Lecture 24

Front 1

Where are the effects focused when re-exposure to allergen triggers an allergic reaction?

Back 1

Site which mast cell degranulation occures

Front 2

What is characteristic of the preformed mediators in the immediate response?

Back 2

Effects are:

short-lived

confined to vicinity of activated cell

Front 3

What is characteristic about the late phase response?

Back 3

Sustained effect

Still confined to site of initial allergen-triggered activation

Particular anatomy of site may determine readily if the inflammation can be resolved

Front 4

What does the clinical syndrome produced by an allergic reaction depend on?

Back 4

Amount of allergen-specific IgE present

Route by which allergen is introduced

Dose of allergen

Front 5

What determines the type of IgE-mediated allergic reaction?

Back 5

Dose & route of allergen administration

Front 6

What are the 2 main anatomical distributions of mast cells?

Back 6

Connective tissue mast cell (vascularized CT)

Mucosal mast cells (submucosal layers of gut)

Front 7

All mast cells at anatomical spaces are loaded with IgE directed against specific allergens. The overall response to an allergen then depends on which _____ _____ are activated

Back 7

Mast cells

Front 8

Which MC do allergens in the bloodstream activate

Back 8

CTMC resulting in systemic release of histamine & other mediators.

Front 9

Which MC does subcutaneous administration of allergen (skin) activate?

Back 9

Local CTMC, leading to local inflammation. Manifest as wheal-and-flare

Front 10

In atopic individuals airborne allergens penetrating the skin may lead to atopic eczema.

Back 10

True

Front 11

What does an inhaled allergen induce?

Back 11

Penetrates mucosal epithelial

Activates MMC mainly

Increased mucus secretion

Irritation in nasal mucosa

Allergic rhinitis/additional bronchoconstriction

Front 12

What does an ingested allergen do?

Back 12

Penetrates gut epithelium

Vomit due to smooth muscle contraction

Diarrhoea due to outflow of fluid across epi

Front 13

What else can happen to food allergens?

Back 13

Disseminated in the bloodstream

Widespread urticaria when allergen reaches skin, or eczema

Front 14

Allergen introduced directly into the bloodstream can cause ____________

Back 14

Anaphylaxis

Front 15

What is a mild & extreme symptom of release into bloodstream?

Back 15

Urticaria (hives)

Anaphylactic shock- potentially fatal

Front 16

When is acute urticaria caused?

Back 16

Ingested allergens released into the bloodstream & reaches skin

Histamine causes large itchy, red swelling all over the body

Front 17

What does anaphyliactic shock lead to?

Back 17

Widespread increase in vascular permeability – resulting from massive histamine release

Catastrophic loss of BP-> shock

Airway constriction-> difficulty breathing

Epiglottis swelling-> suffocation

Front 18

What are some major causes of anaphylactic shock?

Back 18

Wasp & bee stings

Allergic responses to foods e.g. peanuts

Front 19

Anaphylactic shock can be rapidly fatal. What can reverse the histamine reaction?

Back 19

Immediate epinephrine injection

Front 20

What is another pharmaceutical way that anaphylactic shock can occur?

Back 20

Drug is administered to people who have IgE specific antibodies for that drug

Front 21

What is nature's way of inducing an anaphylactic shock?

Back 21

Individuals allergic to insect venom from a bite

Front 22

The most frequent reactions to drugs occur with _________ and its relatives.

Back 22

Penicillin

Administration by injection can cause anaphylaxis & even death

Front 23

What are inhaled allergens associated with?

Back 23

Development of rhinitis & asthma

Front 24

Most common route of entry

Back 24

Respiratory

Front 25

What is allergic rhinitis?

Back 25

Atopic people have mild allergies to inhaled antigens, manifesting as sneezing and a runny nose

Front 26

How does allergic rhinitis result?

Back 26

MMC activation beneath the nasal epithelium by allergens (e.g. pollens that release their protein contents) which then diffuse across the mucous membranes of the nasal passages.

Front 27

How does allergic conjunctivitis occur?

Back 27

Airborne allergens deposited on the conjunctiva of the eye

Front 28

Allergic rhinitis and conjunctivitis are commonly caused by _______________ allergens that are present only during certain seasons of the year.

Back 28

Environmental

e.g. hay fever (seasonal allergic rhinoconjunctivitis)- diverse causes- grass & tree pollens.

Front 29

What causes some summer & autumnal symptoms of hay fever?

Back 29

Weed pollen such as ragweed

Front 30

What are perennial Ag?

Back 30

Cat dander and house dust mites can cause year-round misery.

Front 31

How is allergic asthma triggered?

Back 31

Allergen-induced activation of submucosal mast cells in the lower airways

Front 32

The same allergens that cause allergic rhinitis and conjunctivitis commonly cause asthma attacks.

Back 32

True

Front 33

Allergic asthma can be life-threatening, but doesn't need immediate treatment

Back 33

False

Front 34

What happens within seconds after an allergen is inhaled?

Back 34

Bronchial constriction

Increased secretion of fluid & mucus

Breathing difficult

Inhaled air trapped in lungs

Front 35

What is an important feature of asthma?

Back 35

Chronic inflammation of the airways

Front 36

What characterises chronic inflammation of the airways?

Back 36

Continued presence of increased numbers of TH2 lymphocytes, eosinophils, neutrophils, and other leukocytes

Front 37

What do immune cells cause?

Back 37

Airway remodelling

Front 38

What happens in airway remodelling?

Back 38

Thickening of the airway walls due to hyperplasia & hypertrophy of the smooth muscle layer & mucous glands

Eventual development of fibrosis & permanent airway narrowing.

Front 39

What happens in chronic asthmatics?

Back 39

General hyperreactivity of the airways to non-immunological stimuli also develops.

Front 40

What are some of these non-immunological stimuli?

Back 40

Cigarette smoke

SO2

Front 41

What else might exacerbate acute response in allergic asthma?

Back 41

Viral infections

Induces Th2-dominated local response

Cytokine secretion by Th2 cells & MC

Augment eosinophil activation & degranulation

Chronic inflammation

Front 42

Allergy to foods causes systemic reactions as well as symptoms limited to the gut

Back 42

True

Front 43

What % of the American & European populations does genuine food allergy affect?

Back 43

1-4%

Front 44

Which ubiquitous factors are often misnamed as allergy by the sufferer?

Back 44

Food intolerance

Dislikes

Front 45

Which food item causes allergy in ~ 1/4 of US/European citizens?

Back 45

Peanuts, increasing incidents

Front 46

What are the 2 types of allergic responses seen when an allergen is ingested?

Back 46

Activation of MMC associated with GIT

CTMC in the dermis & subcutaenous tissues

Front 47

What does activation of MMC associated with GIT cause?

Back 47

Diarrhoea & vomitting

Front 48

What can CTMC result in?

Back 48

Urticaria

Ingestion of food allergen-> development of asthma & anaphylaxis with circulatory collapse

Front 49

How can IgE-mediated allergic disease be treated?

Back 49

Inhibit effector pathways that lead to symptoms or by desensitization techniques that aim in restoring tolerance to the Ag

Front 50

What do antihistamines treat?

Back 50

Symptoms only

Front 51

What are corticosteroids?

Back 51

General inflammatory drugs

Front 52

Current drug treatments are largely ____________, than curative, often need to be taken for life.

Back 52

Palliative

Front 53

What is used to treat anaphylactic reactions?

Back 53

Epinephrine

Front 54

How is epinephrine useful?

Back 54

Stimulates reformation of endothelial tight junctions

Promotes relaxation of bronchial smooth muscle constriction

Stimulates the heart

Front 55

What are inhaled bronchodilators?

Back 55

Acts on β-adrenergic receptors

Relax constricted muscle are used to relieve acute asthma attacks

Front 56

How do antihistamines reduce urticaria?

Back 56

Blocking H1 receptors

Front 57

How does urticaria result?

Back 57

Release of histamine from MC & basophils

Front 58

It is important to treat and prevent chronic inflammatory injury to tissues

Back 58

True

Front 59

What are corticosteroids?

Back 59

Used to suppress chronic inflammatory changes seen in asthma, rhinitis & eczema

Topical or systemic

Front 60

A means of regulating the T-cell response to the allergenic peptide antigen in an ________________ manner is needed.

Back 60

Antigen-specific

Front 61

What are the 2 treatments commonly used in clinical practice?

Back 61

Desensitisation or specific allergen immunotherapy

Blockade of effector pathways

Front 62

What does desensitization aim to restore?

Back 62

Tolerance to the allergen by reducing its tendency to induce IgE production

Front 63

What is the key to the desensitization?

Back 63

Induction of T-cells secreting IL-10 and/ or TGFβ, which turn the response away from IgE.

e.g. beekeepers- naturally protected- IL-10 secreting T cells

Injection with increasing doses of allergen that gradually decreases IgE-dominated response

Front 64

Which Ig is produced with increased IL-10?

Back 64

IgG4, subtype selectively promoted by IL-10

Front 65

What does allergen injection immunotherapy downregulate?

Back 65

TH1- and TH2-driven hypersensitivity disease, with its induction of Treg-cells.

Front 66

What is desensitization also associated with?

Back 66

Reduction in the numbers of late-phase inflammatory cells at the site of allergic reaction

Front 67

What is a complication of the desensitization?

Back 67

Risk of inducing IgE-mediated allergic responses

e.g. treating severe reactions against peanut allergy

Front 68

What is an alternative approach to desensitization?

Back 68

Vaccination with peptides derived from common allergens.

Induces Treg cells which produce IL-10

Front 69

IgE-mediated responses are not induced by peptides. Why?

Back 69

Recognizes only intact allergens

Front 70

Patients with different MHC class II molecules respond to different allergen-derived peptides.

Back 70

True

Front 71

What is another approach?

Back 71

Give cytokines that promote Th1 type responses.

Front 72

Which cytokines can reduce IL-4-stimulated IgE synthesis?

Back 72

IFNγ, IFNα, and IL-12

Front 73

Administration of which cytokine can cause adverse side effects?

Back 73

IL-12

Front 74

What is another target for therapeutic intervention?

Back 74

High affinity IgE receptor

Front 75

What will an effective competitor for IgE result in?

Back 75

Prevents binding of IgE to surfaces of MC, basophil & eosinophils

Front 76

What is Omalizumab?

Back 76

Humanised anti-IgE monoclonal antibody

Binds to portion of IgE that ligates the high affinity IgE receptor

Front 77

What does omalizumab bring about?

Back 77

Decrease in IgE levels

Front 78

What else is an effect?

Back 78

Downregulation of the no. of high affinity IgEr on MC & basophil

Front 79

What was observed of Omalizumab in experimentally inhaled allergen?

Back 79

Ab blocks both immediate & late-phase responses

Front 80

What is a potential target when blocking recruitment of eosinophils to sites of allergic inflammation?

Back 80

CCR3

Front 81

What does a blockade of IL-5 cause?

Back 81

Production of eosinophils in BM & their exit into circulation is reduced

Front 82

Innocuous antigens can cause Type __ hypersensitivity reactions in susceptible individuals by binding to the surfaces of circulating blood cells

Back 82

II

Front 83

What do antibiotics like penicillin & cephalosporin do to some cells?

Back 83

Cause antibody-mediated destruction of RBC (haemolytic anaemia) or platelets (thrombocytopenia)

Front 84

What happens in type II hypersensitivity reactions?

Back 84

Drug binds to the cell surface & serves as a target for anti-drug Ab that destroy the cell

Cell-bound Ab triggers clearance of cell from circulation

Front 85

What is the predominant means by which the cell-bound Ab are cleared from circulation?

Back 85

Tissue macrophages in the spleen which bear Fcγ receptors.

Front 86

What causes systemic disease?

Back 86

Immune-complex formation following administration of large quantities of poorly catabolised Ag

Front 87

Type III hypersensitivity reactions can arise with soluble antigens

Back 87

True

Front 88

What is an immune complex?

Back 88

Ag:Ab

Front 89

Pathology of type III hypersensitivity

Back 89

Immune complex at the tissues and sites

Front 90

What happens to larger IC?

Back 90

Aggregates fix C'

Readily cleared from circulation by the mononuclear phagocyte system

Front 91

What happens to smaller IC?

Back 91

Forms when Ag is in excess

Deposited in BV walls

Ligates FcR on leukocytes-> leukocyte activation & tissue injury

Front 92

What is a local type III hypersensitivity reaction called?

Back 92

Arthus reaction

Front 93

How is an Arthus reaction triggered?

Back 93

In the skin of sensitized individuals who possess IgG Ab against the sensitizing Ag

Front 94

What happens when Ag is injected into skin?

Back 94

Circulating IgG Ab diffuses into skin forms IC locally

Front 95

What do these IC do?

Back 95

Bind FcR (FcγRIII) on MC & other leukocytes

Local inflammatory response

Increased vascular permeability

Fluid enters inflammatory site from local BV

Front 96

What other component of the IS do IC activate?

Back 96

C', generating C5a which attracts cells to inflammatory site

Front 97

What components are required for the experimental induction of an Arthus reaction in the lung by macrophages in the alveoli walls?

Back 97

C5a & FcγRIII

Probably also required for reaction induced by MC in the skin & linings of joints (synovia)

Front 98

Activation of FcγRIII on MC induces their degranulation

Back 98

True

Front 99

What is type III hypersensitivity known as?

Back 99

Serum sickness

Front 100

What does serum sickness result from?

Back 100

Injection of large qualities of a poorly catabolised foreign Ag

Front 101

Antiserum made by immunising _______ in pre-Ab era and used to treat ____________ ____________

Back 101

horses; pneumococcal penumonia

Front 102

What is antivenin?

Back 102

Serum from horses immunised with snake venom

Front 103

What happens with serum sickness?

Back 103

Occurs after 7-10 days after injection of horse serum

Front 104

What does the time period after which serum sickness sets in allow?

Back 104

IgG-switched primary IR against foreign Ag

Front 105

Clinical features of serum sickness

Back 105

Chills

Fever

Rash (urticaria is a prominent feature)

Arthritis

Sometimes glomerulonephritis

Front 106

How is MC degranulation triggered in this case?

Back 106

Ligation of cell-surface FcγRIII by IgG-containing IC

Front 107

What does the onset of serum sickness coincide with?

Back 107

Development of Ab against soluble proteins in the foreign serum

Front 108

What is the course of serum sickness?

Back 108

Ab development

IC formation

Fix C', bind to & activate leukocytes bearing Fcr/C'R

Widespread tissue damage

Front 109

What do the ICs cause?

Back 109

Clearance of the foreign Ag, so serum sickness is usually a self-limiting disease

Front 110

When is pathological IC deposition seen?

Back 110

Ag persists as when an adaptive Ab response fails to clear the infecting pathogen

e.g. subacute bacterial endocarditis, chronic viral hepatitis

Front 111

What happens in these pathological situations?

Back 111

Pathogen continuously generates new Ag in presence of persistent Ab response, with formation of ICs

IC deposition within small BV, with consequent injury in many tissues & organs

Front 112

IC disease also occurs when _________ allergens provoke IgG rather than IgE Ab responses

Back 112

inhaled

Front 113

What happens to a farmer's lungs who are repeatedly exposed to hay dust or mould spores?

Back 113

IC forms in alveoli walls

Accumulation of fluid, protein & cells in alveolar wall

Blood-gas interchange slowed

Compromised lung function

Lung lining can be permanently damaged

Front 114

Hypersensitivity reactions are mediated by ____________ & _________

Back 114

Th1 cells; CD8+ cytotoxic T cells

Front 115

What is type IV hypersensitivity aka?

Back 115

Delayed-type hypersensitivity

Front 116

How are DTH reactions mediated?

Back 116

Ag-specific effector T cells

Front 117

What is the prototype DTH reaction?

Back 117

Tuberculin test

Front 118

What is this reaction used determine in patients?

Back 118

Whether person has been previously infected with Mycobacterium tuberculosis

Front 119

What happens in the Mantoux test?

Back 119

Small amounts of tuberculin

Complex mixture of peptides & carbs derived from M. tuberculosis are injected intradermally

Front 120

How would people have been previously exposed to it?

Back 120

BCG vaccine (attenuated form of M. tuberculosis)

Infection

Front 121

What happens in people who have been exposed to it after they receive the vaccine?

Back 121

Local T cell mediated inflammatory reaction evolves over 24-72hrs

Front 122

List some Ag that induce DTH?

Back 122

Insect venom, mycobacterial proteins

Front 123

What are the consequences of DTH?

Back 123

Local skin swelling:

erythema

induration

cellular infiltrate

dermatitis

Front 124

What type of Ag mediate contact hypersensitivity?

Back 124

Absorbed into skin

Haptens:

poison ivy

DNFB

Small metal ions:

nickel & chromate

Front 125

What are the consequences of CH?

Back 125

Local epidermal reaction:

erythema

cellular infiltrate

vesicles

intraepidermal abscesses

Front 126

What type of Ag mediate gluten-sensitive enteropathy (Celiac disease)?

Back 126

Absorbed by the gut

Gliadin

Front 127

What is the consequence of gluten-sensitive enteropathy?

Back 127

Villous atrophy in small bowel malabsorption

Front 128

Stages in DTH

Back 128

Ag injected into subcutaneous tissue

Processed by local APC

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

Phagocytes recruited

Visible lesion

Front 129

Cytokines released & their effects

Back 129

IFN-γ and TNF-β.

Stimulates expression of adhesion molecules on endothelium

Increase local blood vessel permeability

Allowing plasma and accessory cells to enter the site

Swelling

Front 130

How long do these phases take?

Back 130

Several hours

Fully developed response appears 24-28hrs

Front 131

Chemokines are also secreted. What effects are caused?

Back 131

Recruit macrophages to site of Ag deposition

Front 132

IL-3/GM-CSF is also secreted. What effects are caused?

Back 132

Stimulate monocyte production by bone marrow stem cells

Front 133

How do Th1 cells activate macrophages?

Back 133

Release of IFN-γ and TNF-α

Kill macrophages & other sensitive cells through the cell-surface expression of the Fas ligand

Front 134

What is allergic contact dermatitis?

Back 134

Immune-mediated condition caused by direct Ag contact with skin

Caused by activation of CD4/8 T cells, depending on how Ag is processed

Front 135

Describe the typical Ag that cause cutaneous hypersensitivity responses?

Back 135

Highly reactive small molecules that can easily penetrate intact skin, especially if they cause itching that leads to scratching

Front 136

These chemicals then react with self proteins, creating ________________ complexes that can be processed to form _______________ complexes capable of being presented by MHC molecules and recognised by T cells as foreign antigens.

Back 136

hapten:protein;hapten:peptide

Front 137

What are the 2 phases to a cutaneous allergic response?

Back 137

Sensitization

Elicitation

Front 138

What happens in the sensitization phase?

Back 138

Cutaneous Langerhans cells take up & process Ag

Migration to regional lymph nodes

T cells activated

Production of memory T cells, which end up in the dermis.

Front 139

What happens in the elicitation phase?

Back 139

Subsequent exposure to the sensitising chemical leads to Ag presentation to memory T cells in dermis, with the release of T-cell cytokines such as IFNγ and IL-17.

Front 140

What does the release of cytokines & Ag presentation lead to?

Back 140

Stimulates the keratinocytes of the epidermis to release cytokines & chemokines which enhance the inflammatory response by inducing the migration of monocytes into the lesion and their maturation into macrophages & by attracting more T cells

Front 141

What causes the rash produced by poison ivy?

Back 141

CD8 T cell response to a mixture of pentadecacatechols in the plant.

Front 142

Pentadecacatechols

Back 142

Lipid-soluble chemicals that cross the cell membrane & modify intracellular proteins

Front 143

What happens to the modified proteins?

Back 143

Generates modified peptides within cytosol

Translocation to ER

Delivered to cell surface-bound to MHC Class I

CD8+ recognizes peptide

Damage caused either by killing it or secreting cytokines like IFNγ.

Front 144

Coeliac disease has the features of both an __________ ___________ & ______________________

Back 144

Allergic response; autoimmunity

Front 145

Coeliac disease

Back 145

Chronic condition of the upper small intestine caused by an IR directed at fluten

Front 146

What is gluten?

Back 146

Complex of proteins present in wheat, oats & barley

Front 147

What does elimination of gluten from the diet do?

Back 147

Restore normal gut function

Front 148

What is coeliac disease characterised by?

Back 148

Loss of villi formed by the intestinal epithelium (a condition termed villous atrophy)

Increase in the size of the sites in which epithelial cells are renewed (crypt hyperplasia).

Front 149

What do these abnormal changes result in?

Back 149

Mature epithelial cells that cover the villi which normally absorb & digest food

Severe inflammation of the intestinal wall

Increased no. of T cells, macrophages & plasma cells in the lamina propria

Increased no. of lymphocytes in the epithelial layer

Front 150

Does coeliac disease show an extremely strong genetic predisposition?

Back 150

Yes

More than 95% of patients expressing the HLA-DQ2 class II MHC allele

Front 151

Most individuals expressing HLA-DQ2 do not develop coeliac disease despite the almost universal presence of gluten in the Western diet. What does this mean?

Back 151

Other genetic factors must make important contributions to susceptibility.

Front 152

Autoimmunity features are detected in coeliac disease

Back 152

True

Front 153

What are the autoantibodies directed against in all victims?

Back 153

Tissue transglutaminase

Front 154

Is there evidence that these autoantibodies contribute to tissue damage?

Back 154

No