Lecture 31 & 32: Autoimmunity, Hypersensitivity, and Skin Flashcards
Describe the structure of the skin
Skin is composed of three layers which are:
- Epidermis (mainly composed of keratinocytes with melanocytes at the basal layer that give the skin colour)
- Dermis (connective tissue, blood vessels etc.)
- Fat layer (also called the panniculus)
The junction between the epidermis and dermis is called dermo-epidermal junction. It is a complex area composed of many proteins that stick the epidermis to the dermis.
Diagnose
- 17 year old woman
- 12 month of an intensely itchy rash
- Intermittent lasting less than 24 hours on all parts of the body
- Expressed suicidal ideation and not attending school
- No preceding infection
- All treatment tried so far ineeffective
- PMH: Nil
- DH: cetrizine 20mg od
Intermittent lasting less than 24 hours on all parts of the body = classic sign of the hives
Urticaria
Describe this type of rash as: Weals
How would you describe this rash?
Weals
Why do the symtoms in Urticaria occur?
- There are mast cells in the dermis
- For various reasons (inc autoimmunity) the mast cells become unstable
- The mast cells are then sending out packets of histamine, which is causing an excitatory reaction
There are lots of types & causes of urticaria
- Physical
- Allergicc ingestion - anaphylaxis
- Angiodema
- Allergic contact
- Cold - ice cube test
- Cholinergic - exercise
- Drugs
Describe Autoimmune Urticaria
Antibodies (autoantibodies) bind to mast cells and cause them to de-granulate
Functional IgG autoantibodies are detected in 30-50% of patients with “ordinary” urticaria ad bind to IgE receptor.
How do you treat urticaria?
- Most are treated with antihistamine
- Treat with ciclosporin (immunosupresive treatment) after failure of multiple other modalities
What causes the symtoms in Immune Skin Disease Associated With Autoimmunity? (e.g. Bullous pemphigoid)
(Clinical Scenario “Blisters”) **
- Dermo-epidermal junction represents the boundary between epidermis and dermis. There is a complex group of interacting proteins, among those, an important structure is hemi desmosomes.
- If antibodies are produced against hemi desmosomes, it allows separation between epidermis and dermis, thus forming blisters.
Diagnose
80 year old lady. Presents with a 4 month history of itch and recent development of blisters.
Significant cognitive impairment due to multiple cerebrovascular accidents prior to onset of her skin problems (hidden clue).
Bullous Pemphigoid (BP)
Mechanisms
Bullous pemphigoid is an autoimmune disease due to the formation of IgG antibodies against hemi desmosomal proteins
- BP is the most likely immunobullous disease you will encounter clinically.
- It usually presents in older patients over the age of 70 years. Patients complain of an itchy rash and then develop blisters.
BP is due to an autoimmune reaction against two proteins in the hemi desmosomes (BP180 and BP 230), which help stick the epidermis to the dermis.
- Antibodies to these proteins loosen this adhesion causing epidermis to split from dermis.
- There are different isoforms of the bullous pemphigoid antigen (BPag), which are
- (1) neural form (e.g. stroke),
- (2) skin form,
- (3) muscular form.
Describe the relationship between Neurological diseases and Bullous Pemphigoid
Recent research has shown an association of cerebrovascular injury prior to the onset of Bullous Pemphigoid in some patients.
- In stroke, blood brain barrier is impaired because of cerebrovascular accident,
- This allows blood mixing with brain tissue, autoantibodies are then produced.
- Thereofore, cross over reaction occurs in the skin between neural form of antibodies against BP skin antigen at the hemidesmosome protein.
- This leads to weakening of epidermis attachment to dermis, and formation of blisters and BP.
There are strong associations between specific neurological diseases and later development of bullous pemphigoid.
How do the symptoms arise in Pemphigus Vulgaris (PV)
Pemphigus vulgaris (PV) is a rare disorder but it is helpful to contrast it with BP.
An autoimmune disease due to IgG autoantibodies against keratinocytes desmosome
PV presents in y_ounger patients_ and depending on the pemphigus sub-type can also involve mucous membranes as well as the skin.
- Keratinocytes are anchors by desmosome, which forms epidermis.
- PV is due to an autoimmune reaction due to I_gG autoantibodies desmogleins proteins in desmosomes_
You can then understand why PV produces “shallow” blisters and skin erosions. This is because immune “attack” is within the epidermis (rather than tense blisters seen in BP where immune “attack” is at the dermo-epidermal junction).
- It commonly affects central back and central chest.
- It can also affect _oral mucos_a, since keratins are expressed within oral mucosa, which are similarly affected by this disorder. This leads to painful mouth ulcerations.
Name some immune skin deases associated with autoimmunity
1) Bullous Pemphigoid
2) Pemphigus Vulgaris
Describe Direct Immunoflorescence
Direct immunofluorescence technique helps to decide where immune “attack” (antibody) is occurring. It is used routinely and diagnostically in the laboratory. Small pinch biopsy is taken where small core of skin is taken under local anesthetics.
- Anti-human antibodies with a _fluorescing tag a_re directed against the antibodies causing BP and PV.
- Since tagged autoantibodies are attached to antigens, staining will occur at the site of immune reaction.
- For bullous pemphigoid (BP), li_near deposit of IgG_ at dermo-epidermal junction.
- For pemphigus vulgaris (PV), there is _intra-epidermal IgG deposition (_within epidermis)
Compare between Bullous Pemphigoid and Pemphigus Vulgaris
BP
- Pemphiogid (common)
- Full thickness blisters
- “Attack” at dermo-epidermal junction
PV
- Pemphigus (rare)
- Superficial blisters and erosions
- “Attack” within the epidermis
Describe the Epidermis
What happens when the epidermis fails?
Epidermis are like a brick wall.
- If keratinocytes and binding proteins are healthy, antigens are u_nable to penetrate the skin._
- If epidermis is dilapidated and broken, it is possible for antigens to penetrate the epidermis, e.g. atopic eczema.
What are the clinical observations of Eczema?
Eczema/Dermatitis
Atopic eczema is a common condition in New Zealand children. It usually improves with age and most, but not all, are resolved by adulthood.
A careful clinical observation was that the skin of patients with atopic dermatitis is dry and similar to a group of genetic disorders called ichthyosis (derived from the ancient Greek word for fish, think scaly).
Describe the Mechanism of action for Atopic eczema
Epidermis is divided into several layers, one of those are granular layer (keratinocytes containing lots of granule). One of those granular component is profilaggrin, which is converted to filaggrin. This forms natural moisturizing factor, essential for integrity of epidermis.
Some patients with atopic eczema have been found to have a genetic mutation for a protein called filaggrin, which forms a natural moisturiser in skin.
- The mutation means the n_atural moisturiser effect is diminished,_ so the barrier function of the skin is impaired.
- This means that antigens can penetrate the skin more easily, leading to immunological reactions.
Patients with a _filaggrin mutatio_n are far more likely to have atopic dermatitis, which have a higher prevalence of allergy compared to those who do not.
A 16 year old girl who plays hockey presented with dermatitis around her shoulders.(most ezcema is around the elbows and behind the knees)
She had childhood atopic dermatitis which had resolved (epidermial barrier function likely impaired).
Ezcema is confined to shoulders (scratched and inflamed). It is s_ymmetrical distribution_ (unlikely to be natural causes). This is due to allergy to hockey uniform (neoprene).
Diagnosis is allergic contact dermatitis to neoprene, most likely s_econdary to thiourea derivatives_ (thiourea helps vulcanization of neoprene rubber making it more stable and pliable).
-Undergo Patch Testing
What is Patch Testing?
In the clinic, an investigation called patch testing is undertaken to determine which antigens are important. Strips with antigens are attached in groups of 10 to patient’s back for two days.
Severe reactions, especially hand dermatitis, can require a change of occupation. In these cases, it is important to work with the accident compensation corporation (ACC).
- Patients with atopic dermatitis can be more susceptible to __________________.
- Defects in the__________ may account for other allergies in atopic dermatitis.
- _____________ testing uses _________ to provoke the dermatitis on the back. Patient can avoid the antigen if it is identified.
- Patients with atopic dermatitis can be more susceptible to allergic contact dermatitis.
- Defects in the epidermal barrier may account for other allergies in atopic dermatitis.
- Patch testing uses purified antigen to provoke the dermatitis on the back. Patient can avoid the antigen if it is identified.
Why might patients be immunosuppressed?
The skin is susceptible to the effects of immunosuppression. Competent immune system is needed to prevent skin infection and skin cancer.
There are several reasons why a patient may be immunosuppressed including:
- Due to the effects of treatment of disease,
- __e.g. some patients with bullous pemphigoid need agents (prednisone, azathioprine, methotrexate) to control their blistering
- Because of the effect of disease,
- e.g. congenital immunodeficiency states, severe combined immunodeficiency, HIV
- Due to the effect of drugs required for organ transplantation,
- e.g. renal transplants, bone marrow transplant
The effect of immunosuppression on the skin can be either infection or neoplasia.
Chronically immunosuppressed patients are at risk of skin cancer as natural immunological surveillance mechanisms are suppressed.
Diagnose
Why is this patient at risk of skin cancer?
Diagnosis is epidermodysplasia verruciformis!!
- This is due to cutaneous infection with human papilloma virus (wart virus).
- This patient cannot defend against the infection due to inherited defect of cell mediated immunity (EVER 1 and 2 genes)
Why is this patient at risk of skin cancer?
- A competent immune system is important to repair ultraviolet induced damage and prevent skin cancer
- Some types of HPV are oncogenic viruses, e.g. induce cervical cancer.
A 65 year old man presents with a lesion on his left ear. It has been growing larger in the last 5 months. He underwent a renal transplant 5 years ago and his current medication is prednisone 5mg od, tacrolimus 3mg bd
Diagose
There is eroded exophytic moist module around tip of left ear. Lesion is squamous cell carcinoma.
- This is on tip of his ear due to higher sun exposure. When the sun shines on the skin, it damages the nucleus of keratinocytes (most cells in epidermis). Therefore, skins around face are vulnerable sites.
- Usually in immunocompetent patients, there are immune surveillance mechanisms to repair UV damage. Immunosuppressed patients have impaired UV damage repair.
- The cumulative damage of UV exposure leads to squamous cell carcinoma, and other skin cancers.
Diagnose
Vitiligo
Vitiligo is a long term skin condition characterized by p_atches of skin losing pigmented melanocytes symmetrically._
- Patches of skin affected become white and usually have sharp margins.
- Patches are symmetrical due to migration of neural crest cells (include melanocytes) embryologically.
There is evidence of innate immune mechanisms in vitiligo.
What is hypersensitivity and what are the 4 types of hypersensitivity?
Hypersensitivity is over-reactive immune response resulting in host pathology. It has traditionally been divided into four types of reaction (Gell and Coombs classification).
- Type I (IgE-Mediated) Hypersensitivity
- Type II (Antibody-Mediated) Hypersensitivity
- Type III (Immune Complex-Mediated) Hypersensitivity
- Type IV (Cell-Mediated (Delayed Type, DTH)) Hypersensitivity
Describe Mast Cell Degranulation
- In our blood there are Basophils that differentiate into Mast cells in our tissues and mucosal surfaces
- The Mast cells have FcE receptors and these bind with high affinity to Fc part of IgE
- The Mast cells are therefore always coated with a sample of IgE from blood
- If you meet the antigen that binds to the IgE, then the antigen corss-links with the IgE molecules, and trigger the Mast cell to release the contents of the cytoplasmic granules = Mast Cell Degeneration
What are the consequences of Mast cells Degranulation?
1) Chemoattractants
2) Activators
- Vasodilation
- Complement
- Platelets
3) Spasmogens
- Smooth Muscle contraction
- Mucus secretion
What are some triggers to Mast Cell Degranulation?
1) Antigen crosslinks IgE on mast cells in tissues
2) Drugs
3) C3a and C5a (complement system)
Describe the Mechanism of Action of Type 1 Hypersensitivity
Type I hypersensitivity occurs when divalent allergen crosslinks two IgE molecules, previously passively bound to high affinity Fcε receptors on mast cells in tissues.
It is also triggered by C3a and C5a, some drugs.
Mast cell mediators are then released via degranulation. It can be pre-formed mediators or newly-formed mediators.
- Granule-associated pre-formed mediators include histamine, heparin, enzymes (tryptase, β-glucosaminidase), chemotactic and activating factors (eosinophil chemotactic factor, (ECF), neutrophil chemotactic factor (NCF) and platelet activating factor (PAF))
- Newly formed mediators include lipoxygenase pathway products (SRS (LTC4 and LTD4) and leucotrienes (LTB4)), cyclooxygenase products)(prostaglandins, thromboxanes)
Main functions are chemoattractants, activators (vasodilatation, vascular leakiness, complement, platelets, pruritus) and spasmogens (smooth muscle contraction, mucus secretion). These may be localised.
Describe Type II (Antibody-Mediated) Hypersensitivity
In type II hypersensitivity (usually organ-specific autoimmunity), antibodies produced by the immune response bind to antigens (intrinsic or extrinsic) on the patient’s own cell surfaces.
-
Complement fixation,
- e.g. haemolytic disease of newborn (anti-RhD red cell IgG antibodies), autoimmune haemolytic anaemia
- Antibody dependent cellular cytotoxicity (ADCC) cells have receptors for Fc portion of Ig molecules and lyse target cells when cross-linked.
Describe Type III (Immune Complex-Mediated) Hypersensitivity
Type III hypersensitivity involves binding of antigen and complementary antigen.
Conformational _change in Ig F_c allows binding and activation of complement.
Direct action of complement split products. Recruitment of other inflammatory cells by soluble mediators.
- In systemic, classic example is serum sickness, which caused by injection of foreign protein. Complexes deposit in skin (rash), joints (arthritis) and kidney (nephritis).
- If antibodies appear thwn circulating antigen concentrations are high, Immune complex-induced vasculitis and nephritis can occur
- Formerly seen with often horse immune globulin given for tetanus. A problem with non-human monoclonal antibodies being used in therapy.
- Postulated mechanism for vasculitis and for the renal disease seen in SLE.
- If antibodies appear thwn circulating antigen concentrations are high, Immune complex-induced vasculitis and nephritis can occur
- In localized, it occurs in tissues.
- For example, farmer’s lung is an extrinsic allergic alveolitis caused by inhaled actinomycete fungi, which grow in hay. IgG antibodies from circulation meet this antigen in alveoli. Complement activation and recruitment of inflamed cells
Describe how Vasculitis and Nephritis can occur due to Type III hypersensitivity
- Immune complexes may start to change flow in that area
- Might get some microthrombus formation (due to platelet aggregation)
- Activation of complement system occurs
- Cause release of Neutrophils to the site
- Chemotaxis is released
- Result = Vascular damage triggered by antibodies.
Describe Contact Sensitivity
- In the surface regions, there are dendritic cells.
- If someone is habitually wearing metal, some may leech into her skin (e.g. nickel)
- Some may have the property to attach to the surface of the normal proteins in that area
- This causes a modification of the protein so it has the potential to be antigenic (large enough to cause an immune response)
- Hapten = small molecule that cannot cause a immune response on its own because it’s too small, but when it attaches to a large immunogenic molecule it can be recognised and generate a response to it.
- The hapten/antigen is then transproted to the lymph node and T cell stimulation occurs
- Memory Th1 cells return and provoke an inflammation
What is a Hapten?
small molecule that cannot cause a immune response on its own because it’s too small, but when it attaches to a large immunogenic molecule it can be recognised and generate a response to it.
a small molecule which, when combined with a larger carrier such as a protein, can elicit the production of antibodies which bind specifically to it (in the free or combined state).
Which hypersneitivity types are involved in autoimmunity?
1) Type II = Organ-specific
* Antibody-mediated (cytotoxic)
2) Type III = Systemic
* Immune complex-mediated
Describe the Mechanism of Tolerance
Tolerance of “self” is a central property of normal immune system. If this discrimination is broken, immune system may react to self-structures and cause autoimmune diseases.
Many self-reactive lymphocytes are removed from immune repertoire when they are at an immature stage of development. There are several possible mechanisms:
-
Clonal deletion (central)
- Complete removal of the self-reacting cells.
- The dominant mechanism for antigens that are expressed in primary lymphoid organs (thymus and bone marrow).
-
Clonal regulation (peripheral),
- Where there is no co-stimulation (anergy).
- Self-reacting lymphocytes still exist, but are usually resistant to stimulation. Important for antigens only found in periphery.
-
Suppression (peripheral),
- Where self-reacting B and T lymphocytes are present and potentially active, but are kept in check by T regulator cells.
-
Immunological ignorance,
- Where self-reactive cells present, but do not mount a pathological response when it is not seen by immune system.
- This is due to (1) _antigens sequestered i_n immunologically “privileged” sites, or (2) lacking adequate T cell help.
- The immune system needs to see antigens in the context of certain “danger” signals (e.g. infection) before it gets interested.
- Where self-reactive cells present, but do not mount a pathological response when it is not seen by immune system.
If autoantibodies are common, Why do we present with a autoimmune diseases?
Cross Reactions (Autoimmunity Through Molecular Mimicry)
Tolerance can sometimes be by-passed by immunization with a closely cross-reacting antigen. An alternative term for this theory of autoimmune disease is “molecular mimicry”.
- Mimicry means that T cells think they look the same- not necessarily that they are the same.
- So HLA haplotypes are important
Antibodies against viral RNA or DNA may cross-react with self RNA or DNA. This may help explain autoantibodies to RNA or DNA in connective tissue disease.
-
Infection with certain bacteria (eg Salmonella, Shigella, Chlamydia) can trigger reactive arthritis.
- One postulated mechanism is that antigens on the bacteria cross-react with antigens in the joint.
- Rheumatic fever is thought to be due to cross-reactions between antigens on streptococci and antigens in cardiac muscle.
Similar cross-reactive theories have been put forward for viral infection triggering a wide range of autoimmune diseases.
What are the treatment approaches to autoimmune diseases?
Replacement
- IDDM uses replacement of insulin
- Hashimoto’s disease uses thyroxin replacement
- Addison’s disease uses glucocorticoid and mineralocorticoid replacement
Suppression
- SLE uses immunosuppressive drugs (corticosteroids, azathioprine, cyclophosphamide)
- Rheumatoid arthritis uses immunosuppressive drugs
- Corticosteroids
- Anti-inflammatory drugs (NSAIDS),
- Monoclonal antibodies include TNF, IL-1, IL-6 antagonists
- B cell depletion (Mab)
Systemic responses are much more difficult to manage, because you have to target the immune response, rather than replace what has been damaged in the organ specifically.
