Flashcards in Skin Pathology 5 Deck (35):
MECHANISMS OF TISSUE DAMAGE
Antibody mediated- Type I, II hypersensitivity.
"A whole variety of final pathways means that Th2 cells can cause a variety of immune mediated conditions"
Antibody complex/complement- Type III.
T cell mediated- Type IVa- Th1 cells stimulate macrophages.
-Type IVb- Th2 cells stimulate eosinophils.
-Type IVc- cytotoxic T cells.
-Type IVd- Th17 cells drive neutrophil response.
Type V hypersensitivity- categorises the damage caused by agonist effects of Ab binding to endocrine receptors.
Requires a sensitisation and an effector stage.
HYPERSENSITIVITY REACTIONS CAUSE TISSUE DAMAGE.
Often a mixture of hypersensitivity reaction types are seen causing tissue damage.
Disease results as a consequence of MISDIRECTED IMMUNITY.
Effector mechanisms are those of normal immunity and hypersensitivity.
Arises via complex interactions between genetic and environmental factors, which influence immune regulation. There is no simple cause of autoimmunity- we often don't know why it arises in the individual.
-Loss of tolerance to self-antigens
-Exposure of altered/cryptic self-antigens
There is interaction between genes, the environment and immune regulation. If interaction occurs in the wrong way, autoimmune disease can develop.
TOLERANCE OF SELF ANTIGENS
ACTIVE process- requires the body to initiate and maintain tolerance.
Central and peripheral tolerance are required:
CENTRAL- deletion of self-reactive T cells during development in the thymus.
PERIPHERAL- inhibition of mature self-reactive T cells or B cells (LYMPHOCYTES) in peripheral tissues.
-required for control of reactions to tissue specific antigens that are not expressed in the central lymphoid organs.
FAILURE of peripheral inhibition of lymphocytes is thought to be essential for emergence of autoimmune disease.
Primary lymphoid organs produce lymphocytes from lymphoid precursors.
Lymphocytes produced that are specific for self antigens present in the generative organs (primary lymphoid organs) are deleted- CENTRAL TOLERANCE.
Non-reactive newly emerged clones are allowed to enter the peripheral (secondary) lymphoid tissues.
If they react here, they are deleted/inhibited- PERIPHERAL TOLERANCE.
Lymphocytes that react with neither central or peripheral self-antigen, only foreign antigen, are allowed to mature.
CENTRAL AND PERIPHERAL TOLERANCE INTERACT to allow induction of immunity and prevention of autoimmunity.
MECHANISM OF CENTRAL TOLERANCE
Immature thymocytes mature via T cell receptor rearrangement in the bone marrow.
STAGE 1- Rearranged thymocytes pass to the thymus, where they undergo MHC restriction in the thymic cortex- only CD4+/8+ thymocytes that interact with MHC receive a positive survival signal. Those that don't interact are deleted by apoptosis. POSITIVE SELECTION.
STAGE 2- NEGATIVE SELECTION- in the thymic medulla, those thymocytes that interact too much with self MHC or self antigens are deleted by apoptosis.
Thymocytes that survive both positive and negative selection can then mature to CD4+ helper T cells or CD8+ cytotoxic T cells.
MECHANISM OF PERIPHERAL TOLERANCE
CD4+ Th cells are master controllers of immune responses to protein antigens. Many autoimmune diseases are thought to arise form a breakdown of immunological tolerance in CD4+ T cells.
Peripheral tolerance is maintained by various mechanisms:
ANERGY (induced by inhibitory receptors)
Peripheral tolerance prevents overreaction to self antigens.
SUGGESTED PATHOGENIC MECHANISMS IN AUTOIMMUNITY
FAILURE OF TOLERANCE- escape of auto-reactive clones (from primary lymphatic organs)
-Lack of regulatory T cells
-Failure of peripheral tolerance (lymphocyte suppression) thought to be a KEY factor in autoimmune disease development.
EXPOSURE OF SELF ANTIGENS (not normally exposed to the immune system!)- molecular mimicry, altered or cryptic self antigen, action of superantigens, bystander activation and epitope spreading.
Details of the various mechanisms above are still not fully understood; they are areas of active research.
Pathogen peptides can be similar to self-antigen in amino acid sequence or tertiary structure.
This cross reactivity leads to activation of autoreactive T and B cells, and subsequent cell damage.
OR foreign antigen can become fixed in host tissue, resulting in self tissue damage via macrophages.
ALTERED OR CRYPTIC ANTIGEN
Infectious agents cause tissue damage- oxidative injury, free radical production, cell death.
This damage can alter structure of self antigens.
They are changed to the extent that they can be recognised as NON-self by the host immunity.
An immune response occurs.
Tissue damage can also expose CRYPTIC antigens, which have been sequestered and shielded from immune recognition. Exposure causes an immune response via T cells. eg. Lens proteins are normally shielded from the immune system, but can become exposed if damaged.
Proteins produced by infectious agents (bacteria, mycoplasma, virus infected cells), superantigens can bind to TCR (T Cells Receptors) regardless of specificity.
A large number of T lymphocytes of different antigenicity are activated -> self tissue damage.
T cells are activated through a mechanism that is independent of specific TCR stimulation.
Infectious antigens do not have to bind to TCRs for bystander activation.
Damaged cells can then damage adjacent cells.
The enhanced processing and presentation of self antigens induces the expansion/spreading of the immune response towards different self antigens.
This process has been widely involved in the pathogenesis of many systemic autoimmune diseases, as well as in the determination of different expression of such diseases.
THE PATHOGENESIS OF AUTOIMMUNITY- SUMMARY
GENETIC FACTORS influence the maintenance of self tolerance. eg. susceptibility genes.
ENVIRONMENTAL FACTORS- eg. tissue damage via infection, inflammation- stimulates influx and activation of self reactive lymphocytes.
Interplay between factors can result in self reactive lymphocyte influx in to tissues, activation, and subsequent tissue damage.
Over 100 different conditions recognised in humans.
Prevalence in US estimated to be 7-16%. Higher for individual conditions, affects women more than men.
Higher incidences are seen every year- believed to be due to a combination of GENETIC AND ENVIRONMENTAL factors.
IMMUNE MEDIATED DISEASES (IMDs)
Increasing evidence of genetic linkage between types of IMD- immune mediated and inflammatory eg. atopy.
autoimmune disease eg. SLE (Systemic Lupus Erythematosus).
Hypersensitivity and autoimmune diseases are increasingly thought to be linked.
Complex disorders involve complex genetic and environmental disorders over time.
MHC genes are believed to be the strongest genetic influence on susceptibility to IMDs.
Mechanism of pathogenesis of both types of IMDs are similar.
PROINFLAMMATORY Th17 CELLS
Play a key role in a variety of autoimmune diseases. "Critically involved"
Produce IL-17, IL-22 -> stimulation of neutrophils, fibroblasts, keratinocytes, endothelial cells.
-Neutrophils- recruitment and induction of increased survival in the tissues.
-Fibroblasts- induction of chemokine release of IL-6, IL-8.
-Keratinocytes- induction of expression of adhesion molecules, MHC class I, IL-6, IL-8
-Endothelial cells- increased vascular permeability, expression of IL-22R, IL-23R, release of MCP-1, IL-6, IL-8.
-STIMULATED CELLS PRODUCE INFLAMMATORY MEDIATORS AND MIGRATE TO INFLAMED SITES.
Th17 cells play a role that was previously thought to be undertaken by Th1 cells.
Th17 AND Treg CELLS
Th17 cell action is balanced by Treg (regulatory) cells- proinflammation or suppression of inflammation.
Which T cells are expressed depends on cytokines produced by APCs (Antigen Presenting Cells), which itself depends to an extent on which receptors are present eg. TLRs activate APCs, so they can produce cytokines and allow differentiation of T cells to specific types.
Autoimmunity can be induced by Th17 action.
AUTOIMMUNE DISEASES IN ANIMALS
Increasingly recognised in domestic animals. Pathophysiology in animals and humans is similar.
Higher prevalence in some dog breeds than others- >25% for certain conditions in predisposed breeds.
An inbred population has fewer risk factors, but higher genetic risk in individuals.
MHC II gene region has been recognised as a major genetic risk factor in canine autoimmune disease- risk is linked to particular DLA (Dog Leukocyte Antigen) haplotypes.
Autoimmune diseases may be SYSTEMIC- typically antibody mediated; antigen is widely disseminated (eg. SLE antibodies vs. nuclear antigens)
or ORGAN SPECIFIC- mediated by antibody or T cells eg. pemphigus (skin)
SYSTEMIC LUPUS ERYTHEMATOSIS (SLE)
Multisystemic autoimmune disease. Immune response is self-directed against various CELLULAR (NUCLEAR) antigens.
Cytotoxic antibodies, immune complexes and T cells contribute.
Rare, but some breeds may be predisposed- Akita, collies, German Shepherd Dog.
Clinical manifestation includes- POLYARTHRITIS, GLOMERULONEPHRITIS, ANAEMIA AND/OR THROMBOCYTOPAENIA, SKIN DISEASE (ULCERATION AND DEPIGMENTATION.
SYSTEMIC LUPUS ERYTHEMATOSUS- PATHOGENESIS
-Genetic susceptibility- conferred by multiple genes
-Defective immune regulation and loss of tolerance- due to genetic/environmental/hormonal interaction.
-Cytokine imbalance due to increased antigenic loads, excess T cell help, defective B cell suppression, shifting from Th1 to Th2 immune response.
All of the above points interact and contribute to B cell hyperactivity and PRODUCTION OF PATHOGENIC AUTOANTIBODIES.
CUTANEOUS (DISCOID) LUPUS ERYTHEMATOSUS
Autoimmune disease; apparently tissue specific to skin (perhaps a mild form of SLE?)
Uncommon, though some breeds are predisposed- Akita, collies, German Shepherds.
Lesions may be restricted to face and feet.
Lesions are exacerbated by exposure to sunlight- photosensitive (this is also a component of SLE) eg. "Collie nose"- photosensitive nasal dermatitis.
Histology is characterised by INTERFACE DERMATITIS- Classical CLE lesion. Basal vacuolation indicates epidermal cell degeneration. Shows as skin erosions, ulcers and pigment alteration.
AUTOIMMUNE DISEASE IN THE AKITA
Akitas are at high genetic risk of developing autoimmune disease and atopy.
Numerous autoimmune diseases are seen in the skin:
-Cutaneous (discoid) lupus erythematosus
-Uveodermatologic syndrome (UV syndrome)
Systemic or targeted (other organs) disease is also seen:
-Systemic lupus erythematosus
-Juvenile meningitis/polyarthritis syndrome
-Hashimoto's thyroiditis (hypothyroidism)
-Acquired myaesthenia gravis.
THE PEMPHIGUS COMPLEX
Uncommon bullous autoimmune skin disease- causes vesicle and bulla formation.
TYPE II HYPERSENSITIVITY reaction- antibody dependent - binds to antigen with complement, then cells react.
Autoantigens are components of intracellular adhesion molecules (desmosomes)
HUMANS- desmoglein 1, 3, desmocollin 1.
DOGS- desmocollin 1 recently seen to be presiding autoantigen/core protein.
Severity depends on the level of epidermis affected:
PEMPHIGUS FOLIACEUS- most common form; acanthyolysis of subcorneal layers means only epidermis is affected- milder.
PEMPHIGUS VULGARIS- less common but more severe- acantholysis of suprabasal layers- epidermis is stripped, exposing basal layer.
EPIDERMAL INTRACELLULAR ADHESION MOLECULES
aka DESMOSOMES. Hold keratinocytes together.
Tonofilamets and plaques are held together by a core.
Plaque proteins- keratocalmin, desmoplakin 1, 2, plakoglobin, band 6 protein, desmoyokin.
CORE PROTEINS- TARGET FOR PEMPHIGUS COMPLEX DEVELOPMENT- desmoglein 1, 3, desmocollin 1, 3.
Desmocollin 1 appears to be presiding autoantigen in dogs.
Intercellular deposits of immunoglobulin (antibody against autoantigens) can be visualised using labelled (fluorescein or immunoperoxidase- for histo) anti-canine IgG.
Intercellular deposits are visible in upper epidermis.
Autoantibody binds to protein component (desmocollin) of protein core of desmosome.
Cell adhesion fails and keratinocytes dissociate.
ACANTHOLYTIC cells lie FREE within an INTRAEPIDERMAL VESICLE.
Neutrophils infiltrate after this, forming a vesicopustule.
Grossly, intact or ruptured vesicles/pustules may be seen, with crusting of the skin.
Damage occurs lower down, at the basal layer.
Epidermis separates at basal layer, causing more exposure of underlying tissue.
Vesicles are more fragile; severe ulcers can form.
TOMBSTONE cells can be seen histologically on the deep (bottom) margin of vesicles.
UVEODERMATOLOGIC SYNDROME (VKH)
VKH- Vogt-Koyanagi-Harada Syndrome.
Relatively common in susceptible breeds(Akita), becomes chronic in affected individuals.
Facial skin depigmentation and severe bilateral uveitis.
Encephalitis occurs in humans; may occur in dogs but has not been confirmed.
T LYMPHOCYTE MEDIATED DESTRUCTION OF MELANIN PRODUCING CELLS.
Target antigen has not been identified- possibly tyrosinase group.
Th1 and Th17 cells together with IL-17, IL-23 are likely involved in the initiation and maintenance of the inflammatory process.
Also see histiocytic dermatitis- histologically, many macrophages can be seen engulfing pigment.
Inflammatory reaction targets sebaceous glands.
Accumulations of lymphocytes seen in early lesions. May progress to granulomatous/pyogranulomatous inflammation.
Absence of sebaceous glands in late phase- can be difficult to diagnose.
Aetiopathogenesis is poorly understood- presumably immune mediated.
Breed disposition (Akita, Viszla, standard Poodle) suggests genetic component.
Clinically: Patchy alopecia (unknown why), scale, nodular inflammation centred on sebaceous glands, lymphocytic infiltrate, loss of sebaceous glands.
(Hypersensitivity, autoimmunity- see previous)
IMMUNODEFICIENCY- primary (genetic) or secondary (due to underlying disease, thymic damage etc.)
A variety of syndromes involve one or more components of innate or adaptive immunity.
Some congenital syndromes are lethal.
Most predispose to various infections- the immunodeficient animal is more susceptible to infection.
PRIMARY IMMUNODEFICIENCY DISORDERS
-DEFICIENCY OF INNATE IMMUNITY- Phagocytic cell and complement system deficiencies are well recognised.
-DEFICIENCY OF ADAPTIVE IMMUNITY- Primary T cell deficiency, primary B cell deficiency, combined B and T cell deficiency.
SECONDARY IMMUNODEFICIENCY DISORDERS
-Immunosuppressive viral infections
-Cytotoxic drugs eg. chemotherapy
-Other factors eg. malnutrition, ageing, systemic disease- all of these can interfere with the immune system.
Common; certain breeds are predisposed to generalised disease, including Boxers, Scottish terriers.
Suggested inherited primary deficit in cell mediated immunity- T cell dysfunction.
Immunosuppression due to secondary staphylococcus infection may be a contributing factor.
More severe form of demodecosis.
Generalised lesions with secondary bacterial (staphylococcal) infection.
Granulomatous reaction to demodex mite fragments in dermis.
Giant cells can be seen histologically.
Animal will be systemically unwell.
Disease is difficult to control; often have to resort to euthanasia.