Basement membrane/ Skin development maintenance Flashcards
from superficial to deep, what are the four subregions of the basement membrane zone
- cytoskeleton, hemidesmosomal plaques, plasma memranes of basal keratinocytes
- lamina lucida (electron lucent region)
- lamina densa
- sublamina densa containing anchoring fibrils, plaques, filamentous proteins
Elastin, types 1, 3 and 7 collagen are found in which layer
sublamina densa
laminin 332 and type 4 collage are found in which region
Lamina densa (not sublamina)(
Integrin subunits alpha 6/ beta4 and BPAG2 are found ____
lamina lucida
BPAG1, the epidermal isoform of ____,
plectin
BPAG1 and plectin interact with the lamina densa via which subunits
Integrin subunit a6, b4
BPAG2 is targeted by autoantibodies from patients with ___, _______, ______ and _____
BP, Pemphigoid gestationis, MMP and LABD
The autoantibodies of MMP, LABD, PG and BP target BPAG2, the difference with MMP autoantibodies is __
it targets the distal carboxy terminus - deeper into the basement membrane
The difference between BPAG1 and BPAG2
BPAG2 HD anchoring filament complexes in basal keratinocytes
BPAG1 connects keratinocytes together
BPAG1 and BPAG2 (collagen 17) disease association and genetic disease association (2 total)
Bullous pemphigoid
Genetic = recessive EB complex
Type XVII collagen aka _____, is involved in which bullous diseases (4)
BPAG2, BP, PG, MMP, linear IgA bullous dermatosis
Bonus: junctional EB (mild)
Which autoimmune disease is associated with Ab’s against integrin subunit B(beta)-4
Occular MMP
Auto-abs against type 7 collagen is seen in
EB acquisita
Bullous eruption of SLE
Kindler syndrome - autosomal ______
Caused by mutations in ____
Path?
Autosomal recessive
FERMT1 gene
trauma induced blisters, photosensitivitry, pokiloderma, variable mucosa involvement, increased risk of mucosal SCC
Pemphigoid gestiationis targets which auto ab
BPAG2 180 HD
linear IgA bullous dermatosis ABs target
BPAG2 HD
EB Acquisita / bullous eruption of SLE targets ___ (auto antibody)
Type 7 collagen
BP auto ab’s
BPAG1 and 2
Aka BP230 *BPAG12) and BP180 (BPAG2 aka collagen 17)
skin derived from which embryonic germ layers?
Ectoderm -epidermis, Merkel cells, adnexal structures, melanocytes (neural crest derivatives), nerves (neuroectoderm)
Mesoderm - fibroblasts, LCs, vessels, inflammatory cells
Lines of blaschko are thought to represent ____ in organogenesis
migration pathways of epidermal cells during embryogenesis
Harlequin icthyosis (HI) is from a deletorious mutation in _____
ABCA12
Plectin mutations are associated with which diseases?
hint: three out of the five are the same disease, but different variants
Epidermolysis bullosa simplex w/ muscular dystrophy, EB with pyloric atresia, EB Ogna variant
Paraneoplastic pemphigus
Bullous pemphigoid
Where are integrins located
Which ones do we need to know (related to a disease)
Talk about their functions
Basal keratinocytes, hemidesmosomes
- in the lamina lucida layer*
- a6b4 mutations lead to junctional EB with pyloric atresia*
function: structure/ integrity, epidermal homeostasis (adhesion), cell signaling, hair growth
Autoantibodies vs collagen 17 = which disease associations?
bullous pemphigoid, gestational pemphigoid, mucous membrane pemphigoid, LP pemphigoides, and LABD
here is BP:
- Vesicles/Bullae on normal or erythematous skin +/- urticarial plaques (annular/figurate pattern)•Symmetrically, flexural areas
- Blisters 1-3 cm tense, clear fluid or hemorrhagic persist for several days leaving eroded and crusted areas
- Residual PIH, rarely milia
- Oral cavity involved in 10-30%•50% patients with peripheral eosinophilia
What are laminins, where are they and which do we need to know?
Laminin 332, 311 and 511
Found in lamina lucida/ densa
Disease associations include
Junctional EB (LAMC2)
Herlitz type EB, generalized atrophic EB, SCC
Collagen 7 autoantibody disease associations?
Bullous lupus erythematosus
epidermolysis bullosa (NUMEROUS types)
for studying
Key features of pemphigoid group of disease
Mean age:
Female vs. male
any allele associations?
Understand the pathogenesis of target antigens → what is main target, then name the other two
mean age 75-81 yo
male > female
a/w HLA DqB-0301
Main target = BPAG2 atNC16A domain and also BPAG1 via epitope spreading
Which disease process is this?
this is BP but in the early urticarial phase
Here we see the eczematous phase
What is DDx for this>?
maybe even bullous LP
What is going on here?
Gestational Pemphigoid / pemphigoid gestiationis
rapid onset in 2nd/3rd trimester, associated with graves/ anti-TPO antibodies, choriocarcinoma, hydatiform mole
HLA-DR3, HLA-DR4 or both
- DIF: linear C3 (100%), linear IgG (30%)*
- Neonate can develop transient blistering!*
remember: Pemphigus vulgaris (desmoglein 3) auto ab’s can blister babies too because their skin configuration is essentially mucous membrane adult like
What is this disease?
Pemphigus vegetans
What is the mnemonic for drug induced pemphigoid?
PF ChANGs
Penicillamine/ PCN derivatives/ photons (radiation)
Furosemide
Captopril
Amoxicillin/ ciprofloxacin
NSAIDS
Gold
Sulfasalazine
how is BP and bullous LP similar?
same circulating autoantibodies to BP180 (BPAG2/ collagen 17)
however there is LP like lesions on unaffected areas (blisters)
what is mucous membrane pemphigoid AKA?
How many subtypes are there?
Cicatricial pemphigoid
Four subtypes:
- Ocular CP (antibodies to the b4 subunit of the a6b4 integrin)
- Combined mucocutaneous CP (BPAG2 Abs aka BP180)
- Mucous membrane only (MMP)
- Anti-epiligrin CP (laminin 332 Ab’s)
What do you see in DIF or IIF for pemphigoid diseases?
DIF → most reliable (80-95% sensitive) linear IgG, IgA and/or C3 along the BMZ
IIF → only 20-30% have detectable circulating auto-antibodies
1st line treatment for BP
2nd line etc.
- systemic steroids and steroid sparing immunosuppressants (cellcept, Imuran, MTX, cyclophosphamide)
- tetracyclines, niacinamide
- Dapsone for mucosal predominant
- Rituximab for treatment resistant cases
- IVIG, plasma exchange
Epidermolysis bullosa aquisita epidemiology, disease associations
Which autoantibody?
Describe the two different forms?
Most common in adults, it is rare and acquired
Associated diseases: Crohns > myeloma, SLE, RA, diabetes, thyroiditis
Target: IgG autoantibodies to collagen 7
Form 1: classic mechanobullous → noninflammatory bullae form on trauma prone sites, heals with atrophic scars, milia and dyspigmentation
Form 2: Inflammatory → clinically indistinguishable from BP/ MMP → heals without scars!
Pemphigus has 3 groups
What are they and what are the autoantibody targets?
Pemphigus vulgaris - IgG to Desmoglein 3 or both desmoglein 1 and 3
pemphigus foliaceus - IgG to desmoglein 1
paraneoplastic pemphigus - Autoantibodies against Plakin molecules as well as T cell mediated autoimmune reaction leading to interface dermatitis
Describe this and what is it
Pemphigus foliaceous
Autoantibody to DG1
well demarcated, transient, impetigo like crusted erosions on an erythematous base favoring seborrheic distr. (cornflake scale), no mucosal involvment
What is this?
Pemphigus erythematosus aka senear usher syndrome
Lupus/ P. foliaceus overlap
Malar region and seborrheic areas
DIF shows intercellular pemphigus pattern + lupus pattern (granular to linear IgG and c3 along BMZ)
sun protection, steroids +/- dapsone
Laminins 111 and 332 interact with _____
Integrins a6b4 (Hemidesmosome)
Is BPAG1 the primary mediator of autoantibodies for BP?
No, it is targeted via epitope spreading
BPAG2 is the primary target as it connects Hd with basement membrane
specifically autoantibodies target the NC16A domain
Which gene encodes type 7 collagen and what diseases are associated with nonsense./ missense mutations?
COL7A1 mutations cause both recessive and dominant forms of dystrophic EB
- These patients have no anchoring fibrils in their epidermal BM and manifest extreme skin fragility, scars, increased risk for SCCs*
- Recessive carriers usually only have 1 allele and thus have less fragility*
The Epidermolysis bullosa acquisita autoantigen (mechanical trauma) / acquired bullous lupus autoantigen
type 7 collagen
Spongtiotic dermatitis with Eosinophils in the epidermis differential
HAPPIED
herpes gestationis
Arthropod bite/ Allergic contact
Pemphigoid
Pemphigus
Incontinentia pigmenti
ETox
Drug
Mounding perakeratosis diff.
PR
Seb derm
Nummular eczema
PRP
Superficial epidermal pallor differential
Any nutritional deficiency
Irritant contact Derm histo
Superficial pallor
Mild spongiosis
ulcerations
Also think of CNH
Incontinentia pigmenti path
Dyskeratosis in clumps
Small adnexal structures
Eosinophilic spongiosis
Vesicles early Papillar/
verrucal is stage 2
Pigmented/blaschkoid stage 3
Atrophy/ scarring in stage 4
Collagen 4 is in the
Lamina Densa
Which diseases are anti collagen 4 alpha3 Abs present?
goodpastures/ alport
