Exam 2: Hypersensitivities Flashcards

Question

Systemic Anaphylaxis Manifestations

Answer 1

* SOB and labored breathing * Throat tightness * Generalized warmth * Headache * Restlessness * Drop in BP (shock) * GI cramping / incontience * Bladder cramping / incontinence * Catastrophic hypothension or bronchiole constriction may lead to death within 10-20 minutes

Answer 2

* **Limited to specific tissue or organ system** * Involves local IgE-mediated mast cell degranulation * ~20% of the population in developed countries have some form * _Includes:_ * Allergic rhinitis * Contact urticaria * Food allergies * Some forms of asthma

Answer 3

**"Hay Fever"** * Affects ~10% of US population * **Induced by mast cells in nasal mucosa and conjunctivae of eye** * _Symptoms:_ * Watery exudates of nasal mucosa, conjunctivae, and URT * Itching * Sneezing * Coughing

Answer 4

Type I hypersensitivity of the skin characterized by **hives**

Answer 5

* **Involves mast cell degranulation in the upper and lower GI tract** * Absorption can allow enough Ag into the blood for systemic sx * Asthma attacks * Hives * Systemic anaphylaxis * Affects ~4% of US population * Most often appear in **infants and young children** * Can develop at any age to food eaten for years * Most common foods are **peanuts, tree nuts, soy, shellfish, fish, eggs**

Answer 6

**Localized Type I Hypersensitivity** Biphasic change in FEV₁ **_Early Phase:_** * Inhaled Ag causes **mast cell** **degranulation in lower respiratory tract** and **arachidonic products** * Results in: * **Bronchoconstriction** * **Airway edema** * **Mucus secretion** * **Inflammation** * **Characteristic drop in FEV₁ during 1st hour** **_Late Phase_** * **Lymphocytes (especially T_H2) infiltrate** * _IL-4_ * ↑ IgE production * Mast cell development * Mucus production * Drives T_H2 response * _IL-5_ * Induces eosinophil differentiation and activation * _IL-13_ * Same effect as IL-4 * _Eotaxin_ * FEosinophil recruitment * **Eosinophils** **infiltrate** * Either a primary or secondary effector cell in type I hypersensitivity-associated tissue damage * ↑ mucus production * ∆ matrix formation * Through deposition of granule proteins (**MBP**) * Cytokine production * Lipid mediator release * **Second drop in FEV₁ follows 4+ hours later and continues for 12+ hours** while cellular infiltrates accumulate * Induces lung hypersensitivity

Answer 7

Measures ****_a_**ntigen specific** **IgE** in the serum

Answer 8

Measures **total **_I_**gE** in the serum

Answer 9

**Skin test for allergy that usually correlates with a positive RAST test for that allergen.** Small amount of Ag introduced by either **intradermal injection** or **superficial scratching**. Induces degranulation of local mast cells and mediator release leading to a **wheal-and-flare reaction**.

Answer 10

Normal ⇒ 1-3% eosinophils in peripheral blood Asthmatics ⇒ 5-15% eosinophils

Answer 11

Mast cells / IgE / eosinophils involved in defense against **helminthic parasites (worms) and ectoparasites (ticks)**. 1. Parasites in the gut stimulate IgE & IgG production by GALT 2. Local mast cells become sensitized and activated 3. Degranulation causes edema and attracts inflammatory cells 4. Eosinophils can kill the parasite or make survival difficult

Answer 12

**The genetic predisposition to develop allergies e.g. make IgE.** * Multifactorial inheritance * Candidate genes * IL-4 / IL-5 * Enviromental factors which may affect allergy development * Pollution * Increased/altered Ag exposure * Maternal effects * Hygeine hypothesis

Answer 13

* **Immune reactions damage the cell or membrane where Ab is attached to:** 1. Integral part of cell membrane 2. Components covalently bound to the cell membrane * Penicillin and Quinidine * Immunogenic response * Can lead to cell mediated damage: * **Phagocytosis** * Opsonized targets _in tissues_ removed by local phagocytes * Opsonized targets _in the blood_ removed by fixed macrophages in the spleen and liver * **Complement** * Induces osmotic lysis of RBCs * Damages host tissues ⇒ inflammation * **ADCC** * NK cells, neutrophils, and macrophages kill host cells

Answer 14

Type II Hypersensitivity Ex. Type B blood into Type A individual → C' activation → hemolysis

Answer 15

Type II Hypersensitivity **Clearance of fetal Rh⁺ RBCs coated with maternal IgG by the reticuloendothelial system** \*\*Complement is usually not involved because Ag sparsely distributed on RBC and cannot crosslink.

Answer 16

Type II Hypersensitivity **Preformed Ab binding to graft endothelium**

Answer 17

Type II Hypersensitivity **Auto-Ab bind to RBCs leading to destruction**

Answer 18

Type II Hypersensitivity **Auto-Abs bind to platelets leading to destruction**

Answer 19

Type II Hypersensitivity Auto-Ab react against the **basement membrane of the glomerulus** leading to **glomerulonephritis** and **tissue destruction** Immunofluoresence with a **confulent "lacy" pattern**

Answer 20

Type II Hypersensitivity * **Penicillin & Quinidine** break down to form haptens * **Haptens** **bind non-specifically to proteins on RBCs** * Hapten-carrier complexes can **induce Ab production** * Ab binds to the drug bound to the RBC causing destruction

Answer 21

Type II Hypersensitivity **Anti-acetylcholine receptor auto-Ab** binds to the NMJ causing removal from the membrane, destruction and neurological deficits

Answer 22

Type II Hypersensitivity * **Auto-Ab bind to intrinsic factor** on intestinal mucosa causing destruction * Intrinsic factor required for absorption of Vit B₁₂ * Vit B₁₂ necessary for RBC development

Answer 23

Antibodies alters or interferes with normal cell function

Answer 24

Non-cytotoxic Type II Hypersensitivity **Auto-Abs bind to the receptor on acinar cells for TSH** → mimics TSH binding → **unregulated activation** of the thyroid → **over-production** of thyroid hormones Auto-Ab called long-acting thyroid stimulating (LATS) auto-antibodies

Answer 25

**"**_I_**mmune-complex deposition"** _Large doses_ of both Ag and Ab required * Ab bind small Ag ⇒ **immune complexes** * **Deposit near or within blood vessels** * Results in **damage at the sites of deposition** Distribution of the complexes determines the outcome of the reaction: * _Localized reaction_ * Immune complexes **formed in tissues near site of Ag entry** w/ preformed Ab * Commonly called the **Arthrus reaction** * _Systemic reaction_ * Immune complexes **formed in the blood** and deposit at different sites causing damage * Glomerular membrane of the kidney * Blood vessel walls * Synovial membrane of joints * Skin * Commonly called **serum sickness**

Answer 26

Localized reaction with **preformed** **Ab** **Injection of Ag** into tissues Usually takes **4-8 hours** 1. _Subcutaneous or intradermal injection of Ag_ → **formation of immune complexes** **in tissue** 2. **Activation of complement** **cascade** * _Deposition of MAC and C3b_ * MAC generally cannot kill nucleated cells but causes damage and inflammation * _C5a / C3a released_ 3. C5a and C3a → **mast cell** **degranulation** → ↑ vascular permeability → ↑ accumulation of immune complexes at basement membrane 4. _Clumping of platelets_ → release of clotting factors → **microthrombi** 5. **Neutrophils** **recruitment** by C5a → attempts phagocytosis of immune complexes * C3b and Fc-associated opsonization 6. _Phagocytosis unsuccessful_ → **frustrated** **phagocytes** → releases _superoxide radicals & proteolytic enzymes_ into tissue → local destruction of the internal elastic membrane → **tissue damage and capillary damage** * **Non-blanching erythema and ulceration**

Answer 27

* **Insect bites** * **Farmer's lung** * Inhalation of thermophilic actinomycetes from moldy hay * **Pigeon fancier lung** * Inhalation of serum protein in dust containing dried pigeon feces * **Allergy desensitization injections** * Stimulates production of IgG that competes with IgE for Ag binding

Answer 28

_Normal clearance of immune complexes in the blood:_ 1. **Complement** activation 2. **C3b** binds Ab-Ag complex 3. Binding to **CR1 receptors** **on RBCs** 4. Immune complexes carried to the **spleen and liver** (_Reticuloendothelial system_) 5. **"Vacuumed" from RBC** by tissue-dwelling macrophages

Answer 29

**Occurs with antigen excess** ⇒ small immune complexes ⇒ inefficient complement activation ⇒ poor clearance * Ab binds Ag ⇒ immune complexes form * Complexes in blood are not harmful * Pathological effects manifest when deposited in tissues

Answer 30

**If preformed antibodies present ⇒** takes _minutes to a few hours_ to develop **Without preformed antibody ⇒** time needed for Ab synthesis **⇒** effects in _8-12 days_ after Ag exposure

Answer 31

Deposit where there is turbulent flow: * **Kidney** ⇒ glomerulonephritis * **Joints** ⇒ arthritis * **Skin** ⇒ rash * **Arteries** ⇒ vasculitis

Answer 32

* _Autoimmune diseases_ * **Systemic lupus erythematous (SLE)** * See glomerulonephritis, arthritis * **Rheumatoid Arthritis** * Rheumatoid factor binds IgG ⇒ complement activation * _Drug reactions_ * **Penicillin and sulfonamides** * _Infectious diseases_ * **Post-streptococcal glomerulonephritis** * Circulating complexes of Ab-StrepAg deposit in kidney * **Hepatitis B** * Virus releases free Hep B surface Ag into blood to absorb neutralizing Ab * Ab binds free Ag and deposit in the skin causing rash

Answer 33

**"Delayed type hypersensitivity or DTH"** **_Sensitization Phase_** (1-2 weeks) * **Initial exposure to Ag leads to T-cell proliferation and activation** * **T_DTH cells** are mostly **T_H1** but sometimes **T_C** involved * Ag usually extracellular or from phagosome * Most likely on MHC class II * Requires both signals (TCR:MHC II & B7:CD28) * IL-2 dependent * No initial reaction b/c it takes _1-2 weeks_ to generate enough T cells **_Effector Stage_** (48-72 hours) * **Pre-existing memory CD4⁺ T_DTH** cell activated by _subsequent Ag exposure_ * Activated T_DTH cells produce cytokines * IL-2 * IL-3 * GM-CSF * IFN-γ * Macrophage "specific" chemokines (MCAF, MIF) * Recruited/activated **macrophages** generate **ROIs and lytic enzymes** * Some leak out and damage surround tissues

Answer 34

T_H1 cells and macrophages in DTH response critical for control of **intracellular pathogens**. * _Intracellular bacteria_ * Mycobacterium tuberculosis * Listeria monocytogenes * _Intracellular viruses_ * Herpes simplex * Rubella * Variola (smallpox) * _Intracellular parasites_ * Leishmania sp. * _Intracellular fungi_ * Pneumocytis carinii * Candida albicans

Answer 35

* **Immune response is poorly focused** * Tissue damage common * **Pathogen usually cleared rapidly** * Tissue damage minor, localized, and temporary * **If pathogen is not cleared ⇒ prolonged DTH reaction** * Chronic inflammation & granulomas

Answer 36

Painful area of _induration and swelling_ at the site of **injection of Ag** **Ag → APC → T_H1 → IFN-γ → MØ recruitment and activation → release of lytic enzymes and ROIs** Takes _48-72 hours_ for a reaction _Clinical uses:_ * **Test for previous exposure to an organism** * Effector cells need a much lower [Ag] for activation * **Test for immune competence** ⇒ _anergy test_

Answer 37

"Allergic contact dermatitis" _Eczematous reaction_ at site of **contact with sensitizing agent**. Takes 48-72 hours. _Mechanism:_ * Ag exposure * **Langerhan cells** present Ag to **T-cells** at _local lymph nodes_ * **Mononuclear cell infiltration** of _dermis and epidermis_ * **Macrophage** activation & effector functions * **Edema** of the epidermis and **microvesicle** formation

Answer 38

Common agents that induce contact hypersensitivity: **_Salts_** * **Most likely alter the conformation of self-peptides in the groove (Ag appears foreign)** * Ex: * Nickel salts * Chromate * Dinitrochlorobenzene * Rubber accelerators **_Haptens_** * Able to penetrate the epidermis * **Conjugates to proteins found within the skin** * Hapten-protein conjugate **presented on MHC class II to T-cell** * Ex: * Poison ivy - **urushiol** in plant leaves * Poison oak * Some drugs (often topical abx)

Answer 39

* Can be caused by different types of reactions or a mixture of different hypersensitivity reactions * Multiple hypersensitivities can cause **similar manifestations** * A single event can have **multiple underlying mechanisms** in the same individual

Answer 40

* Severe pathological effects involving **T cell-mediated immunity** * Associated with **extensive tissue necrosis and fibrosis** → tissue destruction * Usually results from **persistence of intracellular pathogens within macrophages** or **long-lasting stimulating Ag**

Answer 41

**Prevent infectious microbes from persisting in the circulation** * Ex: form calcified walls around TB finections in the lungs ⇒ Ghon complexes * Can live for decades with TB isolated in granulomas * ↓ T_H function can lead to reactivation * Aging * Infection * Cancer * AIDS

Answer 42

1. Ag ⇒ APC ⇒ **T_H1** ⇒ IFN-γ & chemoattractants 2. Mononuclear cells accumulate around blood vessels ⇒ **perivascular cuffing** 3. **Failure to clear stimulus** 4. **Release of toxic mediators** 5. **Mφ accumulate** @ site of Ag 6. Mφ ⇒ **epitheliod cells** 7. **Mφ and fibroblasts** proliferate & produce _collagen_ 8. _Walls off Ag_ through **granuloma formation**

Answer 43

Inside → Outside * **Central zone of necrosis** * **Mφ** and **epithelioid cells** in surrounding core * Often contain **giant cells** * End-stage Mφ after long-term IFN-γ and GM-CSF stimulation * **Lymphocytes** surround the structure * Produces **IFN-γ** and **GM-CSF**

Answer 44

**_Mediated by:_** IgE **_Onset:_** Early phase 2-30 minutes, late phase 2-8 hours (continues for 24-72 hours) **_Action site:_** Systemic: reflects normal mast cell distribution Local: effected tissues (e.g., upper and/or lower respiratory tract, GI tract, and skin) **_Typical reactions:_** Systemic anaphylaxis, allergic rhinitis (hay fever), bronchial asthma, some food allergies **_Mechanism:_** An IgE-mediated-hypersensitivity reaction can often be viewed as consisting of two phases: **Early phase** - mast cell degranulation and the release of mediators of anaphylaxis **Late phase** - cellular infiltration including lymphocytes, eosinophils, macrophages, basophils, & neutrophils

Answer 45

**_Mediated by:_** Circulating antibody (generally IgM or IgG rarely IgA) which can bind a membrane-bound antigen **_Onset:_** Immediate (minutes to 5-8 hours with preformed antibodies) **_Action site:_** Cell membranes on blood cells or tissues **_Typical reactions:_** Transfusion reactions, hemolytic disease of the newborn, hyperacute allograft organ rejection, certain drug reactions, some autoimmune diseases. **_Mechanism:_** Circulating-antibody binds to a cell-bound antigen. This leads to complement fixation, ADCC (e.g., neutrophils, macrophages and NK cells) and/or changes in cell function.

Answer 46

**_Mediated by:_** Large doses of antigen combine with IgG or IgM **_Onset:_** Preexisting antibodies (minutes to 5-8 hours) Requiring antibody induction (6-12 days) **_Action site:_** Local or perivascular tissues, vascular endothelium and glomerular basement membrane **_Typical reactions:_** Acute inflammatory reactions, vasculitis, serum sickness, Arthurus reaction, certain drug reactions **_Mechanism:_** Large doses of antigen react with high titers of antibodies. Resulting SOLUBLE antigen-antibody complexes overwhelm existing mechanisms of Ag-Ab clearance. Leads to Ag-Ab disposition in a variety of tissues.

Answer 47

**_Mediated by:_** CD4⁺ Th1 cells (predominantly) (occasionally CD8⁺ cells) **_Onset:_** Delayed 24-72 hours (following earlier sensitization) **_Action site:_** Skin and multiple organs **_Typical reactions:_** Contact hypersensitivity, tuberculin reaction, granulomatous reactions, chronic allograft reaction (?) **_Mechanism:_** **Sensitization phase:** T_H1 cells are stimulated by APCs and proliferate. **Effector phase:** T_H1 cell are re-stimulated and secrete cytokines (IFN-γ, TNF-α, MCF, and MIF) that recruit and activate macrophages to the site of the reaction. Macrophages have increased phagocytic activity and release cytotoxic factors including lytic enzymes and by-products from the respiratory burst (ROIs).