IMMUNOLOGICAL DISEASES

AN INTRODUCTION TO HYPERSENSITIVITY

Allergy & hypersensitivity

HYPERSENSITIVITY= harmful immune responses

autoimmunity(self antigen)

allergy( foreign antigen)

Distinct from:•pharmacological intolerance / hypersensitivity•toxicity

Classification of Hypersensitivity

Type Mechanism Example

I IgE mediated Systemic anaphylaxis eg peanut allergyAsthma

II Antibody mediated Haemolytic disease of the newborn

III Immune complex mediated

Arthus reactionGlomerular nephritis

IV Cell mediated (delayed)

Contact dermatitis

Anaphylactichypersensitivity

Cytotoxichypersensitivity

Immune complexhypersensitivity

Cell-mediatedhypersensitivity

Type I hypersensitivity reaction

• Dependant on IgE and Mast cells.

• Requires prior sensitisation to antigen.

Mast cell degranulation

Key Event. Mast cell activation (elicitation phase)

HistamineProstaglandin D2Leukotriene C4Cytokines (TNF-a)

Y Y Y Y Y IgE

antigen

Scanning electron micrographs of RBL-2H3 (rat basophilic leukemia) cells (A) before and (B) after crosslinking IgE-primed FceRI with polyvalent antigen

Effector mechanisms

• Mast cell activation:– preformed mediators

• histamine• enzymes (e.g. tryptase)• TNF-α

– synthesis• leukotrienes C4, D4• IL-4, IL-5

• Results:– vasodilation and increased permeability– increased mucus secretion– bronchoconstriction– Cough– chemotaxis of other inflammatory cells

HYPERSENSITIVITY TYPE II

• Caused by IgM or IgG antibodies to cell surface and

extracellular matrix proteins.

• Abs interact with complement components and

effector cells such as macrophages and neutrophils.

• This results in tissue damage via mechanisms

normally active against foreign antigens.

EXAMPLES

1. Reactions against incompatible blood transfusions.

2. Autoimmune haemolytic anaemia. Sensitised to patients’ own RBCs. Often drug induced.

3. Goodpastures Syndrome. Ab against basement membrane proteins produce nephritis.

4. Myasthenia Gravis. Muscular weakness associated with Abs to acetylcholine receptors.

5. Haemolytic disease of the newborn. Pregnant woman is sensitised to the fetal erythrocytes.

HAEMOLYTIC DISEASE OF THE NEWBORN

• Occurs when mother has become sensitised to Ag on the infant’s erythrocytes. Rhesus D commonly.

• Often Rh –ve mother carrying a second or subsequent rhesus +ve infant.

• Sensitisation of the mother during the birth of the first Rh +ve baby.

• Subsequent children have an increased risk of being affected.

HAEMOLYTIC DISEASE OF THE NEWBORN

First birth Postpartum Subsequent pregnancy

RhD+ foetus

RhD- mother

Exposure sensitisation disease

Exposure no sensitisation no disease

RhD+ foetus

Ag removed prevents sensitisation

Anti D Abs given immediately after birth

First birth PostpartumSubsequent pregnancy

Muscle fibres

Acetyl choline from nerve impulse

Acetyl choline receptors

Normal nerve signal

MYASTHENIA GRAVIS

Ab against the receptor is only part of the disease process

Muscle weakness from reduced signal transmission

Antibodies to the receptor block acetylcholine binding

HYPERSENSITIVITY TYPE III

• Caused by IgM or IgG Abs against soluble antigens.

• Ab/Ag immune complexes normally removed effectively.

• In these reactions complexes that persist are deposited in the circulation or tissue and cause inflammation.

• Frequent complication in autoimmune disease.

Type III Hypersensitivity results from immune complex formation

Can accumulate in tissues leading to increased local concentrations

which may be pathogenic

3 basic categories

Cause Persistent Infection

Autoimmunity Inhaled Antigen

Antigen Microbial Self-antigen Mould plant or animal antigen

Site Kidney and infected organs

Kidney, joints and skin

Lung

MECHANISMS IN TYPE III HYPERSENSITIVITY

• Complexes interact with basophils and platelets to

induce release of vasoactive amines.

• Macrophage stimulation results in cytokine

release (TNFα IL-1).

• Complement activation and inflammation.

MECHANISMS IN TYPE III HYPERSENSITIVITY

Experimentally induced Type III hypersensitivity

Immune complex deposition in the skin and resultant pathology is known as the Arthus reaction

TYPE IV HYPERSENSITIVITY

• Delayed type hypersensitivity.

• Typically mediated by TH1 cells and/or

macrophages which produce and respond to

cytokines including TNFα and IFNγ

• Can be shown experimentally by transferring T

cells between animals.

3 BASIC TYPES

Contact hypersensitivity 48-72 hours

Tuberculin reaction 48-72 hours

Granulomatous reaction 21 days

ANAPHYLAXIS

An immediate, severe, systemic hypersensitivity or allergic

reaction, sometimes fatal, usually characterised by at least one

or other of the following symptoms, respiratory difficulty,

hypotension or circulatory failure. Generalised urticaria and

tissue swelling also common.

Mediated by IgE antibodies and Mast cells Immunologically

disease.

‘Type One hypersensitivity’

Common causes of anaphylaxis

• Foods• Serum/vaccines• Bee and wasp stings• Drugs• Latex rubber - gloves

Foods commonly causing anaphylaxis

• Peanuts• Tree nuts (eg. brazil nut, almond, hazlenut)• Fish• Shellfish• Egg• Milk• Sesame

Drugs causing anaphylaxis

• Antibiotics (especially penicillin)• Intravenous anaesthetic drugs• Aspirin• Non-steroidal anti-inflammatory drugs

Features of Anaphylaxis• Erythema• itching• Urticaria• Asthma• Rhinitis• Conjunctivitis• Nausea, vomiting, abdominal pain• Fainting, lightheadedness• Collapse• Lose of consciousness• Hypotension/reduced blood pressure• Circulatory/heart failure

UrticariaRaised, erythematous intensely itchy skin eruption caused by IgE-mediated histamine release from mast cells.

Causes: Drugs Food allergens

penicillinEnvironmental allergens

cephalosporins Insect bites

latex

Is this allergy?

“Please see this patient who is:obviously allergic to something......clearly having allergy-like episodes......presumably to something he/she is eating......

......but can’t tell what he/she is allergic to.”

Case 1

Clinical diagnosis• “oral allergy syndrome”• allergy to birch pollen causing symptoms on exposure to cross-reacting

allergens in a variety of fruits (particularly peach, pear, apple and plum)• other plant-derived foods are sometimes involved, as in this case

Tests• skin prick testing showed a very strong response to birch pollen. Strong responses were also

obtained to hazel nut, almond, carrot and celery. Extracts of the relevant fruits gave negative results. IgE results were:

– total 52.4– birch pollen 22.3– apple 1.01– carrot 1.3– celery 0.8 (peach, pear and plum were negative)

The End