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

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 __________.

Allergies

Initial (or immediate), second (late)

within minutes, for about an hour

2-24 hours after exposure, up to several days

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

A late Phase?

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.

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?

Th2

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

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

List some of the effects of these mediators.

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

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?

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

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

FcεR1

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

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

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.

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

How would mast cell degranulation affect the following:

GI tract

Airways

Blood Vessels

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

Arachidonic acid

Phospholipase A2

Lipooxygenase

Cyclooxygenase

What chemical mediators do Eosinophils produce?

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)

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)

What are some pharmacological treatments for Allergic reactions?

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

What are some immunological treatments for allergies?

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

RadioImmunoSorbentTest

RadioAllergoSorbentTest

These are both quantitative tests for IgE

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

Systemic

drugs

shock

edema

breathing

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

IgM

IgG

IgA (occasionally)

Cell surfaces

Extracellular Matrix (ex. Goodpastures)

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.

Examples of Type 2 Hypersensitivity reactions via mechanism 1

Complement-dependent

transfusion reactions

erythroblastosis fetalis

autoimmune hemolytic anemia/granulocytopenia/thrombocytopenia

certain drug reactions (eg, penicilin sensitivity)

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

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

Glomerular Nephritis

vascular rejection in organ grafts

Goodpasture's Syndrome

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

Otherwise known as __________.

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

Generalized

Localized (ex. joints, kidney, skin)

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)

What is the pathogenesis of Systemic Immune Complex Disease?

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

What morphological finding is prominent in type 3 hypersensitivity reactions?

Hint: Consider where these these complexes are initially forming

Acute Necrotizing Vasculitis.

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

Systemic Lupus Erythematosus

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

Acute Glomerular Nephritis

Serum Sickness

Arthus reaction

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

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, ___________

CD4: Delayed Type Hypersensitivity

CD8: Direct Cell Toxicity

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 ________.

Mononuclear cells

Perivascular cuffing

microvasculature

fibrin

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 ____________.

CD4 T-Cell

Macrophages

epitheloid cells

granuloma

All this leads to granulomatous inflammation in chronic states.

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.

Contact hypersensitivity is another type of hypersensitivity type 4 reaction.

These reactions are induced by what kind of molecule?

Provide a few examples

Haptens.

Poison ivy (pentadecacatechol)

Metal ions -- ex. Ni, CrO3

 Gluten allergies

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

What are they?

T-Cell mediated, a cellular rejection mechanism,

B-Cells mediate a humoral rejection.

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.

Direct

Indirect

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.

Describe the Indirect Pathway for T cell mediated graft rejection.

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.

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

What are the three classifications and defining times?

Hyperacute: hours

Acute (cellular/humoral): Days

Chronic: Months

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?

granuloctes such as neutrophils.

IL-17 and IL-22

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.)

Pre-formed

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

The main target of a hyperacute tissue rejection is ?

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

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

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?

edema and mononuclear infiltrate

endothelitis

Rejection vasculitis

Marked intimal thickening

antidonor antibodies

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

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?

Indirect

interstitial fibrosis

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

Perforin-granzyme-dependent

Fas-FasL-dependent

There is a strong genetic predisposition for many autoimmune diseases.

Provide a few examples and a disease name

CTLA-4 (indicated in some SLE)

AIRE -- APS/APECED

Fas/FasL

FoxP3 -- IPEX

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.

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

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:

anti-DNA

anti-histone

anti-non-histone proteins bound the RNA

anti-nucleolar antigens

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

Describe the four patterns and what they indicate

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

What ANA antibodies are virtually diagnostic of SLE?

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

anti-Sm (smith) antigen (Speckled pattern)

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

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

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

What are the patterns?

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

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

Libman-Sacks Endocarditis-

 might see mitral thickening

also associated with the heart are pericarditis and accelerated atherosclerosis.

There are some drugs that can induce an SLE syndrome.

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

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

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

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

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

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

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

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

Are they diagnostic?

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

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

What are a few?

Rheumatoid Arthritis (30-50% also have Sjogrens)

SLE (50-90% also have Sjogrens)

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

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

Lip biopsy to examine salivary glands.

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

Systemic ________

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

Systemic Sclerosis

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

There are 2 main categories of Systemic Scleroderma.

Well?

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.

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

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.)

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?

Mast cells and macrophages

TGF beta, IL-13, PDGF

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

ANA for Diffuse?

ANA for Localized/CREST?

Diffuse:

Anti-Scl70 -- DNA topoisomerase 1

Localized/CREST:

Anti-centromere

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?

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.

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

cutaneous changes -- especially thickening from underlying fibrosis

Raynoud's Phenom

dysphagia due to esophageal fibrosis

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

ex. dermatomyositis, polymyositis, inclusion-body mysitis

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

However, a distinguishing characteristic may be ANA for

Ribonucleoprotein U1 RNP

Polyarteritis Nodosa and other vasculitides

What are these?

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.

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?

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.

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?

Amyloid light chain (AL amyloid)

Amyloid Associated (AA amyloid)

Aβ Amyloid

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

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

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

What are the minor 3 biochemical forms of amyloidosis?

Transthyretin Amyloid (TTR)

β₂-microglobulin (Aβ₂m)

Prion Proteins

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)

a component of MHC class 1 molecules.

present in hemodialysis-associated amyloidosis

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

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

Many types identified

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

Familial amyloidotic neuropathies (autosomal Dominant, ATTR proteins)

Localized Amyloidosis:

Deposits are restricted to a particular organ.

Infiltrates of lymphocytes and plasma cells frequently surround the amyloid

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

Amyloid of Aging

AKA: Senile Systemic Amyloidosis

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.

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.

over-production

mutation

intracellular

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)