components and inhibitors

Definition

-CDK4: complexes with cyclin D--> phosphorylates Rb, and moves past G1 restriction point

-CDK2: complexes with cyclin E

-CDK1: complexes with cyclin B

 

inhibitors:

-CIP/KIP family- p21, p27,

-INK4/ARF family: p16/INK4 binds cyclin D-CDK4; p14/ARF- increases p53

 

checkpoint proteins:

-p53: tumor supressor gene- causes cell cycle arrest (thru p21) and apoptosis (thru inducing BAX, etc)

-ATM: activated by double-stranded DNA breaks and arrests cell cycle

Term

CH 7 NEOPLASIA

 

Tumor suppressor genes- and associated tumors (as somatic or inherited mutations)

  • TGF-β
  • E-cadherin
  • NF1
  • NF2
  • APC/β-catenin
  • PTEN
  • SMAD2 or D4
  • RB1
  • p53
  • WT1
  • p16/INK4A
  • BRCA1/2
Definition

 

Tumor suppressor genes

Cell surface

  • TGF-β: somatic mut in colon carcinomas
  • E-cadherin: somatic stomach carcinoma; or familial gastric cancer (inherited)

Inner plasma membrane

  • NF1 (neurofibromin1): somatic mut- neuroblastomas; inherited- NF type 1 and sarcomas

Cytoskeleton

  • NF2 (neurofibromin 2, aka merlin): somatic mut- schwannomas and meningiomas; inherited- NF-type 2 (with acoustic schwannomas and meningiomas)

Cytoplasm

  • APC/β-catenin: stomach, colon and pancreas carcinomas, and melanoma in somatic mut; familial adenomatous polyposis coli/CRC (inherited)
  • PTEN: somatic mut- endometrial and prostate ca; inherited (10q23)= Cowden syndrome (="multiple hamartomas syndrome")
  • SMAD2/D4: colon, pancreas in somatic mut

Nucleus

  • RB1: Somatic mut- retinoblastomas; osteosarcoma, carcinoma of breast, colon, lung; inherited--> retinoblastoma and osteosarcoma
  • p53: nearly all human cancers; inherited= L-Fraumeni syndrome; multiple carcinomas and sarcomas
  • WT1: Wilm's tumor somatic or inherited
  • p16/INK4A: somatic- pancreatic, breast and esophageal ca; inherited--> malignant melanoma
  • BRCA1 and BRCA2: inherited--> carcinomas of female breast, ovary; carcinomas of male breast
Term

CH 7 NEOPLASIA

 

Tumor Markers- list the cancer/organ a/w with the tumor marker listed

 

  • hCG
  • Calcitonin
  • catecholeamines
  • AFP
  • CEA
  • PSA
  • NSE
  • Igs
  • PAP
  • CA-125
  • CA-19-9
  • CA-15-3
Definition

Tumor markers

 

  • hCG= trophoblastic tumors, nonseminomatous testicular tumors
  • Calcitonin= medullary carcinoma of thyroid
  • Catecholeamines= pheochromocytoma
  • AFP= liver (HCC), nonseminomatous germ cell tumors of testis
  • CEA= carcinomas- colon, pancreas, lung, stomach, heart
  • PSA= prostate cancer
  • Igs= myeloma
  • PAP (prostatic acid phosphatase)= Prostate cancer
  • NSE= small cell of lung, neuroblastoma
  • CA-125= ovarian cancer
  • CA-19-9= colon cancer, pancreatic cancer
  • CA-15-3= Breast cancer
Term

CH 8 INFECTIOUS DZ

 

List the agents of bioterrorism in

 

Category A

 

Category B

 

Category C

Definition

Category A:

anthrax (Bacillus anthracis)

Botulism (Clostridium botulinum toxin)

Plague (Yersinia pestis)

Smallpox (Variola major virus)

Tularemia (Francisella tularensis)

Viral hemorrhagic fevers (filoviruses- Ebola, Marburg; and arenaviruses- Lassa, Machupo)

 

Category B:

Brucellosis (brucella sp)

Clostridium perfringens- epsilon toxin

Food-borne threats- Salmonella, E. coli O157:H7, Shigella)

Glanders (Burholderia mallei)

Melioidosis (Burkholderia pseudo pseudomallei)

Psittacosis (Chlamydia psittaci)

Q fever (Coxiella burnetti)

Ricin toxin (castor beans)

Staphylococcal enterotoxin B

Typhus fever (Rickettsia prowazekii)

Viral encephalitis (alphaviruses- venezuelan, eastern and western equine encephalitis virus)

Water-borne threats- Vibrio cholerae, cryptosporidium parvum)

 

Category C:

Emerging agents- Nipah and Hantavirus

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