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Flashcards in Skin Pathology 4 Deck (21):
1

HYPERSENSITIVITY TYPES

TYPE I- food allergy, anaphylaxis, atopic skin disease, insect bite hypersensitivity.
TYPE II- introduction to autoimmune disease.
TYPE III- vaccine reaction, cutaneous vasculitis.
TYPE IV- TB test, allergic contact dermatitis, tuberculosis.

2

IMMUNE MEDIATED DISEASE

A broad, 'umbrella' term that encompasses various disorders in which tissue damage is due to immune responses.
"Defence responses can cause tissue damage"- excessive inflammation, due to uncontrolled proinflammatory cytokine/chemokine production from innate immune cells and Th1 cells.
-Eosinophilia and allergic reactions- uncontrolled Th2 cell responses.
-Killing of host cells by CD8+ cytotoxic T cells and NK cells.

3

HYPERSENSITIVITY REACTIONS

One type of immune mediated disorder.
An exaggerated or inappropriate immune response to a mild pathogen or innocuous substance (allergen).
TYPE I- Immediate, anaphylactic.
TYPE II- Antibody dependent (IgG), cytotoxic.
TYPE III- Immune complex mediated.
TYPE IV- Cell mediated, delayed.

4

TYPE I HYPERSENSITIVITY

Exposure to allergen
-> antigen presenting cell presents allergen to naive T cell
-> Th2 effector cell
-> B cells produce ANTIGEN SPECIFIC IgE
-> IgE binds to mast cell membranes via high affinity receptors
-Re-expousure to allergen results in RAPID MAST CELL DENGRANULATION, stimulated by cross linking of bound IgE.
-Rapid release of preformed mediators, including histamine and prostaglandins.
-Results in severe, generalised systemic reaction (anaphylaxis), OR a milder, local reaction.

eg. Food allergy- classic trigger of anaphylaxis in humans and animals.

5

ANAPHYLAXIS

"Immediate systemic reaction caused by rapid, IgE mediated immune release of potent mediators from tissue mast cells and peripheral basophils".
"A serious allergic reaction that is rapid in onset and may cause death"
Involves a variety of tissues- skin, mucosal tissue (respiratory, GI). The extent to which each tissue is involved depends on species etc.

6

ANAPHYLAXIS- TRIGGERS

Foods, medications, venoms, unidentified (<30% human cases, more in animals).
Not all reactions directly involve IgE.
Some triggers DIRECTLY stimulate mast cells- no previous exposure is required eg. VENOMS.

7

MAST CELL ACTIVATION AND DEGRANULATION

Initiated by cross linking of sensitised IgE bound to membrane Fc receptors.
Immediate response mediated by preformed stored mediators- histamine etc.
-Late phase reaction mediated by cytokines and phospholipid derivatives- leukotrienes.

8

TYPE I HYPERSENSITIVITY- EXAMPLES IN ANIMALS

-Atopic dermatitis
-Insect bite hypersensitivity- fleas, culicoides midges (sweet itch)
-Drug eruptions
-Food allergy.
Between them, atopic dermatitis and flea bite hypersensitivity account for the majority of cases of skin disease in dogs and cats.

9

ATOPIC DERMATITIS (AD)

A multifactorial, multifaceted disease, involving complex interactions between GENETIC and ENVIRONMENTAL factors.
Mutations in the gene that codes for profilaggrin- FLG- are considered the most important risk factor for AD in humans (eczema), but this is not the only factor- not all eczema patients have the mutation, and not all those with the mutation develop eczema.

10

FEATURES OF SKIN IN AD PATIENTS

(Human)- lesional and non lesional skin has:
-Decreased filaggrin expression and decreased NMF (Natural Moisturising Factor), due to loss of function mutations in FLG gene.
-More limited and discontinuous lipid later due to decreased synthesis of lipid lamellae.
-Enhanced protease activity(endogenous and exogenous eg. from parasites, bacteria)- alters rate of desquamation
-Altered expression of antimicrobial peptides
-Greater numbers of antigen presenting cells (APCs) bound with IgE
-Th2 cell responses predominate (genetic predisposition)- IL4 promotes Th1 to Th2 switching.
-IL13 induces immunoglobulin class switching, to IgE.

11

CANINE ATOPY

TYPE I HYPERSENSITIVITY REACTION TO ENVIRONMENTAL ALLERGENS.
Common- house dust mites.
Predisposition seems to be inherited- Westies, Cairns, Scotties, Boxers etc. Not a simple inheritance.
PRURITIC DERMATITIS AND OTITIS (sometimes conjunctivitis)- often affects face, feet and ventrum. Characteristic clinical features.
Histology- variable, often minimal. Early biopsies often show no signs, signs in later biopsies are often from cell trauma.

12

ATOPIC DERMATITIS

Includes canine atopy.
Superficial dermatitis, interstitial oedema, acute inflammation, often see mast cell-rich infiltrate.
Secondary skin changes/lesions are often seen (consider chronicity of condition)

Formerly called 'Allergic Inhalant Dermatitis', but it is now well established that allergens can be absorbed via the skin as well as via inhalalation.
An abnormal skin barrier contributes to the pathogenesis of canine atopic dermatitis- variations in filaggrin expression (mutations in FLG excluded as a major cause in Westies), disorganised lipid lamellae, altered balance of antimicrobial peptides.

13

INSECT BITE HYPERSENSITIVITY

Allergic dermatitis, can be acute or, more often, chronic.
Common in horses, dogs, cats, humans.
Triggers- fleas, biting midges, blackflies, mosquitoes.
TYPE I HYPERSENSITIVITY, therefore classed as an atopic disorder in horses and humans.
Considered separate to atopy in cats and dogs.
Horses- ELA (Equine Leukocyte Antigen), a component of MHC II, is a risk factor- if present, will predispose the animal to hypersensitivity.

Lesion distribution reflects insect eg. Culicoides midges bite at the mane and tail.
eg. Fleas often bite around the tail head
eg. Mosquitoes often bite around the head.

Reaction can be localised- focal necrosis beneath exudate crust- or more dramatic- eosinophilic furunculosis with much oedema.
Reaction is often characterised by EOSINOPHILS.

14

FLEA BITE HYPERSENSITIVITY

aka. Flea allergy dermatitis. TYPE I HYPERSENSITIVITY (can be type IV- delayed. Will not respond to antihistamines; use steroids to treat)
-Common; no breed predilection.
-May be seasonal- Summer and Autumn
-PRURITIC PAPULAR DERMATITIS eg. miliary eczema (cats)
-Often affects dorsal lumbosacral area (tail head), neck, inner thighs, abdomen. Hair loss seen from self trauma due to pruritis.
-Histology- may include eosinophils in dermal infiltrate and/or intraepidermal eosinophilic abscesses.

15

TYPE IV HYPERSENSITIVITY

CELL MEDIATED immune response.
DELAYED TYPE HYPERSENSITIVITY (DTH) reactions involves the same processes as cell mediated immunity to microbial infection.
-Balance swings from protection to tissue damage if the stimulus is great or unusually persistent.
-Sensitised T cell population develops after initial contact with antigen, via APCs.
-Reexposure -> lymphocyte activation -> cytokine release -> macrophage infiltration.
-Tissue damage is due to- ACTIVATED MACROPHAGES- release proinflammatory cytokines- and CYTOTOXIC T CELLS- directly cytotoxic.

eg. Tuberculin test- a response is seen if the animal has already been exposed to TB antibodies (ie. it is infected); this has allowed priming of T cells.
Some reactions to insect bites or stings are similar.

16

ALLERGIC CONTACT DERMATITIS

TYPE IV HYPERSENSITIVITY.
Haptens bind to epidermal proteins, producing an allergen response.
Not commonly diagnosed in animals; difficult to distinguish from ICD.
VARIABLY PRURITIC MACULOPAPULAR DERMATITIS.
Sparsely haired areas are affected, especially the ventrum, feet legs, perineum, scrotum, chin and ear pinnae.
Histology- non-diagnostic dermatitis- hyperplastic, (compact) hyperkeratotic, hypergranulotic, lymphocytic exocytosis.
Compact hyperkeratosis can be an indication of the animal rubbing irritated skin- pushes layers of keratin together.

Allergens include plants, bedding, topical medications etc.

17

DELAYED TYPE HYPERSENSITIVITY REACTION

SENSITISATION PHASE- 1. Antigen presenting cells (Dendritic cells, macrophages) present allergen to CD4+ Th cell.
2. Th1 cells, once exposed to allergen, generally act as DTH mediating cells. Occasionally, CD8+ cells can do this as well.

EFFECTOR PHASE- Sensitised Th1 cells activate macrophages via cytokine and chemokine secretion (includes interleuking, IFNy, TNF)
-Activated macrophages increase MHC II expression, TNF factor receptors, oxygen radicals, nitrous oxide.

-> DTH reaction- contact dermatitis, granuloma or other.

18

FORMATION OF AN IMMUNE GRANULOMA

Persistent antigen stimulation means there is a constant drive for influx and stimulation (activation) of macrophages, resulting in them becoming organised as a granuloma.
Granulomas also contain giant cells, epitheliod macrophages, lymphocytes and fibroblasts.

eg. Bovine TB- coalescing granulomas with caseous necrosis.

19

TYPE III HYPERSENSITIVITY

Antibody directed against soluble antigens.
Circulating Ag-Ab complexes are soluble.
DEPOSITION OF AG-AB COMPLEXES WITH EXCESS AG IN TISSUES INITIATES INFLAMMATION.
-Complement fixation and neutrophil chemotaxis (polymorph infiltration)
-> vascular and tissue damage due to proteolytic and hydrolytic enzymes.

Reaction can be systemic (serum sickness) or localised (arthus reaction).
-Renal glomeruli, joints, small blood vessels
-Cutaneous vasculitis, drug eruption
-Bacterial (staphylococcal) hypersensitivity
-Some injections reactions- uncommon, can be local or generalised. Local- arthus reaction in dermis- Ag-Ab complex deposits in dermis.
Type III hypersensitivity underlies many diseases.

20

CUTANEOUS VASCULITIS

Rare, except in dogs and horses.
An example of TYPE III HYPERSENSITIVITY
Several mechanisms may be involved in pathogenesis- other immunological mechanisms, direct infection (eg. rickettsia, herpesvirus).
Antibodies develop in response to INFECTIONS and/or DRUGS.
eg. S. equi (horses), penicillin, sulphonamides.
IMMUNE COMPLEXES DEPOSITED IN THE WALLS OF SMALL BLOOD VESSELS.
-> oedema, haemorrhage, ischaemia.

Histologically, fibrinoid exudate and nuclear debris can be seen around damaged blood vessels.
Inflammatory infiltrate can be seen WITHIN vessel walls.

21

TYPE II HYPERSENSITIVITY

DIRECT DAMAGE, mediated by ANTIBODIES TO EXPOSED CELL SURFACE ANTIGENS.
Antigen is usually endogenous, but may be hapten attached to cell surface.
Binding of antibody (IgG or IgM) +/- complement -> CYTOLYSIS or CYTOTOXICITY.
ADDC- ANTIBODY DEPENDENT CELL-MEDIATED CYTOTOXICITY.

This mechanism underlies various autoimmune disorders affecting a variety of tissues- haemolytic anaemia (affects RBCs), pemphigus/pemphigoid (epidermal cells), thyroiditis (thyroid epithelial cells)