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A. Basal Cell Hemidesmosomenavigator

  1. Not a half-desmosome
  2. Distinct composition
  3. Desmogleins 1 and 3, Bullous Pemphigoid Antigen (BPA)
  4. Main epidermal-basement membrane (BM) adhesion

B. Lamina Lucidanavigator

  1. Anchoring filaments
  2. Cicatricial Pemphigoid Antigen
  3. 20-40nm wide
  4. Filament composition unknown

C. Lamina Densa (Basal Lamina)navigator

  1. Mainly Type 4 Collagen
  2. Nidogen/Entactin anchors
  3. Non-fibrillar Type 7 Collagen
  4. Laminin (cruciate) present here
  5. 30-60nm wide

D. Sublamina Densa Zonenavigator

  1. Connective tissue
  2. Types 1 and 3 Collagen
  3. Anchoring Fibrillar Type 7 Collagen
  4. Together, Types 4 and 7 Collagen make dermal anchoring plaque

BASEMENT MEMBRANE COMPONENTS AND ASSOCIATED PATHOLOGY

A. Heparan Sulfate Proteoglycan (HSPG)navigator
  1. Consists of long protein core with attached long carbohydrate side chains, 120-750K
  2. Entwined in a meshwork with type IV collagen
  3. Because of charge and protein component, suggested roles for HSPG are:
    1. Regulation of fluid and electrolyte balance in BM
    2. Regulation of protein filtration through BM
    3. Possible role in binding growth factors/lymphokines causing local high levels

B. Type IV Collagen navigator

  1. Ubiquitous basement membrane (BM) protein
  2. Responsible for EM density of the lamina densa
  3. MW ~400K on reduced SDS-PAGE
  4. Interacts with laminin, nidogen, heparan sulfate proteoglycan, and Type VII collagen
  5. Basal keratinocytes preferentially adhere to Type IV collagen
  6. Antibodies to type IV collagen occur in Goodpasture's Syndrome

C. Type VII Collagennavigator

  1. Target in multiple bullous diseases [4]
    1. Epidermal Bullosa Acquisita (EBA) Antigen
    2. Cicatricial pemphigoid (minor antigen)
    3. Linear IgA dermatosis
    4. Chronic bullous disease of childhood
    5. Bullous systemic lupus erythematosus
  2. EBA Abs recognize 145K and 200K proteins
    1. Localized to the dermal anchoring fibrils
    2. React with non-collagenous domain of type VII procollagen
  3. Similar Abs also found in bullous eruption of systemic lupus erythematosus

D. Fibronectinnavigator

  1. Ubiquitous material in both tissue and serum
  2. Small amounts within upper papillary dermis and lamina densa
  3. Plays a role in wound healing and leukocyte migration in inflammation
  4. Binds to laminin through RGD (arginine-glycine-aspartic acid) triplet within laminin

E. Other Proteins [4,5]navigator

  1. Bullous Pemphigoid Antigens (BPAG)
    1. BPAG2 is a180K transmembrane protein expressed in basal keratinocytes
    2. BPAG1 is an intracellular protein anchoring BPAG2 to keratin of cytoskeleton
    3. BPAG2 anchors keratinocyte to basement membrane
    4. BPAG2 traverses lamina densa and lamina lucida
    5. Thus, BPAG2 interacts with Collagen Type VII in anchoring plaque
    6. BPAG2 is major autoantigen in bullous pemphigoid
  2. Herpes Gestationis Antigen (HGA)
    1. BPAG2 is the major antigen in herpes gestationis (90% of cases)
    2. Minority (~10%) of HGA patients also detect the 230K BPA
  3. Cicatricial Pemphigoid Antigen
    1. BPAG2, integrin ß4, laminin 5 or 6 and type VII collagen are target autoantigens
    2. The CPA appears to localize in the lower lamina lucida or upper lamina densa
  4. Linear IgA Dermatitis Antigen
    1. Linear IgA dermatosis demonstrate linear (non-granular) deposition of Ab in BM
    2. Antigens include BPAG2, type VII collegen, and LAD-1
    3. LAD-1 is a 97K epidermal antigen which may be external domain of BPAG2
  5. Desmoglein 1 [3]
    1. Component of desmosomes
    2. Abs to desmoglein 1 and 3 found in pemphigus vulgaris
    3. Abs to desmoglein I found in pemphigus foliaceus
    4. Endemic ("fogo selvagem") and sporadic forms of pemphigus foliaceus described
    5. Abs to desmoglein 1 are found in asymptomatic persons in regions of endemic disease
  6. Laminin
    1. Cruciate molecule, glycoprotein, general component of basement membranes (BM)
    2. Composed of three chains: A, B1 and B2
    3. The C terminus of laminin contains the RGD (Arg-Gly-Asp) fibronectin receptor
    4. Anti-laminin Abs are not responsible for any known disease, but occur in Chagas Disease
  7. Extracellular matrix protein 1 (ECM 1) [7]
    1. Pathogenic mutations of ECM 1 in lipoid proteinosis
    2. Autoantibodies to ECM 1 in 67% of patients with lichen sclerosis

F. Dermatitis Herpetiformis [5] navigator

  1. Description
    1. Intensely pruritic skin disease, usually beginning as vesicle
    2. Papulovesicular lesions and urticarial wheals
    3. Blisters on extensor surfaces in symmetric dystribution
    4. Elbows, buttocks, knees frequently involved
    5. Subepidermal blisters
    6. Increased incidence of antithyroid microsomal and antinuclear antibodies
  2. Epidemiology
    1. 10-39 cases per 100,000
    2. Onset usually ages 20-40
    3. Male to Female 2:1
    4. Usually occurs in Whites; rare in Blacks or Asians
  3. Pathology
    1. Granular IgA deposition in sub-basal zone and on dermal papillae of skin
    2. Blistering within lamina lucida zone
    3. Neutrophilic microabscesses in dermal papillae
    4. Similar deposition in intestinal villi with villous atrophy occurs in ~66% of patients
    5. IgA antibodies to gliaden common
    6. Anti-reticulin and anti-endomysial Abs detected in patients' serum
    7. Strongly associated with DR3 (~16X increased risk)
    8. Related to celiac disease (sprue), with anti-gliaden antibodies
  4. Treatment
    1. Gluten free diet - requires about 2 years of gluten free diet for rash to disappear
    2. This diet should be free of wheat, barley and rye; oats are acceptable [2]
    3. Dapsone or sulfapyridine may be used with rapid relief in 1-2 days
    4. Check glucose-6-phosphate dehydrogenase (G6PD) prior to initiating dapsone therapy
    5. Monitor Complete blood counts with concern for hemolytic anemia monthly
    6. Glucocorticoids may be used in severe disease

G. Lichen Planus [6] navigator

  1. Results from cell-mediated cytotoxic effects on basal cells
  2. Affects all types of stratified squamous cell epithelium
    1. Skin
    2. Mucosal Sites
    3. Nails - loss of nails may occur
  3. Skin lesions characterized by 4 P's:
    1. Purple
    2. Polygonal
    3. Pruritic
    4. Papules
  4. Oral Form
    1. Buccal mucosa nearly always affected
    2. Most is asymptomatic
    3. Severe form can present with pain and difficulty eating
  5. Pathology
    1. Subepithelial clefting
    2. Dense, band-like lymphocytic infiltrate
    3. Colloid bodies
    4. Complement C3 staining present
    5. No staining for IgG, IgA, IgM
  6. Infections or drug use can precipitate lichen planus
  7. Hepatitis C virus associated with lichen planus (pathophysiology unclear)
  8. Treatment
    1. Responds to topical or systemic glucocorticoids
    2. Often recurs with discontinuation
    3. Severe disease treated with 50mg/d prednisone or equivalent
    4. Maintain for several weeks
    5. Taper slowly over time
    6. Azathioprine may be used as a glucocorticoid-sparing agent
    7. Cyclosporine mouthwash has been reported to benefit oral disease

References navigator

  1. Fine JD. 1995. NEJM. 333(22):1475 abstract
  2. Hardman CM, Garioch JJ, Leonard JN, et al. 1997. NEJM. 337(26):1884 abstract
  3. Warren SJP, Lin MS, Giudice GJ, et al. 2000. NEJM. 343(1):23 abstract
  4. Stern RS. 2002. NEJM. 346(5):364 abstract
  5. Bickle KM, Roark TR, Hsu S. 2002. Am Fam Phys. 65(9):1861 abstract
  6. Gallagher GT and Lyle S. 2002. NEJM. 347(6):430 (Case Record) abstract
  7. Oyama N, Chan I, Neill SM, et al. 2003. Lancet. 362(9378):118 abstract