Lecture 23 Immune Disorders: Allergy, Hypersensitivity, and Autoimmune disease.

Question 1

What defines allergy and hypersensitivity?

Answer 1

This is an immune system over-reaction. This is often to harmless environmental antigens but can be a normal immune response to agents such as parasites.
These can result in anaphylaxis.

Question 2

What are some common inhaled allergens?

Answer 2

Plant pollen
dander,
mold,
feces or small animals like mites

Question 3

What are some common injected allergens?

Answer 3

insect venom
vaccines
drugs
therapeutic proteins

Question 4

What are some common ingested allergens?

Answer 4

Food

Orally administered drugs.

Question 5

What are some common contact allergens?

Answer 5

Plant leaves, compounds
synthetic chemicals
metals
Industrial products.

Question 6

Which of the four hypersensitivity reactions are immediate and which are delayed? What main effector does each use?

Answer 6

Types 1,2,3 are immediate and mediated by antibody effector molecules.

Type 4 is delayed can caused by cytotocis products of effector T cells.

Question 7

What is the immune reactant of each hypersensitivity type?

Answer 7

Type 1 uses IgE.
Type 2 and 3 use IgG.
Type 4 uses T effector cells. (helper and cytotoxic)

Question 8

Which hypersensitivity types respond to a soluble antigen and which respond to bound antigens?

Answer 8

Types 1 and 3 respond to soluble antigens by IgE and IgG respectively.

Type 2 responds to cell, cell matrix, or cell surface receptor associated antigens with IgG.

Type 4 responds to soluble antigens with T helper cells but to cell-associated antigens with cytotoxic cells.

Question 9

What are the effector mechanisms of hypersensitivity types? Give an example.

Answer 9

Type 1 result in mast cell activation such as in allergic rhinitis, asthma, systemic anaphylaxis.

Type 2 respond to antigen binding by complement, complement receptor cells such as phagocytes and NK cells, and alteration of cell signalling. Drug allergies like to penicillin result in complement activation. Chronic urticaria results from antibody to a receptor altering its signalling.

Type 3 results in complement activation and phagocytosis such as in serum sickness or an arthus reaction.

Type 4 results in macrophage (Th1), eosinophil (Th2) activation or cytotoxicity (CTL). Contact dermatitis or tuberculin reaction results from macrophage activation. Asthma or allergic rhinitis results from eosinophil activation.
Contact dermatitis results from cytotoxicity.

Question 10

Describe Type 1 hypersensitivity in terms of immune reactant, antigen, and effector. Give an example.

Answer 10

IgE
Soluble Antigen
Mast cell activation
asthma, rhinitis, anaphylaxis.

Question 11

Describe Type 2 hypersensitivity in terms of immune reactant, antigen, and effector. Give an example.

Answer 11

IgG

cell, matrix, or receptor associated antigen

Complement / FcR+ cell activation
Altered antibody signalling

Penicillin allergy, chronic urticaria

Question 12

Describe Type 3 hypersensitivity in terms of immune reactant, antigen, and effector. Give an example.

Answer 12

IgG
Soluble antigen
Complement + phagocytes
Serum sickness or arthus reaction

Question 13

Describe Type 4 hypersensitivity in terms of immune reactant, antigen, and effector. Give an example.

Answer 13

Th1
soluble antigen
macrophage activation
contact dermatitis or tuberculin reaction

Th2
soluble antigen
eosinophil activation
chronic asthma or allergic rhinitis

CTL
cell-associated antigen
cytotoxicity
contact dermatitis

Question 14

Describe a type 1 anaphylactic hypersensitivity reaction.

Answer 14

Ag cross linking ag-specific IgE bound to FceR1 on mast cells causing degranulation. This releases inflammatory mediators locally and in some cases systemically resulting in widespread anaphylaxis.

Question 15

What are the immediate phase, prepackaged products released immediately by mast cells upon mast cell activation? What are their effects?

Answer 15

Enzymes like tryptase cause remodelling of connective tissue matrix.

Toxic mediators like histamine increases vascular permeability, cause smooth muscle contraction, and are toxic to parasites.

Cytokines like TNF-1 promote inflammation, stimulate cytokine production by many cell types, and activate the endothelium

Question 16

Which products are synthesized and released after immediate mast cell degranulation?

Answer 16

Cytokines like Il 4, 13 stimulate and amplify the Th2 cell response.

Cytokines Il3, 5, and GM-CSF promote eosinophil production and activation.

Chemokine CCL3 acts as a chemotactic factor to recruit monocytes, macrophages, and neutrophils.

Lipid mediators like leukotrienes act as super-histamines and cause further smooth muscle contraction , vascular permeability, and mucous secretion.

Lipid mediators like platelet-activating factor act as chemotactic factors for leukocytes, amplify production of lipid mediators, and activate neutrophils, eosinophils and platelets.

Question 17

What is the general chemical pathway for the production of prostaglandins and leukotrienes in mast cells?

Answer 17

Linoleic acid is obtained from diet and converted into the unsaturated fatty acid arachidonic acid. Arachidonic acid is produced by the oxidation of cell membrane fatty acids.

Cyclooxyrgenase converts this to prostaglandins.

lipooxygenase converts this into leukotrienes.

Question 18

Where are eosinophils mostly found and what is their main purpose? How are they activated and recruited?

Answer 18

Mostly in loose connective tissues underlying epithelia and mucosa and a minority in peripheral blood. These mount a highly toxic response to host and parasites so numbers are kept quite low when healthy.

Do not present FceRI nor bind IgE until upregulated by inflammatory mediators.

These are recruited to tissues secreting eotaxins produced by endothelial cells, T cells, monocytes

Question 19

What are the pre-packaged products released immediately upon activation in eosinophils and what are their functions?

Answer 19

Enzymes like eosinophil peroxidase or collagenase result in halogenation of targets, histamine release from mast cells, and remodelling of connective tissue matrix.

Toxic proteins such as major basic protein are toxic to parasites and self cells. These trigger histamine release from mast cells.

Toxic eosinophilcationic protein act as a neurotoxin and are toxic to parasites

Toxic eosinophil-derived neurotoxin is a neurotoxin.

Question 20

What are the late phase synthesized and released chemical mediators of eosinophils?

Answer 20

Cytokines Il3, 5, GM-CSF act to amplify eosinophil production by the bone marrow and further activate eosinophils.

Chemokine CXCL8 recruits and promotes leukocytes to areas of infection

Lipid leukotrienes cause smooth muscle contraction, vascular permeability and mucous secretion.

Lipid PAF acts as a chemotactic factor of leukocytes, amplifies production of lipid mediators, and activates neutrophils, eosinophils, and platelets.

Question 21

What are some common IgE-mediated syndromes and their route of entry?

Answer 21

Systemic anaphylaxis: intravenous directly or rapid absorption

Wheal and flare: subcutaneous

Allergic rhinitis: inhaled

bronchial asthma: inhaled

Food allergy: oral

Question 22

How does sensitization occur to an inhaled allergen?

Answer 22

Person inhales antigen (first exposure).

Antigen leached out of pollen into ECF and taken up by APC

Antigen-specific T cells are activated by APC to become Il-4 secreting Th2 helper cells

Il-4 secreting Th2 cells interact with B cells causing them to produce Ab of isotype IgE.

Allergen-specific IgE binds to FceRI receptors on mast cells thus sensitizing them to a further exposure of the allergen.

Question 23

What are the tissue specific effects of mast cell degranulation

Answer 23

In the GI, there is increased fluid secretion, peristalsis resulting in diarrhea or vomiting.

In the airways there is a decreased diameter and increased mucus secretion resulting in coughing, phlegm, trouble breathing

In the blood vessels there is increased blood flow and permeability resulting in edema, inflammation, increased lymph flow.

Question 24

What happens during an acute response in allergic asthma?

Answer 24

In a sensitized individual, a mucosal mast cell captures antigen internalized by the airway. The antigen crosslinks already present IgE on the mast cell.

Mast cell degranulates releasing inflammatory mediators. Contraction of smooth muscle, increased mucus production, increased blood vessel permeability, edema, influx of inflammatory cells results.

Question 25

What mediates / differentiates a chronic response in asthma from an acute response?

Answer 25

The chronic response is mediated by cytokines and eosinophil products. Cytokines are secreted by mast cells, Th2 cells. These recruit eosinophils and activate, causing their degranulation.

The combination cytokines and eosinophil products results in further tissue injury as a result of chronic inflammation.

Question 26

What happens during allergic rhinitis?

Answer 26

Inhaled antigen enters mucosa and activates mast cells locally.

Mast cell degranulation occurs and causes blood vessel permeability and activation of epithelium . (edema)

Eosinophils are recruited from blood and enter nasal passages with mucus.

Question 27

How does a wheal and flare occur?

Answer 27

Antigen introduced subcutaneously in a low dose.

Mast cells activated. Histamine released.

Increased vascular permeability leads to localizes swelling due to influx of fluid, cells, and proteins.

Question 28

How to food allergies usually occur?

Answer 28

Food ingested.

Allergen absorbed .

Mucosal mast cells activated and degranulate.

Histamine released, acting on epithelium, blood vessels, and smooth muscle.

Antigen diffuse into blood vessels causing urticaria. (skin rash)

Vomiting and diarrhea result.

Question 29

What are the 3 main straits for allergic (type 1 hypersensitivity) reaction treatment?

Answer 29

Prevention, pharmacological (block pathways), immunological (desensitize by shifting from IgE to IgG)

Question 30

What is Type II hypersensitivity and how is it caused?

Answer 30

This cytotoxic hypersensitivity results when small molecules bind to the surface of human cells. This produces modified structures that are recognized by the immune system. These cells are destroyed by IgG / complement / phagocytosis. Penicillin can induce Type II among others.

Blood transfusions - incompatibility of blood group antigens, causes Type II.

Question 31

How does penicillin cause type II hypersensitivity?

Answer 31

Penicillin has a reactive bond in its B-lacam ring which can bind to bacterial or human cells such as RBCs.

Binding of penicillin to human cells (RBC) created a foreign epitope.

RBC-penicillin complement coated and phagocytosed.

RBC-penicilin broken down. Peptides from the conjugate are presented using MHCII to CD4 T cells which become Th2 cells.

Th2 cells activate B cells displaying the penicillin-RBC peptide antigen.

B cells become plasma cells and produce penicillin specific IgG which binds to RBCs that have penicillin attached.

This results in the RBC being destroyed by C1-9 MAC or C3b coated phagocytosis

Question 32

What is Type III Hypersensitivity?

Answer 32

This is caused by small, insoluble immune complexes of Ag and Aby (which occur mainly at equimolar concentrations) which deposit on walls of blood vessels (kidneys) or lung alveoli or joints.
These deposits activate complement, inflammation causing damage.

Question 33

Describe Serum Sickness.

Answer 33

This results after intravenous administration of therapeutic proteins or Abys from other species.

This manifests from 4-10 days after exposure when there is approximate eqimolar concentrations of Ag and Aby after the lag phase in Aby production.

This results in fever, swollen lymph nodes, achey joints, rashes, committing, diarrhea, proteinuria, and decreases complement levels.

Question 34

Describe a type III urticarial Rash.

Answer 34

Polycyclic wheal-like swellings with central clearing.

On trunk, extremities, face, lateral borders of hands and feet.

Oral edema without mucosal involvement.

Question 35

What is the Type III Arthus Reaction?

Answer 35

There is localized erythema and hard swelling (induration) due to immune complex formation after subcutaneous Ag injection.

This can be causes by the diphtheria or tetanus vaccines, or fungi or proteins in feathers and furs.

Question 36

What occurs to produce a type III arthus reaction?

Answer 36

Local antigen injected in individual sensitized to Ag (has antigen-specific IgG).

Local immune-complex formation

Complement activation results in opsonization and production of anaphilatoxins which cause mast cell degranulation.

Local inflammation occurs due to movement of fluid, cells, and proteins into tissue.

Blood vessel occlusion and vasculitis results.

Question 37

In Type 3 Hypersensitivity, which diseases result from which routes of introduction of an antigen?

Answer 37

High dose intravenous introduction results in vasculitis (blood vessels), nephritis (glomeruli), and arthritis (joint spaces).

Subcutaneous exposure results in an arthus reaction.

Inhaled antigen results in farmers lung.

Question 38

What are treatments for Type 2 and 3 hypersensitivity reactions?

Answer 38

Discontinue / Avoid antigen.

Monitor blood transfusions for matching types.

epinephrine

Question 39

How do treatments for Type 1 hypersensitivity reactions differ from those for Type 2 and 3?

Answer 39

Type 1 involves mast cell degranulation whereas Type 2 and 3 do not (mainly). Therefore treatments that involve mast cell pathways cannot be used in treatment of type 2 and 3.

Question 40

What are type 4 hypersensitivity reactions?

Answer 40

These are delayed type and contact type hypersensitivity reactions. These are caused by the products of Ag-specific effector T cells.

Question 41

Describe the possible antigens and consequences for delayed and contact hypersensitivity reactions.

Answer 41

For delayed, the antigens are commonly insect venom or mycobacterial proteins which result in local skin swelling.

For contact, the antigens are usually haptens (poison ivy) or small metal ions (Ni, Cr) which result in a local epidermal reaction (contact dermatitis)

Question 42

Describe the process of a delayed-type hypersensitivity reaction. (Type 4).

Answer 42

Antigen introduced subcutaneously, processed, presented by APCs.

Th1 effector cell recognizes antigen, releases cytokines which act on vascular endothelium.

Inflammation results: recruitment of T cells, phagocytes, fluid, protein.

Localizes Swelling results

This process can take a few days to occur, as antigen specific T cells are rare. There is also no initial inflammation to attract cells to the site.

Question 43

What is the treatment for type 4?

Answer 43

Avoid contact, corticosteroids, cyclosporine, immunotherapy.

Question 44

What types of hypersensitivity mechanisms do autoimmune diseases use?

Answer 44

2,3,4

2: aby against cell surface or matrix
3: immune complexes
4: self-directed T cell mediated cytotoxicity.

Question 45

What are some examples of Type 2 Mechanism autoimmune diseases?

Answer 45

These involve antibody against self-cell surface or matrix antigens.

Autoimmune hemolytic anemia (Rh antigen)

Acute rheumatic fever (cross reaction of streptococcal cell wall antigens with cardiac muscle cells)

Question 46

Describe the autoimmune disease Hemolytic Anemia.

Answer 46

IgG and IgM bind antigens on RBC.

Classical Complement activated.

RBC coated with Aby and opsonins like C3b.

These are phagocytosed notably in the spleen by FcR+ cells or undergo MAC-killing.

Question 47

What are some autoimmune diseases associated with the type 3 hypersensitivity mechanism?

Answer 47

Subacute bacterial endocarditis (bacterial antigen results in glomerulonephritis)

Mixed essential cryoglobulinemia (Rheumatoid factor IgG complexes result in systemic vasculitis)

Lupus erythematous (DNA, histones, ribosome immune complexes result in glomerulonephritis, vasculitis, arthritis)

Question 48

What are some autoimmune diseases associated with Type 4 hypersensitivity?

Answer 48

Type 1 diabetes (B-cell antigens result in pancreatic B-cell destruction)

Rheumatoid arthritis

MS: brain degeneration and paralysis by cell mediated toxicity of myelin basic protein and proteolipid protein.

Question 49

How are some infections associated with autoimmune diseases?

Answer 49

There can be cross-reactivity between antibodies created in response to infection by certain pathogens and self-cells.

E.g.) rheumatic fever by S. pyogenes. Aby target pathogen and heart, joint, and kidney tissues.

Question 50

Which HLA isotypes are associated with infections causing autoimmunity?

Answer 50

Autoimmune diseases are most commonly associated with the polymorphic or highly polymorphic HLA/MHC isotypes:

HLA1-A, B, C
HLA2-DP, DR, DQ

Particular alleles of polymorphic HLA genes are combined in HLA haplotypes at a higher frequencey with particular autoimmune diseases.

This preferential allele association is an example of linkage disequilibrium

Question 51

What is lyme disease and how is it caused?

Answer 51

Lyme diseases is a form of chronic arthritis caused by Borrelia burgdorferi transmitted by tick bites.

Can be treated by early course of antibiotics.

Bullseye rash.

Associated with HLA-DR2/4