Hypersensitivity, allergy and inflammation

Question 1

What is appropriate immune tolerance and basic mechanism? How does this differ from immune reactivity?

Answer 1

Appropriate immune tolerance occurs to self and to foreign harmless proteins e.g. food, pollens and commensal bacteria. Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production (an antibody which blocks other antibodies). DIFFERENCE FROM IMMUNE REACTIVITY: antigen recognition in the context of ‘danger’ signals leads to immune reactivity. When there are no danger signals, there is immune tolerance.

Question 2

What do hypersensitivity reactions occur against? (x3 types)

Answer 2

□ Harmless foreign antigens (allergy, contact hypersensitivity). □ Autoantigens (autoimmune diseases). □ Alloantigens (serum sickness, transfusion reactions and graft rejection).

Question 3

What are the four types of hypersensitivity?

Answer 3

□ TYPE 1: Immediate hypersensitivity (IgE). □ TYPE 2: Antibody-dependent cytotoxicity. □ TYPE 3: Immune complex mediated. □ TYPE 4: Delayed cell mediated. □ Note that many diseases involve a mixture of different types.

Question 4

What examples involve Type 1 Immediate Hypersensitivity? (x4) !!!

Answer 4

Anaphylaxis, asthma, rhinitis (seasonal and perennial (throughout year)), and food allergy (i.e. atopy).

Question 5

What is atopy?

Answer 5

Tendency to produce an exaggerated IgE immune response to otherwise harmless environmental substances.

Question 6

What is the mechanism of type 1 immediate hypersensitivity?

Answer 6

□ There is initial antigen exposure which leads to antigen sensitisation (as oppose to tolerance). Sensitisation leads to IgE antibody production which binds to mast cells and basophils.

□ Upon second antigen exposure, there is cross-linking of IgE antibodies by the antigen on mast cells/basophils which leads to more IgE antibody production and degranulation of the mast cell and a hypersensitivity reaction.

Question 7

What examples involve Type 2 Antibody-Dependent hypersensitivity? Examples? (x2 and x2) !!!

Answer 7

□ Organ-specific autoimmune disease including Myasthenia gravis (antibodies to the Ach recepotor) and Glomerulonephritis (antibodies to glomerular basement membrane). □ Autoimmune cytopenia (antibody-mediated blood cell destruction) including haemolytic anaemia and thrombocytopenia.

Question 8

How can you test for specific antibodies in Type II hypersensitivity?

Answer 8

Immunofluorescence of specific antibodies, OR ELISA e.g. anti-CCP which are antibodies for Rheumatoid arthritis.

Question 9

What is the mechanism of Type II Hypersensitivity?

Answer 9

Antibody (IgM or IgG) binds to antigen on a host cell which is perceived by the immune system as being foreign. This leads to cellular destruction via the MAC (membrane attack complex) from complement activation.

Question 10

What is the mechanism of Type 3 Immune Complex mediated hypersensitivity?

Answer 10

Formation of antigen-antibody (IgG) complexes in the blood lead to complex deposition in blood vessels and surrounding tissue. These complexes result in COMPLEX ACTIVATION, inflammatory cell activation, and other cascades including clotting. These lead to localised inflammatory responses – vasculitis (inflammation of blood vessels) and tissue damage.

Question 11

Examples of Type 3 hypersensitivity? (x2) !!!

Answer 11

SLE and Vasculitis diseases such as Poly Arteritis Nodosum.

Question 12

Examples of Type 4 Delayed Hypersensitivity responses? (x4 and x3) !!!

Answer 12

□ MEDIATED BY Th1: □ Chronic graft rejection, □ GVHD (graft-versus-host-disease, following transplantation), □ Coeliac disease, □ Contact hypersensitivity e.g. touching nickel. □ MEDIATED BY Th2: □ Many autoimmune disease (asthma, rhinitis and eczema).

Question 13

What is the mechanism of Type 4 Hypersensitivity – Th1 mechanism?

Answer 13

There is antigen activation of Th1 cells leading to T cell activation of macrophages by IFN-gamma, and activation of cytotoxic T cells (CTLs) by IL-2. Much of the damage to cells is mediated by TNF from activated macrophages, and CTLs which kill cells directly using perforin. Th1 cells also activate fibroblasts with fibroblast generating factor (FGF) which leads to angiogenesis and fibrosis. Fibroblast activation occurs only when there is persistent antigen activation of Th1 cells, and the hypersensitivity response is chronic.

Question 14

What is the mechanism of Type 4 Hypersensitivity – Th2 mechanism?

Answer 14

There is antigen activation of Th2 cells leading to T cell activation eosinophils by IL-4, IL-5 and eotaxins. Activated eosinophils produce cytotoxins and inflammatory mediators leading to tissue damage and inflammation.

Question 15

SUMMARY: What examples are there for each type of hypersensitivity?

Answer 15

1. Anaphylaxis, asthma, rhinitis (seasonal and perennial (throughout year)), and food allergy (atopy). 2. Organ-specific autoimmune disease and autoimmune cytopenia. 3. SLE and Vasculitis diseases. 4. Th1-mediated: Chronic graft rejection, GVHD (graft-versus-host-disease, following transplantation), Coeliac disease, Contact hypersensitivity e.g. touching nickel; Th2-mediated: asthma, rhinitis and eczema.

Question 16

What causes inflammation?

Answer 16

Occurs as a result of immune cell recruitment to sites of injury, activation of immune cells and release of inflammatory mediators such as cytokines and complement.

Question 17

What are the features of inflammation?

Answer 17

Vasodilation, increased vascular permeability, inflammatory mediator and cytokine release, and tissue damage leading to redness, heat, swelling and pain.

Question 18

What causes increased vascular permeability in inflammation? (x4)

Answer 18

Caused by complement activation through C3a and C5a, as well as histamines and leukotrienes.

Question 19

What cytokines are involved in inflammation? (x5)

Answer 19

Pro-inflammatory cytokines interact with other cells to produce an inflammatory response: IL-1, IL-6, IL-2, TNF and IFN-gamma.

Question 20

What chemokines are involved in inflammation? (x2)

Answer 20

These are types of cytokines which induce chemotaxis and therefore recruit inflammatory cells to the site of inflammation: IL-8 which recruit neutrophils, and IP-10 which recruit lymphocytes.

Question 21

What are the causes of allergy? (x7 (x3))

Answer 21

□ GENETIC – allergy familial inheritance is POLYGENIC – involve genes of IL-4 gene cluster on Chr5 linked to raised IgE, genes on Chr11q which encode the IgE receptor, and genes linked to structural cells e.g. protein filaggrin linked to eczema. □ AGE – increases from infancy, peaks in teens and reduces in adulthood. □ GENDER – asthma more common in males in childhood, but females in adults. □ FAMILY SIZE – more common in small families – larger families have greater exposures. □ INFECTIONS – early life infections protect. □ ANIMALS – early exposure protects. □ DIET – breast feeding, antioxidants (Vitamin C) and fatty acids protect.

Question 22

What types of inflammation occur in allergy? What type of hypersensitivity is associated with each? (x3)

Answer 22

□ ANAPHYLAXIS, URTICARIA (nettle-like rash), ANGIOEDEMA (swelling) – associated with Type I Hypersensitivity. □ IDIOPATHIC/CHRONIC URTICARIA – associated with Type II hypersensitivity (IgG mediated). □ ASTHMA, RHINITIS, ECZEMA – is an example of mixed inflammation – associated with Type I (IgE) and Type 4 (chronic inflammation) hypersensitivity.

Question 23

What is required in the mechanism for allergy?

Answer 23

Allergy requires sensitisation to allergens, such that further allergen exposure produces an allergic response – this is called the memory response.

Question 24

What is the mechanism of sensitisation and subsequent exposure in atopic airway disease?

Answer 24

1. Antigen is taken up by dendritic cells embedded in the airways, which process the antigen and presents them to CD4+ T cells. The T cells differentiate to Th1, Th2 or Treg cells. T reg cells result in tolerance; Th1 and Th2 lead to sensitisation.
2. Th1 cells produce IFN-gamma which activates Th2 cells. Th2 cells, once activated, produce IL-4 and IL-13 which causes B cells to switch to IgE production. B cells then differentiate into plasma cells which produce IgE antibodies.
3. Subsequent exposure leads to dendritic cell activation of the Th2 memory cells. These produce IL-5 which activate eosinophils, and IL-4 and IL-13 which activates IgE plasma B cells. Mast cells, as well as eosinophils, mediate inflammation.

Question 25

How do eosinophils work in allergic reactions?

Answer 25

Contain large granules containing toxic proteins – when released, leads to tissue damage.

Question 26

How do mast cells work in the allergic response?

Answer 26

They reside in tissues and have IgE receptors, which bind IgE antibodies (produced by B cells in allergic reactions). Cross-linking of IgE-antigen complexes with the mast cell leads to mediator release of histamines, cytokines, toxic proteins (which are stored in granules), leukotrienes and prostaglandins (which are synthesised upon activation) --\> inflammation and tissue damage.

Question 27

How do neutrophils work in allergic response? What examples?

Answer 27

In asthma and eczema: contain granules of digestive enzymes, and synthesise oxidant radicals, cytokines and leukotrienes once activated.

Question 28

What is the immunopathogenesis of asthma?

Answer 28

□ IMMEDIATE HYPERSENSITIVITY (Type I) leads to acute, early phase of asthma: Acute inflammation of the airways from mast cell activation leading to release of histamines, prostaglandins and leukotrienes. These lead to inflammation and acute airway narrowing, which is a consequence of airway wall oedema, smooth muscle contraction, mucous secretion and plugging. □ This early phase recovers after 30-40 minutes. □ Then, there is TYPE IV HYPERSENSITIVITY which leads to late response of asthma: further narrowing of airway from response by eosinophils, T cells, neutrophils, macrophages and dendritic cells.

Question 29

What are the clinical features of asthma? (x6)

Answer 29

□ Reversible generalised airway obstruction leading to chronic episodic wheeze. □ Bronchial hyperresponsiveness. □ Cough. □ Mucous production. □ Breathlessness. □ Chest tightness.

Question 30

What are the two types of allergic rhinitis?

Answer 30

SEASONAL – hay fever from grass and tree pollens; PERENNIAL – from HDM (house dust mite) and pets.

Question 31

What are the clinical features of allergic rhinitis? (x6)

Answer 31

□ Sneezing. □ Rhinorrhoea (nasal cavity filled with mucous). □ Itchy nose and eyes. □ Nasal blockage. □ Sinusitis. □ Loss of smell/taste.

Question 32

What are the clinical features of allergic eczema?

Answer 32

Chronic itchy skin rash, particularly at flexures of arms and legs.

Question 33

What causes allergic eczema?

Answer 33

HDM sensitisation and dry cracked skin which can be infiltrated and complicated by bacteria, ad rarely viral infections such as herpes simplex.

Question 34

What are the clinical features of mild and severe food allergy? (x4 and x6)

Answer 34

• MILD: itchy lips, mouth, angioedema and urticaria. • SEVERE: nausea, abdominal pain, diarrhoea, collapse, wheeze and anaphylaxis.

Question 35

What is anaphylaxis? Mechanism?

Answer 35

Severe generalised allergic reaction, uncommon and potentially fatal.

Question 36

What is the pathophysiology of anaphylaxis?

Answer 36

Generalised degradation of IgE sensitised mast cells – Type 1 hypersensitivity.

Question 37

What are the symptoms of anaphylaxis? (x6)

Answer 37

• Itchiness around mouth and lips. • Swelling of lips and throat. • Wheeze, chest tightness and dyspnoea. • Faintness and collapse. • Vomiting and diarrhoea. • Death if severe and untreated.

Question 38

What are the signs of anaphylaxis? (x4 systems)

Answer 38

• CARDIOVASCULAR: Vasodilation --\> shock. • RESPIRATORY: Bronchospasm and laryngeal oedema. • SKIN: Erythema (skin reaction), uticaria and angioedema. • GI: vomiting and diarrhoea.

Question 39

How do you investigate and diagnose allergies? (x4 assessments)

Answer 39

• Careful history taking. • Skin pricking test – with allergens, positive control (histamine) and negative control (saline). • RAST (radioallergosorbent test) – similar to skin prick test, although you use a blood test and radioimmunoassay to detect specific IgE antibodies to determine the substances a subject is allergic to. • Total IgE is a measure of total level of IgE in the blood – tells us general allergic susceptibility of patient.

Question 40

How is anaphylaxis treated? (x2)

Answer 40

EpiPen and anaphylaxis kit: containing antihistamine, steroid, adrenaline.

Question 41

How is allergic rhinitis treated? (x3)

Answer 41

Antihistamines (sneezing, itching, rhinorrhoea), nasal steroid spray (nasal blockage) and cromoglycate (used more in children and eyes – blocks degranulation of mast cells).

Question 42

How is eczema treated? (x2)

Answer 42

Emollients – improve barrier aspect of skin to prevent penetration of allergens to the immune cells, and topical steroid cream to suppress the immune response.

Question 43

How is eczema treated if severe? (x3)

Answer 43

Anti-IgE, anti-IL-4/-13 and anti-IL-5 monoclonal antibodies.

Question 44

How is asthma treated? (x4 steps)

Answer 44

1. Use short-acting B2 AGONIST DRUG e.g. Salbutamol. 2. INHALED STEROID – low-moderate dose e.g. Budesonide or Fluticasone. 3. Add LONG ACTING BRONCHODILATORS, LEUKOTRIENE ANTAGONISTS or high dose INHALED STEROIDS. 4. Add courses of ORAL STEROIDS, SLIT, AZITHROMYCIN.

Question 45

What immunotherapies can be used to treat hypersensitivities? (x2)

Answer 45

• SUBCUTANEOUS IMMUNOTHERPAY (SCIT): injection of purified antigen subcutaneously. • SUBLINGUAL IMMUNOTHERAPY (SLIT): purified antigen taken as a tablet under the tongue. • This is a long-term therapy where progressively increased doses of the antigen are exposed to an individual, to teach the patient to become tolerant to the antigen.

Question 46

What is the histological structure of skin?

Answer 46

* Papillary dermis is composed of fine and loosely arranged collagen. * Reticular dermis is composed of irregular connective tissue featuring densely packed collagen fibres. * Hypodermis is mainly for fat storage. * Hair-bearing skin contains hair follicle in the reticular dermis. Sebaceous glands are also found which lubricate hair. * There are two types of sweat gland – apocrine which make a more viscous and smelly sweat (e.g. in axilla), and eccrine sweat glands found in other regions of the body.

Question 47

What is the structure of the epidermis?

Answer 47

Made up of four cell types: keratinocytes, melanocytes, Merkel cells (or tactile cells – involved in sensation) and dendritic cells (called Langerhans cells in the epidermis). Keratinocytes proliferate in the stratum basale and migrate up and mature: they ascend through the stratum spinosum, granulosum, lucidum and corneum where they flake.

Question 48

What is the structure of the stratum corneum? Importance?

Answer 48

Corneocytes are the name of the keratinocytes in this layer. Intercellular spaces are filled with lipids. Together, these lipids and corneocytes create the BARRIER FUNCTION of the skin.

Question 49

What is the pathophysiology of eczema?

Answer 49

The structure of the stratum corneum – which performs the barrier function of the skin, is DEFECTIVE, allowing infiltration of allergens, irritants and pathogens. This leads to activation of CD4+ lymphocytes and the Th2 immune response --\> acute atopic eczema; and activation of CD4+ and CD8+ lymphocytes and the Th1 immune response --\> chronic atopic eczema. The FILAGGRIN gene mutation is common in this pathophysiology.

Question 50

What is atopy?

Answer 50

Tendency to develop hypersensitivity.

Question 51

What examples are there of atopic diseases? (x3)

Answer 51

Eczema, asthma and hay fever.

Question 52

What is the atopic march?

Answer 52

A phenomenon in atopic patients, who sequentially experience different atopic conditions throughout their life. Atopic patients, at around 1-2 years, will experience a spike in incidence of food allergies and eczema. Food allergy and eczema incidence falls after this age, though eczema falls more slowly. Asthma has increased incidence around 6 years. Rhinitis appears from around 9 years of age.

Question 53

What are the clinical features of atopic eczema? (x5) Note about one of the signs.

Answer 53

• Redness of skin. • Swelling. • Itching. • Skin lesions. • PALMAR HYPERLINEARITY (sign of filaggrin gene mutation).

Question 54

How does eczema present in babies?

Answer 54

Called INFANTILE ATOPIC ECZEMA: eczema looks poorly defined and occurs mainly in areas where they are able to rub themselves – the face, elbows and knees.

Question 55

How does the pattern of eczema change with age?

Answer 55

In children, eczema appears predominantly on face, elbows, knees and feet. In adults, eczema is concentrated at flexures – the neck, back of knees and elbows, hands and face.

Question 56

What are the signs of chronic atopic eczema?

Answer 56

There is usually less redness and associated with LICHENIFICATION – the skin has thickened with accentuated skin markings, excoriations (areas of repetitive scratching), and the area of involvement is poorly defined i.e. the boundary of skin where there is and isn’t eczema is not clear.

Question 57

What is eczema herpeticum?

Answer 57

Patients with eczema are susceptible to infiltration by infection, this can worsen and precipitate the eczema. Eczema herpeticum is herpes simplex virus which forms cutaneous vesicular eruptions that arises from eczema.

Question 58

What is seborrheic eczema?

Answer 58

Complication of an overgrowth of yeast and eczema. It is the same as dandruff and affects areas of the skin rich in oil-producing glands – scalp, face and chest.

Question 59

What is allergic contact dermatitis?

Answer 59

It is the manifestation of eczema as an allergic response caused by contact with an allergen.

Question 60

What is discoid eczema?

Answer 60

Skin becomes itchy, swollen and cracked in circular patches, often on legs and the trunk. It is associated with dryness.

Question 61

What are the clinical features of psoriasis? !

Answer 61

Patients develop plaque-like lesions which are well-defined silvery scales. They are well-defined – it is clear where there is and isn’t psoriasis. It is often quire SYMMETRICAL – this is what differentiates inflammatory conditions from infectious ones.

Question 62

What are the causes of psoriasis?

Answer 62

Genetic susceptibilities and environmental triggers such as stress, drugs, alcohol and infections.

Question 63

What is the pathophysiology of psoriasis? Five main features.

Answer 63

In psoriasis, there is over-proliferation of keratinocytes which are being shed when they are immature – they still have their nuclei when they are being shed. It is therefore associated with HYPERKERATOSIS (thickening of the keratin layer (keratin is produced by keratinocytes)), PARAKERATOSIS (in normal skin, corneocytes should have lost their nuclei; in psoriasis, they don’t), ACANTHOSIS (thickening of epidermis), INFLAMMATION (neutrophils in the epidermis; lymphocytes in the dermis), and DILATED BLOOD VESSELS.

Question 64

What areas are particularly affects by psoriasis?

Answer 64

Scalp, eyebrows, crease in skin from nose to edge of lips, armpits, elbows, trunk, umbilicus, groin and genitals, nails and knees.

Question 65

What happens to nails in psoriasis? (x5)

Answer 65

Subungual hyperkeratosis (build-up of debris under the nail plate), dystophic nail (roughening of the nail), loss of cuticle (allowing bacteria and fungi to enter --\> secondary infection), onycholysis (nail lifts away from the underlying skin surface), and pitting (pits form in the nail).

Question 66

What is guttate psoriasis?

Answer 66

A pattern of psoriasis where there are small papules as opposed to large plaques.

Question 67

What is palmoplantar pustulosis?

Answer 67

Psoriasis that just affects mostly the palms of the hand and feet – presents as small pustules (small bumps that contain pus).

Question 68

What is generalised pustular psoriasis?

Answer 68

Extensive involvement of the skin, containing pustules.

Question 69

What is the pathophysiology of pustule formation in psoriasis?

Answer 69

The epidermis contains neutrophils which coagulate together to form pustules. These pustules are superficial because neutrophils are in the epidermis, and they are sterile – not caused by infection.

Question 70

What is the pathophysiology of acne?

Answer 70

1. There is accumulation of dead cells and sebum in a hair pore. This forms a comedone (blackhead/whitehead). 2. The build-up gets colonised by bacteria (Propionibacteria acnes) which proliferate and form the pimple. 3. There is inflammation, and the hair follicle bursts which results in spread of the infection to surrounding dermis.

Question 71

What are the causes of acne? (x2)

Answer 71

Puberty – androgenic stimulation, and genetic predisposition.

Question 72

What is the difference between a blackhead and whitehead?

Answer 72

Whitehead is a closed comedone (with overlying skin); blackhead is an open comedone.

Question 73

What is a papule?

Answer 73

A small inflammatory lesion.

Question 74

What is a nodule?

Answer 74

A large inflammatory lesion.

Question 75

What is a pustule?

Answer 75

A pus-filled inflammatory lesion.

Question 76

What is bullous pemphigoid?

Answer 76

An autoimmune skin condition that involves the formation of blisters (bullae) in the space between the epidermis and dermis – the BASEMENT MEMBRANE.

Question 77

What is the pathophysiology of bullous pemphigoid?

Answer 77

• Epidermis and dermis have differing embryological origins (ectoderm and mesoderm respectively). In order to stick them together, specialised proteins are required. • If any of these proteins are the target of an autoimmune condition, or have a genetic mutation so are ineffective, then the epidermis/dermis will peel away from the basement membrane. • In bullous pemphigoid, B cells produce antibodies against Dystonin (aka Bullous Pemphigoid Antigen 1, BPAg1) or Type XVII Collage (aka Bullous Pemphigoid Antigen 2, BPAg2 – component of hemidesmosomes). This results in an inflammatory reaction resulting in the dermis/epidermis splitting from the basement membrane and blister formation.

Question 78

What is epidermolysis bullosa?

Answer 78

Genetic condition affecting the proteins that hold together the dermis-BM-epidermis arrangement (the same proteins mentioned in the pathophysiology of bullous pemphigoid), resulting in splitting of the skin and blistering after minor trauma.

Question 79

What is pemphigus vulgaris?

Answer 79

An autoimmune condition in which blisters appear superficially.

Question 80

What is the pathophysiology of pemphigus vulgaris?

Answer 80

• Between keratinocytes, there are proteins which connect the keratinocytes together. • In pemphigus vulgaris, autoantibodies are produced against the DESMOGLEINS/DESMOCOLLINS proteins which form these connections. • Therefore, splits form WITHIN the epidermis, between keratinocytes. • Hence, pemphigus vulgaris presents as easily broken blisters because of the superficiality.