Biology of the basement membrane zone

Question 1

What are the 4 layers of the basement membrane zone?

Answer 1

The inferior portion of basal keratinocytes, lamina lucida, lamina densa, sublamina densa

Question 2

What do hemidesmosomes do?

Answer 2

They attach basal keratinocytes to extracellular matrix, made up of 4 components

Question 3

What are the 4 components of a hemidesmosome?

Answer 3

1. BPAG1 (BP230kDa): INTRACELLULAR glycoprotein - anchors keratin 5/14 to the hemidesmosome
2. DPAG2 (BP180kDa aka collagen XVII): TRANSMEMBRANE collage which interacts with BPAG1, beta4 integrin and plectin (has 3 components: amino terminus NC16A intracellular - transmembrane part - extracellular carboxy terminus which is inserted into lamina lucida)
3. Integrin (alpha6beta4 or beta 4) transmembrane cell receptor located at the basal layer of the epidermis and provides cell-cell and cell-matrix interactions- it connects intracellular intermediate filaments to laminin 332 in the lamina dense by traversing through the lamina lucida.
4. Plectin: an intracellular protein that links intermediate filaments to the plasma membrane and cross-links hemidesmosome proteins

Question 4

What is the importance of the NC16A portion of the BPAG2 (BP180kDa)?

Answer 4

It is the target for bullous pemphigoid, pemphigoid gestationis, linear IgA bullous dermatosis (non drug induced type)

Question 5

What is the importance of the carboxy terminus of BPAG2?

Answer 5

One of the targets of cicatricial pemphigoid (mucus membrane pemphigoid or MMP).

Question 6

What are the 3 targets of cicatricial pemphigus?

Answer 6

Carboxy terminus of BPAG2, alpha6beta4, and laminin 5/332

Question 7

What components make up the lamina lucida?

Answer 7

1. Made up of anchoring filaments (lamin 5/332), laminin 1, fibronectin, nidogen, BPAG2 (extracellular portion).
2. Anchoring filaments: arranged perpendicularly to hemidesmosome and stretch from plasma membrane to lamina densa
3. Laminin 5/332: major anchoring filament that attaches to lamina densa and serves as a connection for BPAG2 and integrin

Question 8

What is the lamina densa and what components make it up?

Answer 8

Made of type IV collagen mostly because it is the basement membrane proper.

Heparan sulfate: negatively charged hydrophilic proteoglycan that provides selective permeability barrier.

Question 9

What makes up the sublamina densa?

Answer 9

• Anchoring fibrils, anchoring plaques, elastic microfibrils, and linkin

1. anchoring fibrils: these are type VII collagen which are oriented perpendicularly from lamina densa into the papillary dermis. Connects type IV collagen in the lamina dense to type I/III collagen in dermal matrix
2. Anchoring plaques: the site where anchoring fibrils (type VII collagen, vertical) connect type IV collagen (horizontal) to collagen type I and III (horizontal)

summary: anchoring filaments include laminin 5/332 which are vertical in orientation and anchoring fibrils include type VII collagen which is vertical.

Question 10

What diseases target the BPAG1?

Answer 10

Autoimmune: Bullous pemphigoid

Genetic: Recessive EB simplex

Question 11

What diseases target type XVII collagen (BPAG2)

Answer 11

Autoimmune: Bullous pemphigoid, MMP, linear IgA bullous dermatosis

Genetic: Junctional EB (often milder)

Question 12

What diseases target the integrin subunit alpha6beta4?

Answer 12

Autoimmune: Ocular MMP

Genetic: Junctional EB w/ pyloric atresia

Question 13

What disease targets lamnin 332?

Answer 13

Autoimmune: Anti-epiligrin MMP

Genetic: Junctional EB (often more severe)

Question 14

What diseases target type VII collagen?

Answer 14

Autoimmune: EB acquisita, bullous eruption of SLE and drug-induced linear IgA

Genetic: Dystrophic EB (dominant and recessive types)

Question 15

What is salt splitting?

Answer 15

You use this in subepidermal blistering disease. You split the lamina lucida from the lamina densa to determine if the antibodies are sticking at the epidermal versus dermal side of the split

Question 16

What diseases have antibodies on the dermal side of the salt split skin test?

Answer 16

MMP (anti-epiligrin/laminin 5/332), EBA, Bullous lupus, drug induced linear IgA

Question 17

What diseases have antibodies on the epidermal side of salt spit skin test?

Answer 17

BP, MMP (BPAG2, B4 integrin types), LABD (non-drug induced, targets portion of BPAG-2), LP pemphigoides

Question 18

What disease process splits the lamina lucida from the lamina densa?

Answer 18

Suction Blisters

Question 19

What is the weakest part of the basement membrane zone?

Answer 19

The lamina lucida

Question 20

Describe the basic overview of the components of the basement membrane zone.

Answer 20

Intracellular keratins K5/K14 in the basal keratinocytes attach to electron-dense hemidesmosome plaques [plectin and BPAGI on the basal keratinocyte plasma membrane] –> The hemidesmosome plaque proteins then bind to the intracellular portions of the anchoring filaments (BPAG2 and alpha6beta4 integrin) –> laminda lucida is then the extracellular portion of the anchoring filaments BPAG2, alpha6beta4 integrin and laminin 332) which then extend down from the hemidesmosome to the lamina densa –> the lamina densa is the area that the components of the lamina lucida anchor into. Type IV collagen is the primary component, other proteins include laminin 332 and laminin 331 and nidogen –> the sublamina densa is where loops of type VII collagen which are anchoring fibrils arise from the underside of the lamina densea and extend down into the dermis. These extensions hook around dermal type I and III collagen fibers and then loop back up and reattach to the lamina densa. This anchors the lamina densa to the papillary dermis.

Question 21

What diseases target plectin?

Answer 21

Located in the lamina densa, targeted by EB with muscular dystropy and EB with pyloric atresia

Question 22

What diseases target collagen IV in the lamina densa?

Answer 22

Goodpature disease, Alport syndrome

Question 23

What diseases attach laminin 332?

Answer 23

Mucous membrane pemphigoid (especially antiepiligrin pemphigoid, associated with malignancy) and Junctional Epidermolysis Bullosa-Herlitz (JEB-Herlitz).