13. Vesiculobullous diseases Flashcards
What is an intraepithelial vesicle?
A vesicle within the epithelium
What are the 2 main types of intraepithelial vesicles?
Acantholytic
Non-acantholytic
What is the definition of acantholytic vesicle?
Intraepithelial
Break down of the intercellular attachment that actually holds the epithelial cells attached to each other (destruction of prickle cell layer).
What diseases is acantholytic vesicles seen in?
Pemphigus
Darier’s disease
Benign familiar pemphigus- Hailey Hailey Disease
What are non-acantholytic vesicles due to?
Death and rupture of epithelial cells
What diseases is non-acantholytic vesicles seen in?
Herpes Simplex
Herpes Zoster
Coxsackie A viruses
What is subepithelial vesicle?
Between the epithelium and lamina propria of connective tissue, so the roof of the vesicle is epithelial tissue and bottom of the vesicle is connective tissue.
What are examples of subepithelial vesicle diseases?
Epidermolysis bullosa
Pemphigoid
Bullos lichen planus
Dermatitis herpetiform
Linear IgA disease
Angina bullous haemorrhagica
Erythema multiforme
What are the 4 main mechanisms of vesicle formation?
Infective- death and rupture of intraepithelial cells
Immunological
Traumatic
Idiopathic
What are 3 examples of immunological?
Pemphigus
Pemphigoid
Epidermolysis bullosa acquisita
What are 2 examples of traumatic vesicle formation?
Epidermolysis bullosa
Angina bullosa haemorrhagica
What are 3 examples of idiopathic vesicle formation?
Erythema multiforme
Lichen planus
Angina bullous haemorrhagica
What is pemphigus?
Autoimmune reaction against stratified suprabasal epithelium adhesions proteins.
What antibodies are produced in pemphigus vulgaris?
Anti-desmoglein 3 antibodies
What antibodies are produced in pemphigus foliaceous?
Anti-desmoglein 1 antibodies
What antibodies are produced in peraneoplastic?
Anti desmoplakin 1 and 2 Antibodies or IgA or IgG
What antibodies are produced in IgA pemphigus?
Anti-desmocollin 1, 2 and 3 antibodies or IgA
What are the 6 clinical types of pemphigus?
Pemphigus vulgaris- rarely in mouth
Paraneoplastic
IgA pemphigus
Pemphigus follaceous- less serious, rarely in mouth
Pemphigus vegetans
Pemphigus erythematosus
Why is pemphigus fatal if untreated?
Due to extensive ulceration, electrolyte loss and infection
Where is pemphigus often seen first?
Mouth
What is Nikolksy’s sign?
Pinch the skin of a patient with pemphigus and it should leave a vesicle. If you gently press the vesicle, it will spread laterally. But do not do this, instead look at the rubbed surfaces such as the arm or mouth.
What are cells attached by?
Desmosomes- desmoglein and desmocollins. They are found in the extracellular core region.
What is inside the cells that help attachment?
Attachment plaques and desmoplakin, and plakoglobins.
What does the attachment plaque attach to inside the cells?
Keratin intermediate filaments
What do the vesicles in pemphigus appear like?
Thin-roofed vesicles/bullae followed by ulceration
They are intraepithelial, acantholytic lesions, suprabasal spliit
What can be found in the blister fluid in pemphigus?
Tzanck cells
They are swollen, and have a hyperchromatic nucleus.
They are epithelial cells that do not have anywhere to attach so they float about in the fluid.
What immunofluorence can be used for pemphigus?
IgG and C3 intercellularly
What are the 5 histology factors of pemphigus?
- Thin-roofed vesicles/bullae (acantholytic, intraepithelial, suprabasal split) followed by ulceration
- Tzanck cells in the blister fluid- swollen, hyperchromatic nucleus
- Little inflammatory infiltration until ulceration
- Basal cells remain attached- tombstone appearance
- Immunofluorescence- IgG and C3 intercellularly
How are basal cells attached?
Attached to one another by desmosomes and to the cells above them
Attached to underlying basement membrane by hemidesmosomes.
What is the direct method of immunofluorescence for pemphigus?
Biopsy incubated with fluroscein-conjugated anti-human IgG and anti-c3 sera
What is the indirect method of immunofluorescence for pemphigus?
Patient serum incubated on normal animal mucosa, then labelled with fluoroscein-conjugated anti human globulin.
What is the treatment for pemphigus?
Systemic corticosteroids
Steroid sparing agents
Immunosuppressive agents
What is Benign familial pemphigus?
Intraepithelial-acantholytic
Rare genetic autosomal dominant dermatologic disease
What gene does benign familial pemphigus affect?
ATP2C1 gene on chromosome 3
Codes for SPCA1- secretory pathway Ca/Mn-ATPase
This is a calcium and magnesium pump. Calcium is necessary for binding of desmosomes.
What is the clinical signs of benign familial pemphigus?
First signs appear from 15-40
Nikolsky positive
Red scaly areas or small blisters at areas of friction
Oral lesions similar to skin
What are the histology and immunofluorescence findings of benign familial pemphigus?
Intraepithelial acantholytic
Histologically similar to pemphigus- collapsing brick wall
Immunological findings are negative
What is Darier’s disease/keratosis follicularis, and what gene does it affect?
Autosomal dominant
ATP2A2 gene
Abnormal desmosome-keratin filament complex
What is the clinical presentation of Darrier’s?
Multiple pruritic, hyperkeratotic papules and plaques in head, neck and trunk
Palmar/sole pits
Nail dystrophy
Oral lesions
Peak incidence 11-40 years old
What is the histology of Darrier’s?
Intraepithelial, acantholytic blisters
Corp ronds- round nuclei with perinuclear halo
Corp grains- elongated grain shaped nucleus
What are intraepithelial non-acantholytic lesions?
Herpes Simplex
Herpes Zoster
Coxsackie Type A infections
Which group of people does erythema multiforme affect most?
Relatively common in mild form
Predominantly young patients- 20-40 year olds, male more common
Can be recurrent
What is the aetiology of erythema multiforme?
50% unknown aetiology
Some related to HSV and mycoplasma infection
Drug related- sulphonamides, contraceptive pill, penicillin
May be immune complex mediated as IgM and C3 often found in blood vessels and basement membrane of early lesions
What is the clinical presentation of erythema multiforme?
Symmetrical, 1-2cm erythematous macules, papules, blisters, ulceration.
On elbows, knees, extensor surfaces of extremities
Target iris or bull’s eye lesions
Itching or burning sensation
45% have mucous membrane involvement- mouth and lips
What is the histology of erythema multiforme?
Inter and intracellular oedema
Keratinocyte necrosis leading to subepithelial and intraepithelial vesicles
Vesicle formation in epithelium and sub-epithelium
Inflammatory infiltration
What are the symptoms of Stevens-Johnsons syndrome?
Painful haemorrhagic oral lesions
Erosive genital lesions
Severe conjuctivitis
Fatal in 5% of cases
What is the definition of pemphigoid group?
A general term applied to several immune-mediated blistering diseases producing autoantibodies to the hemidesmosomes and the epithelial basement membrane.
Results in subepithelial vesicle formation
What are the clinical subtypes of pemphigoid related to?
Which antibodies are produced against different basement membrane/desmosome components.
What are the 2 types of pemphigoid?
Bullous pemphigoid- mainly skin
Muocus membrane pemphigoid- mainly mucosa
Oral manifestations occur in almost all MMP patients, and are very rare in BP patients.
What do desmosomes and hemidesmosomes use to attach?
Desmosomes use cadherins to attach to other cells
Hemidesmosomes use integrins to attach to the basement membrane.
What is the lamina lucida/lamina densa?
Component of the basement membrane found between the epithelium and underlying connective tissue.
What proteins do the plaque contain?
BP230 and BP180
Mediates attachment of keratin to the hemidesmosomal plaque
What attaches the lamina lucida and lamina densa?
Laminin
What are found between the laminin molecules?
Collagen 7- attaches basement membrane to connective tissue
Which people does mucous membrane pemphigoid/ciatricial pemphigoid affect most?
Mainly in women- over 50 years old
What is the clinical presentation of MMP and cicatricial pemphigoid?
Mouth almost always affected, sometimes only area- oral pemphigoid
Ulcerations heal slowly leaving scarring- cicatricial pemphigid
90% seen in gingiva- desquamative gingivitis
What are the bulla like in MMP/cicatricial pemphigoid?
Tense- unlike pemphigus as whole epithelium is inact
Occasionally haemorrhagic
Where else are bulla found in MMP?
Ocular, nasal, larynx, pharynx, oesophagus, genital mucosa
What is the histology of MMP?
Separation of epithelium from the lamina propria- bulla with thick roof
As vesicles develop you get infiltration by neutrophils, eosinophils, perivascular infiltration- mainly lymphocytes
What is the immunofluorescence results of mucous membrane pemphigoid?
Linear binding of IgG, IgA, C3 in the basement membrane zone
Antibodies against BP180
Circulating antibodies in serum detected in 80% of patient
What is dermatitis herpetiformis?
Autoimmune blistering of skin
Has variable oral presentation in 75%
Mild form erythema, severe forms will get extensive ulceration
What is the immunofluorescence of dermatitis herpetiformis?
Granular IgA deposits in connective papilla
What are the antibodies against in dermatitis herpetiformis?
Gliadin
Endomysium, reticulin
Epidermal transglutaminase 3
What are the vesicles like in dermatitis herpetiforma?
Subepithelial vesicles with neutrophils then later eosinophils
What do the patients have in dermatitis herpetiforma?
90% have gluten hypersensitivity
Jejunal villous atrophy
Increased infiltration of intraepithelial lymphocytes
What is linear IgA disease?
Rare
Shares similarities with dermatitis herpetiformis and bullous pemphigoid
Subepithelial bullae with neutrophils
What is the immunofluorescence of linear IgA disease?
Linear IgA deposits along the basement membrane
Only some patients may have gluten hypersensitivity
What is epidermolysis bullosa group?
Made of 30 diseases, subepithelial bullae in response to minimal trauma
What is the cause of epidermolysis bullosa?
Abnormal keratins or basement membrane constituents
What is EB simplex epidermolysis bullosa?
Most common, autosomal dominant, intraepidermal
Weber-Cockayne affects palms/soles, non-scarring
Kallin syndrome- autosomal recessive, alopecia, anodontia or hypodontia
Generalised types- 7
What is EB junctional epidermolysis bullosa?
6 types- intra lamina lucida
What is EB dystrophic?
Sub-lamina lucida, 8 types
What is EB acquisita?
Associated with tissue bound and circulating autoantibodies specific to type 7 collagen
What is angina bullosa haemorrhagica?
Subepithelial haemorrhagic bullae- 1-3cm in size, in middle aged/elderly patients
Usually solitary- unrelated to thrombocytopaenia
Where is angina bullosa haemorrhagica lesions found?
Any place of oral mucosa, commonly soft palate
What is angina bullosa haemorrhagic associated with?
Minor trauma
Hot foods
Steroid inhalers
Dental/periodontal treatment
What is the histology of angina bullosa haemorrhagica?
Mild, non-specific mononuclear inflammatory cell infiltrate generally limited to the lamina propria
