Flashcards in Skin Pathology 2 Deck (38):
Largest organ in the body, vital for life.
Most exposed interface with the environment, therefore plays a CENTRAL ROLE IN HOST DEFENCE:
-Passive- BARRIER. Long recognised, assumed inert. Currently the subject of intense research.
-Active- SKIN IMMUNE SYSTEM. Cutaneous immunology emerged after recognition of antibody deposits in skin of patients in the 1960s. Immunological role of Langerhan's cells not recognised until after 1975. An area of current research.
FACTORS AFFECTING THE SKIN
EXOGENOUS- microbial, chemical, physical, parasitic, actinic, allergic, nutritional.
ENDOGENOUS- immunologic, hormonal, metabolic, hereditary, congenital, age (some of the defences of the skin decline with age), internal disease, psychological.
HAIR- thermal insulation and dissipation (new discovery- hair can dissipate heat eg. sparse covering on elephants heads)
MELANOCYTES- Photoprotection and photosensitisation. Active area of research, especially in human medicine.
EPIDERMAL BARRIER- skin surface lipids, stratum corneum.
THE SKIN BARRIER
Cornified cell envelope- comprised of corneocytes and lipid bilayer.
Granular layer- lamellar granules in cells contain lipid precursors, antimicrobial peptides, proteases.
Basal layer- contains dendritic Langerhans cells and melanocytes.
Proteins under the action of protease (from granular layer) are broken down from precursor PROFILAGGRIN to structural protein FILAGGRIN to AMINO ACIDS.
Filaggrin bundles keratin and flattens corneocytes.
Amino acids aid retention of moisture.
OPTIMAL SKIN BARRIER FUNCTION
Depends on various factors:
-LIPID BILAYER- content of lamellar bodies released from granular layer (lipid precursors)
-CORNIFIED ENVELOPE STRUCTURE- loricrin, involucrin, filaggrin.
-FILAGGRIN- from profilaggrin, (keratohyaline granules), binds keratin filaments together then breaks down to amino acids, which are natural moisturising factors.
-CORNEODESMOSOMES- tight junctions, provide structural integrity.
-CONTROL OF DESQUAMATION- control of formation/loss of skin involves balancing of protease inhibitors and proteases. Altering skin pH can alter desquamation.
INNATE AND ACQUIRED RESISTANCE
INNATE- sentinel cells (macrophages, mast cells, dendritic cells)
-Effector mechanism- inflammation, complement activation.
ACQUIRED- antigen presenting cells- dendritic cells, macrophages.
-Effector mechanism- antibody mediated, cell mediated, immunological memory.
There is complex interaction between the components and between innate and acquired immunity.
THE SKIN IMMUNE SYSTEM
-PHYSICOCHEMICAL BARRIERS- strateum corneum, surface lipids, antimicrobial peptides (defensins, cathelicidins).
-SKIN MICROBIOME- commensal bacteria in the skin have an anti-inflammatory role and affect T cell maturation. They produce chemicals for these roles/effects.
-KERATINOCYTES- express Pattern Recognition Receptors (PRRs) eg. TLRs, produce cytokines, can express MHC II.
-DENDRITIC CELLS- dermal or epidermal (Langerhans cells), antigen presentation.
-MAST CELLS- express diverse PRRs, release histamine etc.
-LYMPHOCYTES (T CELLS)- various Th subsets.
"Long considered a graveyard of insoluble keratin fibrils".
Is actually a dynamic tissue in continual operation, providing adaptive and protective properties- a key feature in the bodies defences.
Consider structure- keratin macrofibrils, lipid bilayers, proteins (structural, small proline rich region proteins, late envelope proteins).
Normal, healthy stratum corneum is up to 85% lipid by weight. Comprised of sphingolipids (ceramide), cholesterol and free fatty acids.
Sphingolipids and fatty acids contribute to the physical barrier, permeability barrier and immunologic barrier.
Ceramide (sphingolipid) helps to maintain pH level and participates in cell signalling pathways.
Some molecules have antimicrobial properties- sphingoid bases derived from epithelial sphingolipids, fatty acids derived from sebaceous triglycerides.
Antimicrobial mechanisms vary between molecules and microbes and are not fully understood.
Produced by neutrophils, macrophages, epithelial cells and by bacteria (skin microbiome).
eg. DEFENSINS, CATHELICIDINS. Powerful antimicrobials, activate and recruit inflammatory cells (WBCs), 'alarm and arm' keratinocytes- produce cytokines.
The skin can be flooded with antimicrobial peptides if damaged.
Immunomodulatory function- hence the name 'host defence peptides'
Antimicrobial peptides. Functions:
-PRIMARY DEFENCE- Antibacterial, antifungal, antiviral.
-SECONDARY DEFENCE- Chemotactic
-REPAIR RESPONSE- Protease inhibition, angiogenesis, ECM synthesis.
Always present in follicular epithelium, neutrophils, sweat- constitutive expression.
Inducible expression in keratinocytes.
THE SKIN MICROBIOME
The skin, like the gut, needs microbial signals for proper immune function.
Commensal microbes (eg. S. epidermis) stimulate the skin and immune cells to produce IL-1.
IL-1 activates T cells, which become more responsive to invading organisms.
"Microorganisms living around a hair follicle can alter the responses of the immune cells".
ROLE OF COMMENSAL BACTERIA IN INNATE IMMUNITY
Commensal bacteria produce factors that modulate the skin immune system:
-MODULINS- act as a barrier to pathogenic colonisation.
-SMALL MOLECULES- enhance expression of defensins via TLR signals.
Sentinel cells, active in host defence.
Express a wide variety of PRRs.
Respond to DAMPs (DAMAGE ASSOCIATED MOLECULAR PATTERNS) and PAMPs (PATHOGEN associated).
Are proinflammatory effector cells- react to harmful insult by producing a complex mixture of antimicrobial peptides, proinflammatory cytokines and chemokines.
Are non-professional antigen presenting cells- can express MHC II molecules, and are able to interact with antigen experienced T cells (not naive T cells!)
KERATINOCYTES IN INNATE IMMUNITY
Produce and release antimicrobial peptides, endothelin-1, cytokines.
These products are involved in activation of Mast cells, killing pathogens, recruiting inflammatory cells.
Cornified keratinocytes provide a physical barrier against pathogens.
THE CONCEPT OF SKIN IMMUNE SURVEILLANCE
Skin is comprised of three distinct compartments relevent to it's immune fucntions.
1. EPIDERMIS- keratinocytes, Langerhans cells (specialised dendritic cells), intraepithelial lymphocytes.
2. DERMIS- dermal dendritic cells, mast cells, cutaneous lymphocyte antigen (CLA)+ memory T cells.
3. DERMAL POST CAPILLARY VENULES- in normal skin, we see low level expression of receptors E-selectin, CCL17, ICAM1.
This facilitates emigration of CLA+ memory T cells from blood to non-inflamed tissues.
INNATE IMMUNE RESPONSE TO INJURY OR PATHOGEN INVASION
-Release of primary cytokines from dendritic cells- inflammation, upregulation of endothelial expression of adhesion molecules (E-selectin, ICAM1), recruitment of additional innate effector cells.
-Activation of skin cells and resident innate immune cells- Langerhans cells and dermal dendritic cells carry antigen to draining lymph node.
ADAPTIVE IMMUNE RESPONSES IN THE SKIN
CLA+ memory T cells carry T cell receptors (TCRs) specific for antigen previously encountered in the skin.
Interaction of antigen-specific T cells with antigen presenting cells (APCs) results in T cell activation.
Cytokines also stimulate expression of T cell-specific chemokine ligands on endothelium.
T cells can be recruited by antigen non-specific mechanism as well.
LANGERHANS CELLS (EPIDERMAL DENDRITIC CELLS)
Dendritic cells bridge the innate and adaptive immune responses- what were once thought to be two separate processes.
Langerhans cells interact with skin-resident memory T cells.
-Maintain homoeostasis by activating Tregs (seen in normal skin)
-Direct the immune response via the pattern of cytokines produced following stimulation.
-During infection, T effector memory (Tem) cells are induced.
-BALANCE between Treg and Tem activation maintains homoeostasis in normal skin.
How the Langerhans cells respond determines the response- different cytokines will be produced.
OUTLINE OF CELL INTERACTIONS IN INNATE AND ADAPTIVE IMMUNITY
A balance between multiple cell types of the innate and adaptive immune systems depends on cytokines, which depend on the type of initiating agent (bacterial, parasitic, fungal etc.) tissue environment, host genetics and so on.
Begins with epithelial cells.
Innate- Dendritic cells, monocytes, granulocytes.
Adaptive- Antigen presenting cells, NK cells, T helper precursors.
T cells are activated and target specific initiators eg. Th1 cells target intracellular bacteria, Th2 cells target parasites, Th17- bacteria, fungi, Treg- anti-inflammatory, CD8- cytotoxic, target virus infected cells, B cells- extracellular pathogens.
CD4+ HELPER T CELL SUBSETS
TH1 CELLS- Stimulated by IL-12. Produce IL-2, IFNy. Promote cellular response.
TH2 CELLS- Stimulated by IL-4. Produce IL-4, IL-5. Stimulate humoral response.
TH17 CELLS- Stimulated by a mixture of cytokines, including IL-23. Produce a distinct mix of cytokines- NOT IFNy. Proinflammatory. Can convert in to Th1 cells.
Before discovery of Th17 cells, it was thought that a simple balance between Th1 and Th2 cells existed. Now it is thought to be likely that a continuum exists of Th cell function and marker expression, between the two ends of the spectrum (immunity and hypersensitivity)
AGENTS OF DISEASE
-PHYSICAL OR CHEMICAL DISEASES- UV radiation, contact irritants, heat.
-INFECTIOUS AGENTS- bacteria, fungi, parasites, viruses.
-NUTRITIONAL/METABOLIC DISTURBANCE- endocrine disorder, nutritional disorder.
PORTALS OF ENTRY IN TO THE SKIN
EPIDERMIS- Absorption (eg. lipophilic drugs), direct contact (caustic chemicals), colonisation (dermatophytes), penetration (hookworm larvae, trauma, including UV radiation), impaired skin barrier (microorganisms, allergens)
ADNEXA- entry via follicle ostium (bacteria, parasites, fungi).
-follicle or adnexal gland rupture to allow entry in to dermis
DERMIS AND PANNICULUS- blood vessels, nerves (rare- feline herpesvirus)
UNDERLYING TISSUES- penetration by damaged bone, extension from adjacent tissues.
MECHANISMS OF DISEASE
-Genetic predisposition eg. atopic dermatitis
-Physical damage eg. self trauma
-Toxic products eg. dermatophilosis
-Hypoxia eg. vasculitis
-Immune stimulation eg. hypersensitivity
-Degeneration eg. Feline Skin Fragility Syndrome- can be genetic or drug induced.
In most diseases, sever overlapping processes may occur together. For example, many allergic disorders have a genetic predisposition.
Most conditions provoke an inflammatory reaction.
The skin is limited in how it can respond.
AETIOLOGY OF SKIN DISEASE
-Neoplastic- cutaneous histiocytoma (Langerhans cells)
-Idiopathic- chronic/recurrent urticaria.
-Iatrogenic- iatrogenic canine Cushing's syndrome from prolonged/excess corticosteroid therapy, iatrogenic diabetes mellitus in cats due to prolonged/inappropriate antipruritic treatment (megestol acetate, methylprednisolone)
THE SKIN RESPONSE TO INJURY
EPIDERMIS- release of pro-inflammatory cytokines and growth factors by keratinocytes, altered proliferation and differentiation- hyperplasia, hyperkeratosis, parakeratosis.
DERMIS- stimulation of dermal inflammation- erythema, inflammatory oedema, exudation.
Release of secondary cytokines/growth factors promote further change.
Antigen presenting cells interact with T cells.
SIGNALLING PATHWAYS IN INFLAMMATION OF THE SKIN
-Proliferation and differentiation from the basal to superficial layers, to form protective barrier.
-Changes in proliferation and differentiation change the structure of the skin.
-External stimuli such as trauma or irradiation cause keratinocytes to release primary cytokines, IL-1α and TNF-α.
-Primary cytokines provoke fibroblasts, leukocytes and keratinocytes to express more primary cytokines (IL-1) as well as proinflammatory secondary cytokines and chemokines.
-Trauma also elicits KGF and activin expression which promote repair.
-Foreign antigens are captured by Langerhan's cells (LC) and other antigen-presenting cells (APC) which migrate and interact with T cells.
-Activated T cells, supported by secondary cytokines from the epidermis, dermis and leukocytes, proliferate and release cytokines that promote cellular (Th1, involving IFN-γ) or humoral (Th2, involving IL-4) immune responses.
TERMINOLOGY OF EPIDERMAL RESPONSE TO INJURY
-Orthokeratotic keratosis- 'normal keratinisation but lots of it'
-Parakeratotic keratosis- abnormal, can be induced by increasing cell turnover.
Increase in thickness of anuclear surface keratin.
Layer is composed of normal keratin, but is thickened due to increased stratum corneum production, or abnormal retention of squames.
Prominent granular layer associated with hyperkeratosis and/or hyperplasia.
The granular layer is often barely visible in the skin of the normal animal.
PARAKERATOSIS. Thickened keratin layer WITH RETAINED NUCLEI.
Abnormal keratinocytes- do not see nuclei in normal cells.
Rapid cell turnover results in keratinocytes in the cornified layer having retained nuclei.
May be associated with hypogranulosis.
Broadening of the stratum spinosum (spinous/prickle layer). Often accompanies hyperplasia.
Acanthosis and hyperplasia are often used interchangeably.
Increase in number of cells.
Often irregular, but patterns do occur.
Ridges are normal in human skin, but abnormal in animals- ridges/folds in the cornified layer indicate hyperplasia.
Crowded nuclei in the basal layer can be seen.
A common finding in biopsies of animal skin with self trauma.
-Pigmentary incontinence- leaking pigment is taken up by macrophages, can be seen in healing lesions.
-Hyperpigmentation- often seen in dogs after wound healing.
-Hypopigmentation- often seen in horses after wound healing.
Hyperkeratosis, hyperplasia/acanthosis, DYSPLASIA (disordered growth) adjacent to erosion/ulceration.
Localised areas of skin thickening/lichenification.
Develop over pressure points- elbows/hocks of large breeds, sternum of smaller breeds.
Vulnerable to infection and inflammation- bacterial infection and/or release of follicle contents in to dermis.
Results in CALLUS PYODERMA.
TRAUMATIC SKIN DISEASE
DIRECT- Friction/pressure, chemical (irritant contact dermatitis), heat (burns), light (phototoxicity)
INDIRECT- metabolic (photosensitivity)