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Hypersensitivity, Autoimmune Diseases, and Amyloid
UofL Hypersensitivity
94
Pathology
Professional
09/06/2012

Additional Pathology Flashcards

 


 

Cards

Term
What are the four types of hypersensitivity reactions?
Definition

Type 1 - Immediate.

Involves the crosslinking of IgE on mast cells by an antigen (allergen)

 

Type 2 - Antibody Mediated.

The binding of IgG or IgM antibodies to cells or basement membranes.

 

Type 3 - Immune complex-mediated.

Immune complexes containing antibodies and complement deposit in tissues and mediate the reaction.

 

Type 4 - Cell-mediated.

T cell-directed mechanisms of tissue injury

Term

Type 1 Hypersensitivity reactions are generally called _______.

They can vary in severity from a local whelp to systemic reactions.

There are generally 2 phases, the _______ and _______ phases.

 

The first phase begins ______ and lasts ______. The second phase begins ______ and lasts for __________.

Definition

Allergies

 

Initial (or immediate), second (late)

 

within minutes, for about an hour

 

2-24 hours after exposure, up to several days

 

Term

What physical changes characterize the immediate or acute phase of a type 1 hypersensitivity reaction?

 

 

A late Phase?

Definition

Acute phase:

Vasodilation, vascular leakage, smooth muscle contraction (ex. bronchioles - not vascular smooth muscle), and mucus secretion (depending on the site)

 

Late Phase:

Tissue infiltration with Eosinophils, Neutrophils, Basophils, monocytes, CD4 T cells...tissue destruction, usually in the form of mucosal epithelial damage.

Term

What type of cells do CD4 T cells transform into to induce B-cell production of IgE antibodies during a hypersensitivity type 1 reaction? 

 

 

What signals do these cells release?

Definition

Th2

 

IL-3, IL-4, IL-5, IL-13

Term

Generally, what are the primary mediators of type 1 hypersensitivity released by Mast Cells?

 

List some of the effects of these mediators.

Definition

Biogenic Amine = Histamine

  • Smooth muscle contraction
  • increase vascular permeability
  • increase mucus production

Enzymes = ex. Neutral and acid Proteses

  • Activate Complement
  • generate Kinins (vasodilation, smooth muscle contraction)

Proteoglycans = ex. Heparin, chondroitin sulfate

  • package and bind mediators in granules
  • Anticoagulant properties

Note: These are all Preformed

Term

What are the secondary mediators released by Mast cells to mediate a type 1 hypersensitivity reaction?

 

What are some of their actions?

 

Are these preformed or synthesized de novo during a reaction?

Definition

Leukotrienes -- LT-C4 and LT - D4 and LT-E4 are potent vasoactive and spasmogenic mediators. LT-B4 is a chemotactant for granulocytes

 

Prostaglandin D2 -- causes bronchospasm and mucus production

 

Platelet Activating Factor -- Causes platelet aggregation, Histamine release from platelets, increased vascular permeability, vasodilation, bronchospasm. Also chemotactant for neutro's and Eo's.

 

Cytokines:

TNF α, IL-1, IL-3, IL-4, IL-5, IL-6, GM-CSF. Generally these cytokines cause inflammation (esp, TNF and IL-1) and recruit inflammatory cells

 

These factors are synthesized De novo starting in the acute phase

Term
What even leads to Mast cell degranulation?
Definition
IgE bound by its Fc region to the Mast cell surface recognizes a foreign antigen. Crosslinking of two IgE antibodies the the same antigen brings the two receptors into close proximity, which leads to internal signals telling the mast cell to release its granular content.
Term

What is the name of the receptor to which IgE is bound by its Fc region to the surface of a mast cell?

 

 

Definition

 

 

FcεR1

Term

What receptor for Histamine mediates the acute allergies of a type 1 hypersensitivity reaction?

 

 

Definition

 

 

There are 3 Histamine receptors (H1, H2, H3), but the receptor implicated in type 1 hypersensitivites is H1.

Term

What are the actions of:

IL-3

IL-4

IL-5

IL-13

 

These are the primary cytokines released by Th_ cells in a type _ hypersensitivity reaction.

Definition

IL-13, IL-4 = Activation of B-cells to secrete IgE and IgG4, increase mast cell proliferation and activation of Th2 cells(IL-4)

 

IL-5 = increase the proliferation of Eo's. Also antiparasitic.

 

IL-3 = increase the survival and prolif of myeloid cells (everything but lymphocytes)

 

Th2

type 1

Term

How would mast cell degranulation affect the following:

 

GI tract

 

Airways

 

Blood Vessels

Definition

GI tract -  increased fluid secretion and peristalsis, meant for increased expulsion (vomiting and diarrhea)

 

Airway - bronchoconstriction and increased mucus production, expulsion of airway contents (coughing and phlegm)

 

Blood Vessels - increased blood flow (dilation), and increased permeability, leading to edema, inflammation, increased lymph flow

Term
2ndary synthesis of prostaglandins and Leukotrienes by mast cells depends upon release of __________ from the cell membrane with the enzyme ________. Once released, this molecule can be acted upon by _________ to form Leukotrienes or ____________ to become prostaglandins.
Definition

Arachidonic acid

 

Phospholipase A2

 

Lipooxygenase

 

Cyclooxygenase

Term

What chemical mediators do Eosinophils produce?

 

 

Definition

Major Basic Protein

 

Eosinophilic Cationic Protein

 

Eosinophil Peroxidase

 

As well as products similar to what mast cells release:

LT's, PG's, Cytokines (IL-1,2,4,5,6,8,13 and TNF)

Term
What factors beside IgE crosslinking could cause a mast cell to degranulate?
Definition

Complement C3a and C5a

drugs or chemicals -- codeine, morphine, adenosine, mellitin

Calcium ionophores (ca influx causes vesicle fusion with membrane)

Certain cytokines - ex IL-8

excess cold, hea, irritants

contrast media (as during a CT scan)

Term

What are some pharmacological treatments for Allergic reactions?

 

 

Definition

Anti-histamine - block H1 receptors (the main cause of vascular response)

COX/Lipooxygenase inhibitors

Corticosteroids (decreases transcription of proinflammatory mediators and increases transcription of anti-inflammatory mediators)

Chromolyn Sodium (prevents mast cell degranulation)

Β2 agonists (epinephrine, albuterol) - relaxes smooth muscle

Term

What are some immunological treatments for allergies?

 

 

Definition

Inhibit Th2 activation (desensitization with increasing antigen doses, administer Th1 inducing cytokines to divert -- IFNγ, IL-10, IL-12)

 

Block Th2 cytokines and B cell activation -- inhibilt CD40L, IL-4, IL-13

 

Inhibit eosinophil-dependent inflammation -- inhibit IL-5

 

Block mast cell binding of IgE -- anti IgE or FcεR1 blocker

Term
What are RIST and RAST?
Definition

RadioImmunoSorbentTest

 

RadioAllergoSorbentTest

 

These are both quantitative tests for IgE

Term

_______________ anaphylaxis is an immediate type hypersensitivity reaction usually caused by administration of foreign proteins and _____ characterized by vascular ____, widespread _____, and difficulty _____.

 

Definition

Systemic

drugs

shock

edema

breathing

Term

What antibodies can be implicated in a type 2 hypersensitivity reaction?

 

Definition

IgM

 

IgG

 

IgA (occasionally)

Term
Type 2 hypersensitivity reactions are mediated by antibodies reacting against antigens on what two types of locations?
Definition

Cell surfaces

 

Extracellular Matrix (ex. Goodpastures)

Term
There are 3 mechanisms by which a type 2 hypersensitivity reaction occurs. Name them and provide a description.
Definition
  1. Complement-dependent: complement binds antibody bound to cell surface (opsonization) and enhances uptake by macrophages or hemolysis with MAC. Example: transfusion reaction
  2. Antibody-Dependent Cell-Mediated Cytotoxicity: cells with low concentrations of bound antibodies are lysed by nonsensitized cells the an Fc receptor (example, a neutrophil binding and releasing toxic compounds) Example: Graft Rejection
  3. Antibody-mediated cellular dysfunction: antibodies cause a disruption of cell function. Ex. Graves Disease, Myasthenia Gravis.
Term

Examples of Type 2 Hypersensitivity reactions via mechanism 1

 

Definition

Complement-dependent


 

transfusion reactions

erythroblastosis fetalis

autoimmune hemolytic anemia/granulocytopenia/thrombocytopenia

certain drug reactions (eg, penicilin sensitivity)

Term

Mechanism 2 of type 2 hypersensitivity reactions can be used against both a cell and extracellular proteins such as the basement membrane.

 

elaborate on the mechanism that affects the ECM

Definition
antibodies react with the ECM and attract complement, releasing active complement fragments that attract neutrophils and monocytes. These cells bind the antibodies with Fc receptors and release enzymes and reactive oxygen intermediates and cause tissue damage.
Term

What are examples of diseases caused by the Complement/Fc-receptor mechanism of type 2 hypersensitivities?

 

Definition

Glomerular Nephritis

 

vascular rejection in organ grafts

 

Goodpasture's Syndrome

Term

What factors may lead to the deposition of antibody/antigen complexes in tissue and cause a local or systemic inflammatory process?

 

Otherwise known as __________.

Definition

Type 3 Hypersensitivity Reaction

 

the nature of the antigen/antibody complex -- become insoluble

 

the ratio of antigen:antibody (too much antigen leads to formation of very small complexes that cannot be picked up by macrophages)

 

the inability of phagocytic cells to remove immune complexes due to overload or disfunction

Term
Immune complex formation can be _______, being formed in circulation and be deposited systemically, or they can be ____________ to a particular organ.
Definition

Generalized

 

Localized (ex. joints, kidney, skin)

Term
What are some disease phenotypes associated with Antibody-mediated cellular disfuntion, a mechanism of type 2 hypersensitivity?
Definition

Myasthenia Gravis (antibody against ACh receptor of muscles)

 

Grave's Disease (activating TSH receptor of thyroid)

 

Pemphigus vulgaris (antibodies against desmosomes disrupt epidermal cell junctions, causing vesicles)

Term

What is the pathogenesis of Systemic Immune Complex Disease?

 

 

 

Definition

 

1. Formation of antigen/antibody complex in circulation, complement may bind to these complexes.

 

2. Deposition of immune complex in tissues. The complexes insert into tissues and interact with neutrophils or monocytes via Fc or complement receptors, causing release of vasoactive mediators and cytokines.

 

3. Inflammation reaction illicited by immune complexes. About 10 days after administration. Major events are complement activation (C5a, C3a) and continued phagocyte activation

Term

What morphological finding is prominent in type 3 hypersensitivity reactions?

 

Hint: Consider where these these complexes are initially forming

Definition

 

 

Acute Necrotizing Vasculitis.

 

The necrotizing vessels will be replaces by a smudgy, eosinophilic deposit -- fibrinoid necrosis

Term
What are examples of Type 3 Hypersensitivity reactions?
Definition

Systemic Lupus Erythematosus

 

farmers lung -- caused by fungus (_____ lung, in general -- caused by job-associated allergen)

 

Acute Glomerular Nephritis

 

Serum Sickness

 

Arthus reaction

Term

Hypersensitivity type 4 reactions are mediated by what types of cells?

 

 

Definition
CD4 and CD8 T-cells
Term

There are two general classification of type 4 hypersensitivity reaction.

 

One is mediated by CD4 T cells, ____________

 

The other is mediated by CD8 T cells, ___________

Definition

CD4: Delayed Type Hypersensitivity

 

CD8: Direct Cell Toxicity

 

Term

Delayed type hypersensitivities are characterized by accumulations of ___________ around small veins and venules.

 

This density is referred to as _________________.

 

 

Signals from these cells mediates inflammation, causing increased permeability in the _________, edema, and deposition of ________.

Definition

Mononuclear cells

 

Perivascular cuffing

 

microvasculature

 

fibrin

Term

The main cell type that is seen in perivascular cuffing is __________, which may be replaced by _________ (type of cell) if the antigen cannot be eliminated (over 2-3 weeks).

 

These latter cells undergo a transformation to become __________.

 

The combination of the latter cells and the main, mediating cell type are characteristic of a ____________.

Definition

CD4 T-Cell

 

Macrophages

 

epitheloid cells

 

granuloma

 

All this leads to granulomatous inflammation in chronic states.

 

 

 

Term
What are the cytokines most relevent to Delayed type hypersensitivity reactions? What cells are responsible for releasing them?
Definition

IFN gamma -- Th1 cells. Activate macrophages and B cell Ig class switching

 

IL-12 -- macrophages. Increase Th1 activation, macrophage and NK activation

 

TNF -- Th1 cells. proinflammatory. increases vasc perm, leukocyte mobilization, local coagulation, selectin and integrin expression by endothelium

 

lymphytoxin (LT) -- Th1(?), important in limiting inflammation and leukocyte recruitment.

Term

Contact hypersensitivity is another type of hypersensitivity type 4 reaction.

 

These reactions are induced by what kind of molecule?

 

Provide a few examples

Definition

Haptens.

 

Poison ivy (pentadecacatechol)

Metal ions -- ex. Ni, CrO3

 Gluten allergies

Term

Tissue transplant rejection is mediated by two different types of leukocytes.

 

What are they?

 

Definition

T-Cell mediated, a cellular rejection mechanism,

B-Cells mediate a humoral rejection.

Term

T-cell mediated immunity is a cellular rejection path that can be ___________ or in__________.

 

This has to do with whether or not the donor or recipient APC's present the foreign antigen/MHC complex.

Definition

Direct

 

Indirect

Term
Describe the direct pathway of T-cell-mediated graft rejection.
Definition

Recipient T cells directly recognize DONOR MHC molecules on the surface of DONOR APCs. This sensitizes the CD8 cells and they can directly kill donor cells bearing those antigens.

 

Essentially, there is no middle man. The recipient's cells recognize the Donor's APCs without any cross presentation.

Term

Describe the Indirect Pathway for T cell mediated graft rejection.

 

 

Definition

Recipient T cells recognize antigens from the donor graft presented by the recipient's own APCs.

 

Indirect because the foreign antigen had to be recognized, ingested, and then presented to the recipient T-cells.

Term

There are 3 classifications of tissue reection based on the time frame in which they occur:

 

 

What are the three classifications and defining times?

Definition

Hyperacute: hours

 

Acute (cellular/humoral): Days

 

Chronic: Months

Term

Th17 cells are also implicated in immunologic inflammation.

 

Rather than recruit macrophages to the site of inflammation, Th17 cells recruit what type of cells?

 

What cytokines are responsible for this recruitment and activation?

 

 

Definition

granuloctes such as neutrophils.

 

IL-17 and IL-22

Term

Hyperacute reactions happen when the antibodies to the transplanted tissue are _______.

 

This is why it takes only minutes to hours for a reaction to happen (example ABO incompat.)

Definition

Pre-formed

 

The recipient had previously been exposed to some antigen present in the donor tissue.

Term

The main target of a hyperacute tissue rejection is ?

 

 

This damage is due in part to what component that often works with antibodies?

Definition

Vascular endothelium.

 

 

Complement -- fixation occurs on antibody-coated endothelium, leading to lupus like events...thrombosis

 

There is ultimately neutrophil accumulation to remove debris, vessel occlusion, fibrinoid necrosis

Term

Acute tissue rejection, happening within days or SUDDENLY within months, can utilize both T cell and B cell mediated mechanisms.

 

When the mechanism is mostly CD8 T cell mediated you can expect to find what pathology?

 

 

Definition

edema and mononuclear infiltrate

 

endothelitis

 

 

Term
When Acute tissue rejection is mediated by a B-cell humoral response, what patholoy would you expect to find?
Definition

Rejection vasculitis

 

Marked intimal thickening

 

antidonor antibodies

 

Basically a similar picture to the hyperacute because the antibodies are mediating the inflammation.

Term

The most common cause of graft rejection is a chronic rejection because patients are on immunosuppression.

 

Chronic rejection usually works via the direct/indirect (choose one) pathway?

 

thus, you would expect to see?

Definition

Indirect

 

interstitial fibrosis

Term

Two mechanisms CD8 T cells use to destroy target cells, in tissue rejection, for example, are:

 

 

Definition

Perforin-granzyme-dependent

 

 

Fas-FasL-dependent

Term

There is a strong genetic predisposition for many autoimmune diseases.

 

Provide a few examples and a disease name

Definition

CTLA-4 (indicated in some SLE)

 

AIRE -- APS/APECED

 

Fas/FasL

 

FoxP3 -- IPEX

Term

Systemic Lupus Erythematosus is the classic autoimmunde disease, more common in women than men, and even more so in African-American women.

 

Describe the possible clinical problems a patient with SLE may have.

Definition

Skin rash (malar, butterfly, or discoid often)

Photosensitivity

Arthritis, serositis, oral ulcers

Hemotologic issues -- anti-rbc,leukocyte,plt antibodies

Fever, fatigue, weightloss

Renal, cardiac, CNS involvement

Positive ANA

Term

Though ANAs are not exclusive to SLE, there may be characteristic antibodies found to the nuclear elements of cells.

 

The four main types of anti-nuclear antibodies are:

 

Definition

anti-DNA

anti-histone

anti-non-histone proteins bound the RNA

anti-nucleolar antigens

Term

Indirect immunofluorescence testing will generate particular patterns that help identify what type of ANAs are present.

 

Describe the four patterns and what they indicate

Definition

Homogenous -- chromatin, histones, occasionally ds DNA

 

Rim or peripheral -- double stranded DNA

 

Speckled -- Non-DNA nuclear constituents, such as Sm antigen, ribonucleoprotein

 

Nucleolar -- nucleolar RNA

Term

What ANA antibodies are virtually diagnostic of SLE?

 

 

Definition

Anti-double stranded DNA (rim/peripheral or homogenous staining)

 

anti-Sm (smith) antigen (Speckled pattern)

 

Term
Anti-phospholipid antibodies are present in 40-50% of SLE patients. However, this may also give a false positive if testing for what other disease?
Definition

Syphilis (cardiolipin)

 

The test is called the VDRL.

 

These antibodies give a falsely elevated aPTT in vitro, but actually increase clotting in vivo (pro-coagulatory). May be associated with spontaneous miscarriages and focal cerebral or ocular ischemia

Term

In SLE there will often be what form of vasculitis? (recall type 3 hypersensitivities)

 

 

Definition
Necrotizing vasculitis due to the deposition of immune complexes in tissue, primarily vasculature, leading to inflammation and the aggregation of neutrophils and macrophages.
Term

There are 5 patterns of lupus nephritis, and can show up to varying degrees in different patients.

 

What are the patterns?

 

Definition

1. minimal/none detected  (rare)

2. Mesangial lupus glomerulonephritis -- mesangial cell prolif

3. Focal proliferative glomerulonephritis -- affects <50% of glomeruli

4. Diffuse proliferative glomerulonephritis (most serious form) -- prolif of endothelial, mesangial, and epithelial cells, fibroid necrosis

5. Membranous glomerulonephritis -- widespread thickening of capillary walls

Term

The characteristic SLE rashes are due to immune complex deposition at what morphological junction?

 

 

 

Definition
Dermal-epidermal junction
Term
Before the use of corticosteroids, a particular non-bacterial endocarditis was common. What is this called?
Definition

Libman-Sacks Endocarditis-

 might see mitral thickening

 

 

also associated with the heart are pericarditis and accelerated atherosclerosis.

Term

There are some drugs that can induce an SLE syndrome.

 

What are the drugs and what ANA is present in this form?

Definition

Procainamide

 

hydralazine

 

isoniazid

 

D-penicillamine

 

Anti-histone antibodies are common (homogenous) while anti-dsDNA is rare

 

Renal and CNS symptoms are rare with this form

Term

___________ syndrome is characterized by immunological damage to the lacrimal and salivary glands.

 

This leads to dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia).

Definition
Sjogren syndrome
Term

What are the primary cell types found in infiltrates of the lacrimal and salivary tissues?

 

 

Definition

Primarily CD4 T cells (perivascular and periductal -- type 4 hypersensitivity)

 

There are also Activated B cells responsible for secreting antibody  -- ANA to be specific

Term

What type of ANAs would you expect to see in Sjogren Syndrome?

 

Are they diagnostic?

Definition

antibodies against ribonucleoprotiens: SS-A (Ro) and SS-B (La)

 

This would make a speckled pattern with immunofluorescence.

 

These are disease markers for Sjogrens, but they are not diagnostic because they may also be seen in SLE

Term

Sjogrens is often a secondary syndrome, seen in conjunction with other autoimmune diseases.

 

What are a few?

Definition

Rheumatoid Arthritis (30-50% also have Sjogrens)

 

SLE (50-90% also have Sjogrens)

 

Primary Biliary Cirrhosis (50-100% also have Sjogrens)

Term

If the ANAs aren't diagnostic for Sjogrens, what must you do to confirm a diagnosis?

 

 

Definition

Lip biopsy to examine salivary glands.

 

 

combination of lacrimal and salivary gland inflammation = Mikulicz Syndrome, which is also in other diseases

Term

Systemic ________

 

Names a chronic disease characterized by abnormal accumulations of fibrous tissue in ________ and multiple __________.

Definition

Systemic Sclerosis

 

skin, organ (kidneys, heart, lungs, GI)

Term

There are 2 main categories of Systemic Scleroderma.

 

Well?

Definition

Diffuse Scleroderma -- widespread skin involvement, rapid, with early visceral involvement

 

 

Limited Scleroderma -- skin involvement confined to fingers, foreares, and face. slow progression and late visceral involvement.

Term

People with Limited Sclerosis may also develop a constellation of symptoms involved in what other syndrome?

 

Definition

CREST

Calcinosis

Raynoud's phenomenon

Esophageal dysmotility

Sclerodactyly (a localized thickening and tightness of the skin of the fingers or toes. Sclerodactyly is commonly accompanied by atrophy of the underlying soft tissues.)

Telangiectasia (small dilated blood vessels near the surface of the skin or mucus membranes, measuring between 0.5 and 1 millimeter in diameter.)

Term

Though the antigen responsible for systemic sclerosis is unknown, CD4 T cells secrete a variety of cytokines that lead to recruitment of various cells and to the production of collagen and extracellular matrix proteins.

 

What cells are recruited and what cytokins help mediate the ECM deposition?

Definition

Mast cells and macrophages

 

TGF beta, IL-13, PDGF

Term

The ANA for the diffuse and localized systemic sclerosis are different.

 

ANA for Diffuse?

 

ANA for Localized/CREST?

Definition

Diffuse:

Anti-Scl70 -- DNA topoisomerase 1

 

Localized/CREST:

Anti-centromere

 

Term

Gross features of systemic sclerosis involve diffuse sclerotic atrophy of the skin in the fingers and distal regions of upper extremeties, neck, and face.

 

What would you expect histologically?

 

Definition

edema

perivascular infiltrates containing CD4 T cells with swelling and degeneration of collagen fibers.

 

After degeneration there is repair with extensive fibrosis and deposition of collagen in the dermis. Thinning of the eidermis.

 

Includes GI and esophagus. Also a likelihood of kidneys, heart, and lung involvement. Most deaths are due to renal or pulmonary failure.

Term

What are the features that sets Systemic Sclerosis apart from SLE, RA, and Polymyositis?

 

 

Definition

cutaneous changes -- especially thickening from underlying fibrosis

Raynoud's Phenom

dysphagia due to esophageal fibrosis

Term
What are Inflammatory Myopathies?
Definition

Heterogenous group of disorders characterized by injury and inflammation of mainly skeletal muscles.

 

 

ex. dermatomyositis, polymyositis, inclusion-body mysitis

Term
What is Mixed Connective Tissue Disease?
Definition

Features suggestive of SLE, Systemic Sclerosis, RA, and Polymyositis.

 

However, a distinguishing characteristic may be ANA for

Ribonucleoprotein U1 RNP

Term

Polyarteritis Nodosa and other vasculitides

 

What are these?

Definition

Group of diseases characterized by necrotizing inflammation of blood vessel walls.

 

"non-infectious necrotizing vasculitis" is used to distinguish these from necrotizing vasculits caused by direct infection of vascular wall.

 

May affect all types of vessels.

Term
____________ is a disease that may have immunological components, but is mostly considered a disease related to abnormal protein folding.
Definition
Amyloidosis
Term

By using what dyes on a tissue biopsy can you the usual hallmarks of amyloidosis: amorphous, eosinophilic, hyaline, extracellular substance.

 

How does this build up of "junk" impact the surrounding tissue?

Definition

Congo Red

also the Green Birefringence can be observed when stained for polarized light microscopy

 

Amyloid accumulations exert pressure on the surrounding cells and distort the tissue structure, causing atrophy of cells.

Term

Since amyloid is not a single disease, but a cluster of diseases that create a similar deposition of protein, the exact mechanism is unclear, but often involves inflammatory processes. As such, there are over 15 forms of amyloid protein. However, they all have the same basic conformation, no matter what their chemical makeup.

 

All amyloid proteins are folded in what conformation?

Definition
Beta Pleated Sheets
Term
What are the 3 major forms of amyloid proteins?
Definition

Amyloid light chain (AL amyloid)

 

Amyloid Associated (AA amyloid)

 

Aβ Amyloid

Term
Describe briefly AL amyloid
Definition

Amyloid Light Chain contains Ig light chains, most often the delta chain, or light chain fragments.

 

It is produced by Ig producing cells and it's deposition is associated with some form of monoclonal B cell proliferation.

 

This is a primary type, and the most common

Term
Briefly Describe AA Amyloid:
Definition

Amyloid Assoiciated contains non-immunoglobulin proteins synthesized in the liver. It is derived from a serum precursor called SAA.

 

This might be a result of over production of proteins during a chronic inflammatory response.

 

This is found in secondary, or reactive systemic amyloidosis

Term
Briefly describe AB amyloidosis:
Definition

Found in cerebral lesions of Alzheimer's disease (A,B....What was I talking about?)

 

Deposits are fragments derived from a transmembrane glycoprotein called Amyloid Precursor Protein

Term

What are the minor 3 biochemical forms of amyloidosis?

 

 

Definition

Transthyretin Amyloid (TTR)

 

β2-microglobulin (Aβ2m)

 

Prion Proteins

Term
Briefly describe ATTR:
Definition

Transthyretin Amyloid is a normal serum protein that binds thyroxine and retinol.

 

Mutations in TTR favor its deposition into tissue as amyloid (Familial amyloid polyneuropathies)

 

TTR is also deposited in the heart of aged individuals (Senile systemic amyloidosis)

Term
Briefly describe Aβ2m:
Definition

a component of MHC class 1 molecules.

 

present in hemodialysis-associated amyloidosis

Term
Briefly describe Prion Proteins involved in amyloidosis:
Definition
In prion disease, misfolded prion proteins can aggregate in the extracellular space and form amyloid deposits.
Term

Patients with Multiple Myeloma, a primary amyloidosis (AL/immune type), will have what type of protein measureable in their urine and serum?

 

Definition
Bence Jones
Term
Reactive Systemic Amyloidosis:
Definition

Amyloid deposits are systemic and made of AA protein (from precursor SAA -- or you may recall SAP from the acute phase inflammation).

 

It is normally secondary to chronic inflammatory conditions such as RA, IBD, and connective tissue disorders

Term
Hemodyalisis-Associated Amyloidosis:
Definition
Occurs in long-term dialysis patients due to deposition of serum Beta 2-microglobulin (component of HLA 1)
Term
Heredofamilial Amyloidosis:
Definition

Many types identified

 

Ex. Familial Mediterranean Fever (an autosomal recesive condition causing AA proteins)

 

Familial amyloidotic neuropathies (autosomal Dominant, ATTR proteins)

Term

Localized Amyloidosis:

 

Definition

Deposits are restricted to a particular organ.

 

Infiltrates of lymphocytes and plasma cells frequently surround the amyloid

Term
Endocrine Amyloidosis
Definition

Microscopic deposits of amyloid can be found in several types of endocrine tumors and in the islets of langerhans in DMII patients.

 

Amyloid seems to be derived from peptide hormones

Term

Amyloid of Aging

 

AKA: Senile Systemic Amyloidosis

Definition

the deposition of amyloid in elderly patients (70-80 y.o.).

 

Prominent involvement of the heart results in restrictive cardiomyopathy and arrhythmias. Composed of TRR proteins.

Term

Amyloid deposition can be seen as an ____ production of normal proteins that are prone to misfolding, most cases,

 

Misfolding of proteins due to a ______ that led to structural instability

 

A defective mechanism of ________ degredation of misfolded proteins.

Definition

over-production

 

mutation

 

intracellular

Term
What does the diagnosis of Amyloidosis depend upon?
Definition

Demonstration of amyloid deposits in tissues with a sample obtained from a biopsy (or autopsy)

 

 

Kidney for renal manifestations (most common)

 

Fat pad, rectal, gingival biopsy for systemic amyloid

 

Serum and urine protein electrophoresis (immunocyte associated, eg. Bence Jones protein)

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