1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
a) Keratin 5
b) Type XVII collagen (bullous pemphigoid antigen-2; BP-180)
c) α-6 α-4 integrin
d) Laminin-332
e) Type VII collagen
2. Which of the following is true of antibodies with these features?
a) Utilize complement proteins to cause acantholysis
b) Bind to the intracellular domains of desmoglein 1 and desmoglein 3
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
d) Bind to intracellular domains of desmoplakins
e) Bind to intracellular domains of plakoglobin
To learn the answers, go to page 2
{{pagebreak}}
ANSWERS:
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
e) Type VII collagen
Clinical features of severe generalized recessive dystrophic epidermolysis bullosa (formerly named RDEB, Hallopeau-Siemens subtype) include the widespread blistering, atrophic scarring of the skin and scalp, marked growth retardation, central (axillary) contractures, and pseudosyndactyly (“mitten deformities”) of the hands and feet. Other major complications include but are not restricted to esophageal strictures, renal failure, and potentially life-threatening dilated cardiomyopathy.
The most important extracutaneous complication arising with this epidermolysis bullosa subtype is squamous cell carcinoma (SCC), which occurs in nearly every patient by mid-adulthood, and which usually leads to death from metastatic SCC, despite apparent complete excision of the tumor, within 5 years of its original excision. The underlying molecular defect in this disease is the presence of usually compound heterozygous mutations for premature termination codons within the 2 alleles encoding for type VII collagen. As a result, anchoring fibrils are virtually undetectable within the skin, explaining the presence of marked mechanical fragility and blister formation arising just beneath the lamina densa, the site of insertion of the anchoring fibrils into the skin basement membrane.
References
Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hopkins University Press; 1999:520.
Fine JD, Hintner H, eds. Life with Epidermolysis Bullosa. Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York, NY: Springer; 2009:338.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated issues. J Am Acad Dermatol. 2009;61(3):367-384; quiz 385-386.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009;61(3):387-402; quiz 403-404.
Fine JD, Johnson LB, Weiner M, et al. Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry. Am J Kidney Dis. 2004;44(4):651-660.
Fine JD, Johnson LB, Weiner M, et al. Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986-2002. J Hand Surg Br. 2005;30(1)14-22.
Fine JD, Johnson LB, Weiner M, Suchindran C. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46(2):147-158.
Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159(3):677-682.
Fine JD, Bruckner-Tuderman L, Eady RA, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol 2014; 70(6): 1103-26.
Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009;60(2):203-211.
Fritsch A, Loeckermann S, Kern JS, et al. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy. J Clin Invest. 2008;118(5):1669-1679.
2. Which of the following is true of antibodies with these features?
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
Immunofluorescence binding pattern of these antibodies is characteristic of both pemphigus vulgaris and foliaceus autoantibodies. These antibodies have been shown to cause acantholysis in organ culture and in mouse model by passive transfer. In both systems, acantholysis is complement independent and is largely caused by autoantibodies having poor complement-binding activity (IgG4 subclass). Furthermore, noncomplement binding Fab and Fab2 fragments of pemphigus antibodies are capable of causing acantholysis. Autoantibodies from patients with pemphigus vulgaris bind primarily the extracellular domains of desmoglein 3 (130 kD), and those from patients with pemphigus foliaceus bind extracellular domains of desmoglein 1 (160 kD).
In both cases, the epitopes are conformationally dependent and calcium sensitive. Recent in vitro studies suggest that the mechanism by which pemphigus vulgaris autoantibodies induce acantholysis is quite complex, involving increases in intracellular calcium, inositol 1, 4, 5-triphosphate, protein C kinase activation, and phosphorylation of desmoglein 3 and p38 mitogen-activated protein kinase. Plakoglobin also plays an important role.
References
Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nishikawa T. Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol. 1995;105(2):243-247.
Memar OM, Rajaraman S, Thotakura R, et al. Recombinant desmoglein 3 has the necessary epitopes to adsorb and induce blister-causing antibodies. J Invest Dermatol. 1996:106(2):261-268.
Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol. 1999;29(7):2233-2240.
Sato M, Aoyama Y, Kitajima Y. Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest. 2000;80(10):1583-1592.
Caldelari R, de Bruin A, Baumann D, et al. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J Cell Biol. 2001;153(4):823-834.
Sánchez-Carpintero I, España A, Pelacho B, et al. In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades. Br J Dermatol. 2004;151(3):565-570.
de Bruin A, Cadelari R, Williamson L, et al. Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris. Exp Dermatol. 2007;16(6):468-475.
Müller EJ, Hunziker T, Suter MM. Keratin intermediate filament retraction is linked to plakoglobin-dependent signaling in pemphigus vulgaris. J Am Acad Dermatol. 2008;56(5):890-891.
Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubernstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103(34):12855-12860.
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
a) Keratin 5
b) Type XVII collagen (bullous pemphigoid antigen-2; BP-180)
c) α-6 α-4 integrin
d) Laminin-332
e) Type VII collagen
2. Which of the following is true of antibodies with these features?
a) Utilize complement proteins to cause acantholysis
b) Bind to the intracellular domains of desmoglein 1 and desmoglein 3
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
d) Bind to intracellular domains of desmoplakins
e) Bind to intracellular domains of plakoglobin
ANSWERS:
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
e) Type VII collagen
Clinical features of severe generalized recessive dystrophic epidermolysis bullosa (formerly named RDEB, Hallopeau-Siemens subtype) include the widespread blistering, atrophic scarring of the skin and scalp, marked growth retardation, central (axillary) contractures, and pseudosyndactyly (“mitten deformities”) of the hands and feet. Other major complications include but are not restricted to esophageal strictures, renal failure, and potentially life-threatening dilated cardiomyopathy.
The most important extracutaneous complication arising with this epidermolysis bullosa subtype is squamous cell carcinoma (SCC), which occurs in nearly every patient by mid-adulthood, and which usually leads to death from metastatic SCC, despite apparent complete excision of the tumor, within 5 years of its original excision. The underlying molecular defect in this disease is the presence of usually compound heterozygous mutations for premature termination codons within the 2 alleles encoding for type VII collagen. As a result, anchoring fibrils are virtually undetectable within the skin, explaining the presence of marked mechanical fragility and blister formation arising just beneath the lamina densa, the site of insertion of the anchoring fibrils into the skin basement membrane.
References
Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hopkins University Press; 1999:520.
Fine JD, Hintner H, eds. Life with Epidermolysis Bullosa. Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York, NY: Springer; 2009:338.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated issues. J Am Acad Dermatol. 2009;61(3):367-384; quiz 385-386.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009;61(3):387-402; quiz 403-404.
Fine JD, Johnson LB, Weiner M, et al. Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry. Am J Kidney Dis. 2004;44(4):651-660.
Fine JD, Johnson LB, Weiner M, et al. Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986-2002. J Hand Surg Br. 2005;30(1)14-22.
Fine JD, Johnson LB, Weiner M, Suchindran C. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46(2):147-158.
Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159(3):677-682.
Fine JD, Bruckner-Tuderman L, Eady RA, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol 2014; 70(6): 1103-26.
Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009;60(2):203-211.
Fritsch A, Loeckermann S, Kern JS, et al. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy. J Clin Invest. 2008;118(5):1669-1679.
2. Which of the following is true of antibodies with these features?
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
Immunofluorescence binding pattern of these antibodies is characteristic of both pemphigus vulgaris and foliaceus autoantibodies. These antibodies have been shown to cause acantholysis in organ culture and in mouse model by passive transfer. In both systems, acantholysis is complement independent and is largely caused by autoantibodies having poor complement-binding activity (IgG4 subclass). Furthermore, noncomplement binding Fab and Fab2 fragments of pemphigus antibodies are capable of causing acantholysis. Autoantibodies from patients with pemphigus vulgaris bind primarily the extracellular domains of desmoglein 3 (130 kD), and those from patients with pemphigus foliaceus bind extracellular domains of desmoglein 1 (160 kD).
In both cases, the epitopes are conformationally dependent and calcium sensitive. Recent in vitro studies suggest that the mechanism by which pemphigus vulgaris autoantibodies induce acantholysis is quite complex, involving increases in intracellular calcium, inositol 1, 4, 5-triphosphate, protein C kinase activation, and phosphorylation of desmoglein 3 and p38 mitogen-activated protein kinase. Plakoglobin also plays an important role.
References
Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nishikawa T. Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol. 1995;105(2):243-247.
Memar OM, Rajaraman S, Thotakura R, et al. Recombinant desmoglein 3 has the necessary epitopes to adsorb and induce blister-causing antibodies. J Invest Dermatol. 1996:106(2):261-268.
Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol. 1999;29(7):2233-2240.
Sato M, Aoyama Y, Kitajima Y. Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest. 2000;80(10):1583-1592.
Caldelari R, de Bruin A, Baumann D, et al. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J Cell Biol. 2001;153(4):823-834.
Sánchez-Carpintero I, España A, Pelacho B, et al. In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades. Br J Dermatol. 2004;151(3):565-570.
de Bruin A, Cadelari R, Williamson L, et al. Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris. Exp Dermatol. 2007;16(6):468-475.
Müller EJ, Hunziker T, Suter MM. Keratin intermediate filament retraction is linked to plakoglobin-dependent signaling in pemphigus vulgaris. J Am Acad Dermatol. 2008;56(5):890-891.
Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubernstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103(34):12855-12860.
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
a) Keratin 5
b) Type XVII collagen (bullous pemphigoid antigen-2; BP-180)
c) α-6 α-4 integrin
d) Laminin-332
e) Type VII collagen
2. Which of the following is true of antibodies with these features?
a) Utilize complement proteins to cause acantholysis
b) Bind to the intracellular domains of desmoglein 1 and desmoglein 3
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
d) Bind to intracellular domains of desmoplakins
e) Bind to intracellular domains of plakoglobin
,
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
a) Keratin 5
b) Type XVII collagen (bullous pemphigoid antigen-2; BP-180)
c) α-6 α-4 integrin
d) Laminin-332
e) Type VII collagen
2. Which of the following is true of antibodies with these features?
a) Utilize complement proteins to cause acantholysis
b) Bind to the intracellular domains of desmoglein 1 and desmoglein 3
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
d) Bind to intracellular domains of desmoplakins
e) Bind to intracellular domains of plakoglobin
To learn the answers, go to page 2
{{pagebreak}}
ANSWERS:
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
e) Type VII collagen
Clinical features of severe generalized recessive dystrophic epidermolysis bullosa (formerly named RDEB, Hallopeau-Siemens subtype) include the widespread blistering, atrophic scarring of the skin and scalp, marked growth retardation, central (axillary) contractures, and pseudosyndactyly (“mitten deformities”) of the hands and feet. Other major complications include but are not restricted to esophageal strictures, renal failure, and potentially life-threatening dilated cardiomyopathy.
The most important extracutaneous complication arising with this epidermolysis bullosa subtype is squamous cell carcinoma (SCC), which occurs in nearly every patient by mid-adulthood, and which usually leads to death from metastatic SCC, despite apparent complete excision of the tumor, within 5 years of its original excision. The underlying molecular defect in this disease is the presence of usually compound heterozygous mutations for premature termination codons within the 2 alleles encoding for type VII collagen. As a result, anchoring fibrils are virtually undetectable within the skin, explaining the presence of marked mechanical fragility and blister formation arising just beneath the lamina densa, the site of insertion of the anchoring fibrils into the skin basement membrane.
References
Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hopkins University Press; 1999:520.
Fine JD, Hintner H, eds. Life with Epidermolysis Bullosa. Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York, NY: Springer; 2009:338.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated issues. J Am Acad Dermatol. 2009;61(3):367-384; quiz 385-386.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009;61(3):387-402; quiz 403-404.
Fine JD, Johnson LB, Weiner M, et al. Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry. Am J Kidney Dis. 2004;44(4):651-660.
Fine JD, Johnson LB, Weiner M, et al. Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986-2002. J Hand Surg Br. 2005;30(1)14-22.
Fine JD, Johnson LB, Weiner M, Suchindran C. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46(2):147-158.
Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159(3):677-682.
Fine JD, Bruckner-Tuderman L, Eady RA, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol 2014; 70(6): 1103-26.
Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009;60(2):203-211.
Fritsch A, Loeckermann S, Kern JS, et al. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy. J Clin Invest. 2008;118(5):1669-1679.
2. Which of the following is true of antibodies with these features?
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
Immunofluorescence binding pattern of these antibodies is characteristic of both pemphigus vulgaris and foliaceus autoantibodies. These antibodies have been shown to cause acantholysis in organ culture and in mouse model by passive transfer. In both systems, acantholysis is complement independent and is largely caused by autoantibodies having poor complement-binding activity (IgG4 subclass). Furthermore, noncomplement binding Fab and Fab2 fragments of pemphigus antibodies are capable of causing acantholysis. Autoantibodies from patients with pemphigus vulgaris bind primarily the extracellular domains of desmoglein 3 (130 kD), and those from patients with pemphigus foliaceus bind extracellular domains of desmoglein 1 (160 kD).
In both cases, the epitopes are conformationally dependent and calcium sensitive. Recent in vitro studies suggest that the mechanism by which pemphigus vulgaris autoantibodies induce acantholysis is quite complex, involving increases in intracellular calcium, inositol 1, 4, 5-triphosphate, protein C kinase activation, and phosphorylation of desmoglein 3 and p38 mitogen-activated protein kinase. Plakoglobin also plays an important role.
References
Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nishikawa T. Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol. 1995;105(2):243-247.
Memar OM, Rajaraman S, Thotakura R, et al. Recombinant desmoglein 3 has the necessary epitopes to adsorb and induce blister-causing antibodies. J Invest Dermatol. 1996:106(2):261-268.
Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol. 1999;29(7):2233-2240.
Sato M, Aoyama Y, Kitajima Y. Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest. 2000;80(10):1583-1592.
Caldelari R, de Bruin A, Baumann D, et al. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J Cell Biol. 2001;153(4):823-834.
Sánchez-Carpintero I, España A, Pelacho B, et al. In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades. Br J Dermatol. 2004;151(3):565-570.
de Bruin A, Cadelari R, Williamson L, et al. Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris. Exp Dermatol. 2007;16(6):468-475.
Müller EJ, Hunziker T, Suter MM. Keratin intermediate filament retraction is linked to plakoglobin-dependent signaling in pemphigus vulgaris. J Am Acad Dermatol. 2008;56(5):890-891.
Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubernstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103(34):12855-12860.
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
a) Keratin 5
b) Type XVII collagen (bullous pemphigoid antigen-2; BP-180)
c) α-6 α-4 integrin
d) Laminin-332
e) Type VII collagen
2. Which of the following is true of antibodies with these features?
a) Utilize complement proteins to cause acantholysis
b) Bind to the intracellular domains of desmoglein 1 and desmoglein 3
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
d) Bind to intracellular domains of desmoplakins
e) Bind to intracellular domains of plakoglobin
ANSWERS:
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
e) Type VII collagen
Clinical features of severe generalized recessive dystrophic epidermolysis bullosa (formerly named RDEB, Hallopeau-Siemens subtype) include the widespread blistering, atrophic scarring of the skin and scalp, marked growth retardation, central (axillary) contractures, and pseudosyndactyly (“mitten deformities”) of the hands and feet. Other major complications include but are not restricted to esophageal strictures, renal failure, and potentially life-threatening dilated cardiomyopathy.
The most important extracutaneous complication arising with this epidermolysis bullosa subtype is squamous cell carcinoma (SCC), which occurs in nearly every patient by mid-adulthood, and which usually leads to death from metastatic SCC, despite apparent complete excision of the tumor, within 5 years of its original excision. The underlying molecular defect in this disease is the presence of usually compound heterozygous mutations for premature termination codons within the 2 alleles encoding for type VII collagen. As a result, anchoring fibrils are virtually undetectable within the skin, explaining the presence of marked mechanical fragility and blister formation arising just beneath the lamina densa, the site of insertion of the anchoring fibrils into the skin basement membrane.
References
Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hopkins University Press; 1999:520.
Fine JD, Hintner H, eds. Life with Epidermolysis Bullosa. Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York, NY: Springer; 2009:338.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated issues. J Am Acad Dermatol. 2009;61(3):367-384; quiz 385-386.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009;61(3):387-402; quiz 403-404.
Fine JD, Johnson LB, Weiner M, et al. Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry. Am J Kidney Dis. 2004;44(4):651-660.
Fine JD, Johnson LB, Weiner M, et al. Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986-2002. J Hand Surg Br. 2005;30(1)14-22.
Fine JD, Johnson LB, Weiner M, Suchindran C. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46(2):147-158.
Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159(3):677-682.
Fine JD, Bruckner-Tuderman L, Eady RA, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol 2014; 70(6): 1103-26.
Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009;60(2):203-211.
Fritsch A, Loeckermann S, Kern JS, et al. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy. J Clin Invest. 2008;118(5):1669-1679.
2. Which of the following is true of antibodies with these features?
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
Immunofluorescence binding pattern of these antibodies is characteristic of both pemphigus vulgaris and foliaceus autoantibodies. These antibodies have been shown to cause acantholysis in organ culture and in mouse model by passive transfer. In both systems, acantholysis is complement independent and is largely caused by autoantibodies having poor complement-binding activity (IgG4 subclass). Furthermore, noncomplement binding Fab and Fab2 fragments of pemphigus antibodies are capable of causing acantholysis. Autoantibodies from patients with pemphigus vulgaris bind primarily the extracellular domains of desmoglein 3 (130 kD), and those from patients with pemphigus foliaceus bind extracellular domains of desmoglein 1 (160 kD).
In both cases, the epitopes are conformationally dependent and calcium sensitive. Recent in vitro studies suggest that the mechanism by which pemphigus vulgaris autoantibodies induce acantholysis is quite complex, involving increases in intracellular calcium, inositol 1, 4, 5-triphosphate, protein C kinase activation, and phosphorylation of desmoglein 3 and p38 mitogen-activated protein kinase. Plakoglobin also plays an important role.
References
Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nishikawa T. Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol. 1995;105(2):243-247.
Memar OM, Rajaraman S, Thotakura R, et al. Recombinant desmoglein 3 has the necessary epitopes to adsorb and induce blister-causing antibodies. J Invest Dermatol. 1996:106(2):261-268.
Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol. 1999;29(7):2233-2240.
Sato M, Aoyama Y, Kitajima Y. Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest. 2000;80(10):1583-1592.
Caldelari R, de Bruin A, Baumann D, et al. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J Cell Biol. 2001;153(4):823-834.
Sánchez-Carpintero I, España A, Pelacho B, et al. In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades. Br J Dermatol. 2004;151(3):565-570.
de Bruin A, Cadelari R, Williamson L, et al. Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris. Exp Dermatol. 2007;16(6):468-475.
Müller EJ, Hunziker T, Suter MM. Keratin intermediate filament retraction is linked to plakoglobin-dependent signaling in pemphigus vulgaris. J Am Acad Dermatol. 2008;56(5):890-891.
Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubernstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103(34):12855-12860.
ANSWERS:
1. The molecular basis for this generalized inherited bullous disorder involves mutations in the gene encoding for:
e) Type VII collagen
Clinical features of severe generalized recessive dystrophic epidermolysis bullosa (formerly named RDEB, Hallopeau-Siemens subtype) include the widespread blistering, atrophic scarring of the skin and scalp, marked growth retardation, central (axillary) contractures, and pseudosyndactyly (“mitten deformities”) of the hands and feet. Other major complications include but are not restricted to esophageal strictures, renal failure, and potentially life-threatening dilated cardiomyopathy.
The most important extracutaneous complication arising with this epidermolysis bullosa subtype is squamous cell carcinoma (SCC), which occurs in nearly every patient by mid-adulthood, and which usually leads to death from metastatic SCC, despite apparent complete excision of the tumor, within 5 years of its original excision. The underlying molecular defect in this disease is the presence of usually compound heterozygous mutations for premature termination codons within the 2 alleles encoding for type VII collagen. As a result, anchoring fibrils are virtually undetectable within the skin, explaining the presence of marked mechanical fragility and blister formation arising just beneath the lamina densa, the site of insertion of the anchoring fibrils into the skin basement membrane.
References
Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hopkins University Press; 1999:520.
Fine JD, Hintner H, eds. Life with Epidermolysis Bullosa. Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York, NY: Springer; 2009:338.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated issues. J Am Acad Dermatol. 2009;61(3):367-384; quiz 385-386.
Fine JD, Mellerio J. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009;61(3):387-402; quiz 403-404.
Fine JD, Johnson LB, Weiner M, et al. Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry. Am J Kidney Dis. 2004;44(4):651-660.
Fine JD, Johnson LB, Weiner M, et al. Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986-2002. J Hand Surg Br. 2005;30(1)14-22.
Fine JD, Johnson LB, Weiner M, Suchindran C. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46(2):147-158.
Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159(3):677-682.
Fine JD, Bruckner-Tuderman L, Eady RA, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol 2014; 70(6): 1103-26.
Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009;60(2):203-211.
Fritsch A, Loeckermann S, Kern JS, et al. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy. J Clin Invest. 2008;118(5):1669-1679.
2. Which of the following is true of antibodies with these features?
c) Bind to calcium sensitive epitopes on extracellular domains of desmogleins 1 and 3
Immunofluorescence binding pattern of these antibodies is characteristic of both pemphigus vulgaris and foliaceus autoantibodies. These antibodies have been shown to cause acantholysis in organ culture and in mouse model by passive transfer. In both systems, acantholysis is complement independent and is largely caused by autoantibodies having poor complement-binding activity (IgG4 subclass). Furthermore, noncomplement binding Fab and Fab2 fragments of pemphigus antibodies are capable of causing acantholysis. Autoantibodies from patients with pemphigus vulgaris bind primarily the extracellular domains of desmoglein 3 (130 kD), and those from patients with pemphigus foliaceus bind extracellular domains of desmoglein 1 (160 kD).
In both cases, the epitopes are conformationally dependent and calcium sensitive. Recent in vitro studies suggest that the mechanism by which pemphigus vulgaris autoantibodies induce acantholysis is quite complex, involving increases in intracellular calcium, inositol 1, 4, 5-triphosphate, protein C kinase activation, and phosphorylation of desmoglein 3 and p38 mitogen-activated protein kinase. Plakoglobin also plays an important role.
References
Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nishikawa T. Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol. 1995;105(2):243-247.
Memar OM, Rajaraman S, Thotakura R, et al. Recombinant desmoglein 3 has the necessary epitopes to adsorb and induce blister-causing antibodies. J Invest Dermatol. 1996:106(2):261-268.
Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol. 1999;29(7):2233-2240.
Sato M, Aoyama Y, Kitajima Y. Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest. 2000;80(10):1583-1592.
Caldelari R, de Bruin A, Baumann D, et al. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J Cell Biol. 2001;153(4):823-834.
Sánchez-Carpintero I, España A, Pelacho B, et al. In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades. Br J Dermatol. 2004;151(3):565-570.
de Bruin A, Cadelari R, Williamson L, et al. Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris. Exp Dermatol. 2007;16(6):468-475.
Müller EJ, Hunziker T, Suter MM. Keratin intermediate filament retraction is linked to plakoglobin-dependent signaling in pemphigus vulgaris. J Am Acad Dermatol. 2008;56(5):890-891.
Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubernstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103(34):12855-12860.
