Mss 08: Basement Membrane Zone (Bmz)

Front 1

What kind of adhesions occur at the Basement Membrane Zone?

Back 1

Dermo-epidermal adhesion

Front 2

What does the Basement Membrane Zone regulate?

Back 2

- Cell differentiation
- Motility
- Transmission of extracellular signasl

Front 3

What are the components of the Basement Membrane Zone?

Back 3

- Hemidesmosomes
- Lamina lucida
- Lamina densa
- Sublamina densa

Front 4

What is the function of hemidesmosomes? What are the components?

Back 4

- Attach one cell to the ECM
- Made of BP-230 (Bullous Pemphigoid Antigen 1) and BP-180 (Bullous Pemphigoid Antigen 2)

Front 5

What is BP-230 (Bullous Pemphigoid Antigen-1) part of?

Back 5

Component of hemidesmosomes:
- Plakin family of proteins
- Cytoplasmic localization
- Important for organization of cytoskeletal architecture

Front 6

What is BP-180 (Bullous Pemphigoid Antigen-2) part of? Function?

Back 6

Component of hemidesmosomes:
- Now known as Type XVII collagen
- Transmembrane protein connecting basal keratinocytes through BP 230 to cytoskeleton and through laminin 332 to dermal collagen VII

Front 7

Patients with acquired, autoimmune blistering diseases have circulating auto-antibodies, what do they target?

Back 7

Important structural proteins in epidermal basement membrane

Front 8

What diseases are due to issues with the Basement Membrane?

Back 8

- Bullous Pemphigoid (BP)
- Mucous Membrane Pemphigoid (MMP)
- Epidermolysis Bullosa Acquisita (EBA)
- Epidermolysis Bullosa (EB)

Front 9

What happens if there are auto-antibodies against BP-230 and BP-180? What is this targeting?

Back 9

Bullous Pemphigoid (BP)
- Tense blisters w/ serous or rarely hemorrhagic content
- Components of hemidesmosomes

Front 10

What kind of disease is Bullous Pemphigoid (BP)? Who does it primarily effect?

Back 10

- Most common autoimmune bullous dermatosis
- Primarily in elderly (but young people too)
- Causes subepidermal blisters

Front 11

What are the clinical characteristics of Bullous Pemphigoid (BP)?

Back 11

- Starts as highly pruritic (itching) urticaria (hives) without blistering
- Progresses to tense blisters w/ serous or rarely hemorrhagic content (appear in phases)
- Blisters are extremely stable, as roof consists of entire epidermis

Front 12

What kind of diagnostic tests are done to confirm Bullous Pemphigoid?

Back 12

- Direct Immunofluorescence (DIF) shows linear deposits of IgG and C3 along Basement Membrane
- Indirect Immunofluorescence (IIF) shows linear staining on epidermal side of salt-split skin
- BP180 and BP230 ELISA show positive results correlating w/ disease activity

Front 13

How does Bullous Pemphigoid compare to Pemphigus Vulgaris?

Back 13

BP has better prognosis than PV

Front 14

How do you treat Bullous Pemphigoid?

Back 14

- Less severe cases can be treated w/ high potency steroids
- Oral steroids and other immunosuppressants are used for severe disease w/ caution d/t potential side effects in elderly

Front 15

What structure is immediately underlying the hemidesmosomes in the basement membrane?

Back 15

Lamina Lucida (may be an artifact of tissue preparation and dehydration)

Front 16

What is one of the major components of the Lamina Lucida?

Back 16

BP-180

Front 17

What structure is immediately underlying the Lamina Lucida in the basement membrane? What is it made of?

Back 17

Lamina Densa - mostly type IV collagen and laminins (332)

Front 18

What type of collagen is one of the most abundant in the Basement Membrane?

Back 18

Type IV collagen (more than half of its mass)

Front 19

What is the most important laminin in the Basement Membrane? What layer? Function?

Back 19

Laminin 332 - found in Lamina Densa
- Binds to hemidesmosomal protein integrin α6β4 on basal keratinocytes
- Also binds to type VII collagen in dermis providing adhesion between structures

Front 20

Who is most commonly affected by Mucous Membrane Pemphigoid?

Back 20

Older people

Front 21

What are the clinical characteristics of Mucous Membrane Pemphigoid (MMP)?

Back 21

- Recurrent blistering of mucous membranes, but also skin
- Develop scars, strictures, synechiae, and blindness (20%)

Front 22

What is the cause of Mucous Membrane Pemphigoid (MMP)?

Back 22

- Majority have antibodies against BP-180
- Some have antibodies against BP-230, Integrin β4, and laminin 332

Front 23

In which blistering disease should cancer screening examinations be performed? Why?

Back 23

- Anti-laminin 332 version of Mucous Membrane Pemphigoid
- Associated w/ malignancies in 30% of cases

Front 24

What kind of diagnostic tests are done to confirm Mucous Membrane Pemphigoid?

Back 24

- Direct Immunofluorescence shows linear deposits of IgG and C3 along the Basement Membrane Zone (same as for Bullous Pemphigoid)
- Indirect Immunofluorescence shows linear staining of epidermal, dermal and epidermal, or just dermal (in case of anti-laminin 332 MMP) side of salt-split skin

Front 25

What structure is immediately underlying the Lamina Densa in the basement membrane? What is it made of?

Back 25

Sublamina Densa
- Type VII Collagen - large protein composed of 3 identical α chains which form anchoring fibrils

Front 26

What is the function of Type VII collagen in the basement membrane?

Back 26

- Necessary to maintain epidermal-dermal cohesion
- Binds to both type I and type IV collagens
- Helps join lamina densa to papillary dermis

Front 27

What kind of disease is Epidermolysis Bullosa Acquisita (EBA)? Cause?

Back 27

- Rare autoimmune bullous dermatosis
- Target antigen is type VII collagen
- Slight trauma elicits blistering and erosions of skin

Front 28

What are the clinical characteristics of Epidermolysis Bullosa Acquisita?

Back 28

- Slight trauma elicits blistering and erosions of skin
- Mechanically stressed areas such as hands, feet, elbows, and knees are more commonly affected
- Healing of lesions leaves atrophy, milia, scars, and pigemntation disorders
- Severe cases cause fibrosis of hands and feet
- Nail dystrophy possible
- Some hemorrhagic erosions of oral mucosa

Front 29

What kind of diagnostic tests are done to confirm Epidermolysis Bullosa Acquisita?

Back 29

- Direct Immunofluorescence shows deposits of IgG and C3 along Basement Membrane
- Indirect Immunofluorescence shows staining of dermal side of salt-split skin
- ELISA not available

Front 30

Mutations in the genes encoding Basement Membrane Zone proteins, results in what?

Back 30

Group of inherited skin fragility disorders known as Epidermolysis Bullosa (EB)

Front 31

What are the types of Epidermolysis Bullosa (inherited)? What genes have mutations?

Back 31

- EB Simplex (keratin 5, 14)
- Junctional EB (laminin, BP-180, integrins)
- Dystrophic EB (type VII collagen)
- Kindler Syndrome (kindlin 1)

Front 32

What are the clinical characteristics of Epidermolysis Bullosa (inherited)?

Back 32

Erosions and blisters after minimal mechanical trauma (similar to acquired version)

Front 33

What skin disorders are associated with mutations or antibodies against Desmoglein 1 and/or 3?

Back 33

* Autimmune (auto-Abs): PEMPHIGUS VULGARIS
- Genetic (mutations): Striate Palmoplantar Keratoderma

Front 34

What skin disorders are associated with mutations or antibodies against Keratins 5 and/or 14?

Back 34

* Genetic (mutations): Epidermolysis Bullosa Simplex

Front 35

What skin disorders are associated with mutations or antibodies against BP-230?

Back 35

* Autoimmune (auto-Abs): Bullous Pemphigoid

Front 36

What skin disorders are associated with mutations or antibodies against α6β4 integrins?

Back 36

* Genetic (mutations): Epidermolysis Bullosa
* Autoimmune (auto-Abs): Bullous Pemphigoid

Front 37

What skin disorders are associated with mutations or antibodies against BP-180 (collage type XVII)?

Back 37

* Autoimmune (auto-Ab): Bullous Pemphigoid and Mucous Membrane Pemphigoid
* Genetic (mutation): Junctional Epidermolysis Bullosa (NON-HERLITZ)

Front 38

What skin disorders are associated with mutations or antibodies against Laminin 332?

Back 38

* Autoimmune (auto-Ab): Mucous Membrane Pemphigoid
* Genetic (mutation): Junctional Epidermolysis Bullosa (HERLITZ)

Front 39

What skin disorders are associated with mutations or antibodies against Type VII collagen?

Back 39

* Autoimmune (auto-Ab): Epidermolysis Bullosa ACQUISITA
* Genetic (mutation): DYSTROPHIC Epidermolysis Bullosa

Front 40

What kind of tests are done for autoimmune bullous disorders?

Back 40

- Biopsy for histological evaluation w/ H&E staining to determine blister level and inflammatory infiltrate
- Direct IF (DIF) detects Ig and Complement w/in biopsy specimen of PERILESIONAL skin
- Indirect IF (IIF) detects Ab against BMZ in patient's SERUM
- ELISA screens for detection of auto-antibodies

Front 41

What is accomplished in a routine biopsy of a blister?

Back 41

Taken from edge of blister and processed w/ H&E staining to determine:
- Blister level
- Inflammatory infiltrate

Front 42

What happens in a Direct Immunofluorescence test (DIF)?

Back 42

- Detects molecules like Igs and Complement (C3) within biopsy specimens (perilesional skin)
- Fluorescein-conjugated Abs against human Igs or complement used to detect in-situ deposits of immunoreactants under fluorescence microscope

Front 43

What happens in a Indirect Immunofluorescence test (IIF)?

Back 43

- Detects circulating Ab against BMZ in patient's SERUM
- Patient serum is applied to a foreign substrate such as normal human skin (sometimes with an artificial split at level of lamina lucida created by salt), monkey esophagus, or rodent bladder
- Circulating Abs from sera bind to BMZ antigen in substrate
- Ab antigen complex is then detected by fluorescein-conjugated Ab and visualized under fluorescence microscope

Front 44

What happens in ELISA?

Back 44

Enzyme-Linked Immunosorbent Assay (ELISA)
- Used as an initial screen for detection of patient's circulating Auto-Abs
- Based on principle of antibody-antibody interaction, test allows for easy visualization of results and can be completed in short period of time