Basement membrane zone

First identification of Basement membrane

by….

George F. Odland
In 1958
Basement membrane zone is a highly
specialised structure with numerous
macromolecules which acts as an interface
between epidermis and dermis of the skin.
Histology…
With routine E & H staining-
Barely perceptible thin
Undulating membrane beneath
The epidermis

With PAS staining, basement

Membrane appears reddish purple
Due to mucopolysaccharides,
Glycogen & mucin
 Why???????
• Substrate for cell binding
• Physical barrier
• Scaffold for tissue architecture
• Selective permeability barrier
• Cell migration, differentiation, morphogenesis,
apoptosis etc.,
 Four distinct subregions
1. Keratin-
Hemidesmosome-
Plasma
membrane
2. Lamina lucida
3. Lamina densa/
Basement
membrane proper
4. Sublamina densa
region
 Cytoskeleton

• Keratin 5

• Keratin 14
 Keratin
• Intermediate filament of
diameter 10nm

• Maintains the intracellular

architecture and organisation of
basal keratinocytes

• Course through basal cells and

gets inserted into desmosomes
and hemidesmosomes
 Disorders associated with keratin
Epidermolysis bullosa
simplex:
- Weber cockayne

- Koebner

- Dowling Meara

- Mottled pigmentation
WC

DM
 Hemidesmosome-Anchoring
filament
• Plectin
• BPAg1
• BPAg2
• Integrin a6
• Integrin b4
• Tetraspan CD151
• Laminin 5
 PLECTIN
• Large protein associated with the cytoplasmic
plaque of hemidesmosomes

• Plakin family-cytolinker- Between cytoskeleton

and junctional complexes

• Binds keratin at one end

• BPAg-2, integrin b4, actin at other end

 Disorder associated with plectin
• Only inherited/ no autoimmune

• EBS with limb girdle muscular dystrophy

(sarcolemma)
• EBS ogna
• EBS with pyloric atresia
 BPAg 1/BP230
• Located to cytoplasmic plaque of HD

• One end binds keratin

• Other end binds BpAg 2, integrin b4, ERBIN-

protein associated with transmembrane
tyrosine kinase receptor Erb B2
 Disoder associated with BPAg 1
• Autoimmune blistering disease- Bullous
pemphigoid
• Inherited- EBS
 BPAg 2/collagen XVII/BP180

• Associated with HD
anchoring filament
complexes

• Intracytoplasmic globular
head and extracellular
central rod with flexible
tail
BPAg 2/ collagen XVII/BP180

Amino terminal
NC-16A
Ectodomain- collagenous
15 gly-X-Y repeats named as
Col 1 to 15
 Disorders associated with BPAg2
Autoimmune blistering Mutations involving
diseases involving BPAg2 COL17A1
targetting NC 16-A:
• Bullous pemphigoid
• JEB non Herlitz type
• Pemphigoid gestationis
• Linear IgA bullous
dermatosis
Targetting C terminal of
BPAg2:
• Cicatricial pemphigoid
 Integrin
• Heterodimeric transmembrane receptor
containing alpha and beta subunits

• Cell adhesion, signal transduction, gene

expression, growth, and other fundamental
biological processes.
• Integrin involved in HD
assembly is a6b4 integrin

• Specific ligand is laminin 5

• B4 binds to plectin and BPAg

2 and BPAg 1

• A6 links to NC16 A domain of

BPAg2
 Disorders associated with integrin

• Mutations in integrin a6b4- JEB with pyloric

atresia

• Pts with one form of ocular CP have

autoantibodies targeted against integrin b4
 a3b1 integrin
• Receptor for laminin 332-
311 complex

• Link between basement

membrane and epithelial
actin network
 CD151/tetraspanin
• Component of
HD

• Mutation-
hereditary
nephritis, SNHL,
pretibial EB, b-
thalassemia
major
 Lamina densa
• Collagen IV

• Perlecan

• Nidogen/entactin

• Laminin 5
 Collagen IV
• Major component of
basement
membrane proper
• Heterotrimer with 3
alpha chains-
genetically distinct
and structurally
similar
3 domains:
1. N terminal 7S domain
2. central triple helical domain
3. C terminal non collagenous domain (NC-1)
 Disorders associated with collagen IV

Alport syndrome Good pasteur syndrome

• Mutations inv alpha5 chain
in XR
• Alpha 3 & 4 in AR
• Hematuria, SNHL,
progressive renal failure,
ocular abnormalities
• Autoantibodies NC1 of
alpha3 chain
• Pulmonary hemorrhage and
glomerulonephritis

Alpha 5 chain of type 4 collagen is found to be

an autoantigen in a rare disease characterised
by subepidermal blisters and glomerulonephritis
 Laminin
• Component of lamina densa-lamina lucida
interface
• Heterotrimeric glycoprotein with alpha, beta
and gamma subunits
• Asymmetrical cross or cruciform structure
• 15 types- most important in BM is laminin
5/laminin 332
 Disorders associated with laminin
JEB- Herlitz type Antiepiligrin CP
• Laminin 5 mutation • Antibodies against laminin 5
 Nidogen/Entactin
• Glycoprotein in lamina densa

• Link between laminin and type 4 collagen

• Also to perlecan and fibulin

 Nidogen can bind only to gamma1 subunit of
laminin. Then how does laminin 332 binds to
nidogen?
Disorders associated with nidogen

• No mutations or autoimmune diseases

• Targeted deletion of nidogen in mice – severe

defect in lung and heart.. No effect in
epidermal basement membrane
 Perlecan
• Heparan sulphate proteoglycan

• Ubiquitous

• Bottle brush arrangement

• Matrix of basement membrane

• Sulphate- negative charge-

selective permeability
 Sublamina densa region
• Collagen VII

• Microfibrils

• Micro thread like fibres

• Collagen 1

• Collagen III
 Collagen VII
• Homotrimer containing 3 identical alpha
chains

• N terminal domain is the large globular and

trident like NC-1

• C terminal domain is also globular NC-2

 Anchoring fibrils
• They are made up of collagen type 7
• Dimerisation occurs at NC-2 domain in anti
parallel direction
• Bundles- wheat stack appearance- anchoring
fibrils
• one end of anchoring fibril attaches to LD and
other end either to LD or anchoring plaques
• Anchoring plaques are portions of LD that has
been dropped out and fallen into sublamina
densa region due to BM remodelling
 Disorders associated with collagen VII
• Mutations - DEB • Acquired:
-EBA, Bullous LE
 Microfibrils
• Elastic fibres- resilience & elasticity
• have two components – amorphous and
microfibrillar

- amorphous : electrolucent core- Elastin

- microfibrillar: electrondense- fibrillin, fibulin,
latent TGF-b binding protein etc.,
• Microfibrils
inserting
vertically into the
LD- Oxytalan
fibres
• Inferior aspect of
oxytalan fibres
merges with
microfbrils
oriented parallel
to skin surface
known as elaunin
fibres
 Microthread like fibres

LINKIN:
• Interconnect elastic microfibrillary bundles,
anchoring fibrils and interstitial collagen fibres
 Interstitial collagens
• Collagen I & collagen III

• Collagen I- 80% of total collagen in dermis

• Collagen III- 10% of total collagen in dermis

• 8:1

• Mutations- various forms of EDS

 Salt split skin technique
• Developed in 1984

• Increases the sensitivity of detection of anti-

BMZ antibody in supepidermal vesiculo
bullous dermatosis
 Procedure
• Incubation of normal skin in 1M NaCl for 24
hrs at 4degree C
• Splitting or artificial separation occurs in
Lamina Lucida(LL)
• Roof of the split(epidermal side) contains HD
antigens( plectin and BPAg1)
• Floor of the split (dermal side) contains
antigens in lamina densa- laminin 5, type 4
collagen and type 7 collagen in SLDR
 Summary…

BP, EBS

OcularCP BP, PG,

CP, LABD

Antiepiligrin
CP
EBA
 References
• Bolognia Textbook of Dermatology 2nd Edition
• Rook’s Textbook of Dermatology 8th edition
• Fitzpatrick’s Dermatology in General medicine
8th Edition
• Vidal EM.The Basement membrane zone:
Making the connection. American academy of
Dermatology 1st edition. 2013.
• Aoki V, Sousa JX Jr, Fukumori LMI, Perigo AM,
Freitas EL, Oliveira ZNP. Direct and Indirect
immunoflourescence. An Bras Dermatol.
2010;85(4):490-500