Acquired and Inherited Bullous Diseases
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1 Acquired and Inherited Bullous Diseases Erin Wei MD Brigham and Women s Hospital, Department of Dermatology Instructor, Harvard Medical School Director, Bullous Disease Clinic
2 No disclosures Conflict of Interest 2
3 Outline Part I. Acquired Bullous Disease (Q&A) majority of this talk Part II. Inherited Bullous Disease (Q&A) 3
4 Acquired Bullous Diseases
5 What is the antigenic target in anti-p200 pemphigoid? A. Laminin B. BP230 C. BP180 D. LAD fragment of BP180 E. Collagen IV Question 1 5
6 What is the antigenic target in anti-p200 pemphigoid? A. Laminin B. BP230 C. BP180 D. LAD fragment of BP180 E. Collagen IV Answer 6
7 Anti-p200 Pemphigoid Clinically resembles bullous pemphigoid However, can also resemble linear IgA bullous dermatosis or dermatitis herpetiformis Antigenic target is the 200kDa gamma-1-chain of Laminin localized on the floor of the salt split skin 7
8 Study Tip Know the targets of autoimmune bullous diseases (including the newfound variants)
9 Which of the following 130kDa protein is an antigenic target in pemphigus vulgaris? A. Desmoglein 1 B. Desmoglein 3 C. Collagen VII D. Desmocollin 1 E. BPAG1 Question 2 9
10 Which of the following 130kDa protein is an antigenic target in pemphigus vulgaris? A. Desmoglein 1 B. Desmoglein 3 C. Collagen VII D. Desmocollin 1 E. BPAG1 Answer 10
11 The molecular weights of Both Dsg 1 and Dsg3 antibodies can be found in PV Dsg1 is 160 kda Dsg3 is 130 kda common antigens Antigen Plectin 500 Desmoplakin I 250 BPAG1 230 Desmoplakin II & Envoplakin 210 a6b4 integrin 200 Periplakin 190 BPAG2 180 Dsg1 160 Dsg3 130 Desmocollin 110/100 LAD portion of BPAG2 97 Plakoglobin 86 Molecular Weight (kda)
12 Study Tip Know the molecular weight of common antigens in autoimmune bullous diseases
13 Antibodies to which of the following component is most likely to cause blistering in babies born to mothers with pemphigus? A. Desmoglein 1 B. Desmoglein 3 C. Collagen VII D. Desmocollin 1 E. BPAG1 Question 3 13
14 Antibodies to which of the following component is most likely to cause blistering in babies born to mothers with pemphigus? A. Desmoglein 1 B. Desmoglein 3 C. Collagen VII D. Desmocollin 1 E. BPAG1 Answer 14
15 Quick Review of the Desmoglein Compensation Theory In the mucosa: Dsg 1 antibodies are unable to cause blistering due to the compensation of the dsg3, expressed throughout the mucosa Neonatal Dsg1 Neonatal Dsg 3 Adult Dsg1 Adult Dsg3 Dsg3 antibodies are able to cause blistering because dsg 1 expression is unable to compensate for the loss of dsg 3 at the base of the mucosa 15 Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders.
16 Neonatal Desmolgein Expression Neonatal skin is similar to adult mucous membrane desmoglein 1 and 3 are coexpressed in the upper epidermis only desmoglein 3 is heavily expressed at the lower epidermis Neonatal skin Dsg1 Neonatal skin Dsg 3 Adult skin Dsg1 Adult skin Dsg3 Neonates develop blisters only if the mother has anti- Dsg3 antibodies Wu et al. Protection against Pemphigus Foliaceus by Desmoglein 3 in Neonates. N Engl J Med 2000; 343:
17 Study Tip Review diagrams, charts and photos from Bolognia (or other major text(s) that you are learning from) Also, flip through major journals pay special attention to abstracts, diagrams and photos
18 The 230kDa antigen in bullous pemphigoid is found in which of the following? A. Anchoring fibril B. Hemidesmosomal plaque of the basal keratinocyte C. Anchoring filament Question 4 D. Sub-basal dense plate 18
19 The 230kDa antigen in bullous pemphigoid is found in which of the following? A. Anchoring fibril B. Hemidesmosomal plaque of the basal keratinocyte C. Anchoring filament D. Sub-basal dense plate Answer 19
20 BP230: Located in the interior aspect of hemidesmosome of basal keratinocytes BP180: is a transmembrane collagenous protein spanning from the basal keratinocyte to the lamina densa Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders. 20
21 Study Tip Know the location of common targets of bullous diseases
22 The antigenic target in pemphigus forms a dimer with which of the following protein in the desmosome? A. E-cadherin B. P-cadherin C. BPAg1 D. Anchoring plaque E. Desmocollin Question 5 22
23 The antigenic target in pemphigus forms a dimer with which of the following protein in the desmosome? A. E-cadherin B. P-cadherin C. BPAg1 D. Anchoring plaque E. Desmocollin Answer 23
24 Both desmoglein and desmocollin belong to the cadherin family Desmosomes Desmoglein forms an adhesive dimer with desmocollin in a Ca 2+ - dependent manner in desmosomes Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders. 24
25 Study Tip Know the binding partner(s) of major antigens in bullous diseases
26 Skin incubated in 1M NaCl at 4ºC separates at which level? A. Below the lamina densa B. In the lamina densa C. In the granular layer D. In the lamina lucida Question 6 E. In the stratum corneum 26
27 Skin incubated in 1M NaCl at 4ºC separates at which level? A. Below the lamina densa B. In the lamina densa C. In the granular layer D. In the lamina lucida Answer E. In the stratum corneum 27
28 Salt-Split Technique Salt Split technique is variant of indirect immunofluorescence Deposits on the roof Normal skin is taken and split in 1M NaCl at the level of the lamina lucida Patient s serum is directed against salt-split skin Deposits on the floor Lamina lucida Lamina lucida 28 Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders.
29 Study Tip Know the details of common diagnostic techniques
30 Question 7 A patient with a positive IIF to guinea pig esophagus and a negative IIF to monkey esophagus, most likely has which of the following clinical exam findings? A. Itchy urticarial plaques and tense blisters B. Mucosal erosions-only C. Erosions and tense vesicles/bullae healing with milia and scarring on trauma prone sites D. Superficial blisters, crusted erosions on scalp, face and upper trunk 30
31 Answer A patient with a positive IIF to guinea pig esophagus and a negative IIF to monkey esophagus, most likely has which of the following clinical exam findings? A. Itchy urticarial plaques and tense blisters B. Mucosal erosions-only C. Erosions and tense vesicles/bullae healing with milia and scarring on trauma prone sites D. Superficial blisters, crusted erosions on scalp, face and upper trunk 31
32 Pemphigus foliaceus Pemphigus foliaceus is caused by autoantibody to Dsg1 Characterized by superficial blisters, crusted erosions and scales on the scalp, face and predominantly upper trunk Mucosa is typically not involved 32
33 IIF Substrates PF: Guinea pig esophagus PV: Monkey esophagus PNP: Transitional rat bladder epithelium Picture the following: a guinea pig eating foliage a vulgar monkey Jiao D, Bystryn JC. Sensitivity of indirect immunofluorescence, substrate specificity, and immunoblotting in the diagnosis of pemphigus. J Am Acad Dermatol Aug;37(2 Pt 1):
34 Study Tip Re-read the question if you are not sure what it is asking Know the IIF substrates for different types of pemphigus Know the clinical descriptions of common dermatologic diseases
35 In epidermolysis bullosa acquisita, autoantibodies are directed against which component of the skin? A. Anchoring filament B. a6b4 integrin C. Laminin 5 D. Anchoring fibril E. Type IV collagen Question 8 35
36 In epidermolysis bullosa acquisita, autoantibodies are directed against which component of the skin? A. Anchoring filament B. a6b4 integrin C. Laminin 5 D. Anchoring fibril E. Type IV collagen Answer 36
37 Antigenic target EBA is collagen VII, which make up the anchoring fibril Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders. 37
38 Study Tip Know the interchangeable names of the components targeted in autoimmune bullous disease For example: Col VII make up the anchoring fibril BP180 = Col XVII
39 Which of the following condition is most likely found in a EBA patient? A. Lichen planus B. Inflammatory bowel disease C. Alopecia areata D. Graves disease Question 9 E. Systemic lupus erythematosis 39
40 Which of the following condition is most likely found in a EBA patient? A. Lichen planus B. Inflammatory bowel disease C. Alopecia areata D. Graves disease Answer E. Systemic lupus erythematosis 40
41 EBA and IBD Type VII (the antigenic target in EBA) also exists in the BMZ of the colon Anti-Col VII autoantibodies have also been detected in IBD patients In the US, an estimated 25% of EBA patients also have inflammatory bowel disease, especially Crohn s Disease Chan LS, Woodley DT. Pemphigoid: Bullous and cicatricial. In: Lichtenstein LM, Fauci AS, editors. Current Therapy in Allergy, Immunology and Rheumatology. St Louis: pp
42 Study Tip Know the associations!
43 Which of the following autoimmune blistering disease has a salt-split positivity on the floor of the split? A. Classic Bullous pemphigoid B. Pemphigus vulgaris C. Pemphigus foliaceus Question 10 D. Epidermolysis bullosa acquisita 43
44 Which of the following autoimmune blistering disease has a salt-split positivity on the floor of the split? A. Classic Bullous pemphigoid B. Pemphigus vulgaris C. Pemphigus foliaceus Answer D. Epidermolysis bullosa acquisita 44
45 Roof Salt-Split Bullous pemphigoid Mucous membrane pemphigoid Floor Mucous membrane pemphigoid Epidermolysis bullosa acquisita Bullous lupus erythematosus Anti-p200 pemphigoid 45
46 Study Tip Know which autoimmune bullous diseases split to the roof and floor of a salt split
47 Question 11 Which of the following best describes the most common DIF finding in dermatitis herpetiformis? A. Linear IgG, IgA and C3 at the dermal-epidermal junction B. Granular IgG, IgA and C3 at the dermal-epidermal junction C. Granular IgA deposits localized in the dermal papillae D. Intraepidermal IgA deposits around the keratinocytes 47
48 Answer Which of the following best describes the most common DIF finding in dermatitis herpetiformis? A. Linear IgG, IgA and C3 at the dermal-epidermal junction B. Granular IgG, IgA and C3 at the dermal-epidermal junction C. Granular IgA deposits localized in the dermal papillae D. Intraepidermal IgA deposits around the keratinocytes 48
49 Dermatitis Herpetiformis Cutaneous manifestation of gluten sensitivity (DH) 90% of patients with DH have gluten-sensitive enteropathy 20% have symptoms of Celiac Disease DIF: 85% show granular IgA at dermal papillae 5-10% show continuous granular deposition of IgA along BM Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders. 49
50 Study Tip Know the DIF patterns of common autoimmune blistering diseases
51 Antibody towards which of the following is most closely related to development of cutaneous finding of dermatitis herpetiformis? A. Gliadin B. Gliadin crossed-linked to transglutaminase 2 C. Transglutaminase 2 Question 12 D. Epidermal transglutaminase 3 51
52 Antibody towards which of the following is most closely related to development of cutaneous finding of dermatitis herpetiformis? A. Gliadin B. Gliadin crossed-linked to transglutaminase 2 C. Transglutaminase 2 Answer D. Epidermal transglutaminase 3 52
53 Dermatitis Herpetiformis IgA antibodies to all the answer choices (gliadin, gliadin crosslinked to TG2, TG2 and epidermal TG3) can be found in DH However, development of IgA against epidermal TG3 via epitope spreading is believed to be responsible for the cutaneous development of DH As evidence by the co-localization of TG3 with IgA in the dermal papillae in DH Note: Anti-TG2 IgA correlates with gluten sensitive enteropathy and compliance with gluten avoidance 53
54 Study Tip Know serological factors that correlate with disease activity in autoimmune diseases
55 Antibodies to which of the following protein is least likely to be found in paraneoplastic pemphigus patients? A. BPAG1 B. Desmoplakin C. Envoplakin D. BPAG2 E. Periplakin Question 13 55
56 Antibodies to which of the following protein is least likely to be found in paraneoplastic pemphigus patients? A. BPAG1 B. Desmoplakin C. Envoplakin D. BPAG2 E. Periplakin Answer 56
57 Paraneoplastic pemphigus BPAg2 is typically not found to be antigenic in PNP Similarly, antibodies to integrin a6b4 are also typically not found in PNP The antigenic targets reported in PNP include: Plectin (500 kda) Desmoplakin 1 (250 kda) BPAg1 (230 kda) Envoplakin (210 kda) Desmoplakin 2 (210 kda) Periplakin (190 kda) Unknown protein (170 kda) Desmogleins 1 & 3 (160 and 130 kda) 57
58 Question 14 Which of the following is most commonly associated with paraneoplastic pemphigus in adults? A. Chronic myelogenous leukemia B. Non-Hodgkin s lymphoma C. Chronic lymphocytic leukemia D. Acute myelogenous leukemia E. Waldenstrom s macroglobulinemia 58
59 Answer Which of the following is most commonly associated with paraneoplastic pemphigus in adults? A. Chronic myelogenous leukemia B. Non-Hodgkin s lymphoma C. Chronic lymphocytic leukemia D. Acute myelogenous leukemia E. Waldenstrom s macroglobulinemia 59
60 Question 15 Which of the following is most commonly associated with paraneoplastic pemphigus in children? A. Thymoma B. Chronic lymphocytic leukemia C. Castleman disease D. Non-Hodgkin s lymphoma E. Retroperitoneal sarcoma 60
61 Answer Which of the following is most commonly associated with paraneoplastic pemphigus in children? A. Thymoma B. Chronic lymphocytic leukemia C. Castleman disease D. Non-Hodgkin s lymphoma E. Retroperitoneal sarcoma 61
62 Paraneoplastic Pemphigus Hallmark: intractable stomatitis earliest presenting sign Other features include polymorphic cutaneous eruption, pseudomembranous conjunctivitis Pulmonary destruction can lead to bronchiolitis obliterans Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders.
63 Paraneoplastic Pemphigus Most commonly associated conditions in adults: Non-Hodgkin s lymphoma (40%) Chronic lymphocytic leukemia (30%) Castleman disease (10%) Malignant and benign thymomas (6%) Sarcomas (6%) Waldenstrom s macroglobulinemia (6%) PNP in children and adolescents is most often a presenting sign of occult Castleman disease Mimouni D, Anhalt GJ, Lazarova Z, Aho S, Kazerounian S, Kouba DJ, Mascaro JM Jr, Nousari HC. Paraneoplastic pemphigus in children and adolescents.br J Dermatol Oct;147(4):
64 Study Tip Know the most common associated cancer(s) in the paraneoplastic syndromes
65 Inherited Bullous Diseases
66 Question 1 Which of the following congenital blistering disease is characterized by herpetiform blisters and clumped tonofilaments in basal keratinocytes on EM? A. Dowling-Meara EBS B. Herlitz JEB C. Hallopeau-Siemens DEB D. EBS with muscular dystrophy 66
67 Answer Which of the following congenital blistering disease is characterized by herpetiform blisters and clumped tonofilaments in basal keratinocytes on EM? A. Dowling-Meara EBS B. Herlitz JEB C. Hallopeau-Siemens DEB D. EBS with muscular dystrophy 67
68 Dowling-Meara EBS Autosomal dominant Mutation in K5/14 Onset at birth Characterized by: Grouped or herpetiform blisters Mucosal erosions (hoarseness) Nail dystrophy Confluent PPK High mortality
69 Study Tip Know the buzz-word features of subtypes EBS, JEB and DEB
70 Epidermolysis bullosa simplex with muscular dystrophy results from genetic defect in: A. a6b4 integrin B. Collagen XVII C. Keratin 5 & 14 D. Laminin-332 E. Plectin Question 2 70
71 Epidermolysis bullosa simplex with muscular dystrophy results from genetic defect in: A. a6b4 integrin B. Collagen XVII C. Keratin 5 & 14 D. Laminin-332 E. Plectin Answer 71
72 EBS-MD Autosomal recessive form of EBS Caused by mutation in Plectin Plectin is expressed in hemidesmosomes of basal keratinocytes and in skeletal muscles Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders.
73 Study Tip Know the mutations of each type of epidermolysis bullosa
74 Question 3 An infant with blisters and pyloric atresia may have defects in which basement membrane zone structure? A. Laminin or Type XVII collagen B. Type XVII collagen or plectin C. Type VII collagen or laminin D. a6b4 integrin or plectin E. Keratin 5 & 14 or a6b4 integrin 74
75 Answer An infant with blisters and pyloric atresia may have defects in which basement membrane zone structure? A. Laminin or Type XVII collagen B. Type XVII collagen or plectin C. Type VII collagen or laminin D. a6b4 integrin or plectin E. Keratin 5 & 14 or a6b4 integrin 75
76 Pyloric atresia can be seen in 1. EBS with pyloric atresia: mutation in plectin 2. JEB with pyloric atresia: mutation in genes encoding either subunit of a6b4 integrin
77 Study Tip Know some of the overlapping features of genodermatosis
78 A child with acral blisters, photosensitivity, poikiloderma, and poor dentation has mutation in which of the following? A. Gap junction B. Mismatch repair Question 4 C. Keratinocyte adhesion and polarity D. Telomere maintenance 78
79 A child with acral blisters, photosensitivity, poikiloderma, and poor dentation has mutation in which of the following? A. Gap junction B. Mismatch repair Answer C. Keratinocyte adhesion and polarity D. Telomere maintenance Description refers to Kindler Syndrome! 79
80 Kindler Syndrome Autosomal recessive genodermatosis Characterized by: skin fragility and bullae formation in sights of trauma photosensitivity with erythema burning and blistering progressive poikiloderma cutaneous atrophy severe peridontal disease Mutation in FERMT1 (KIND1) encodes for Kindlin-1 Kindlin-1 plays a role in linking the actin cytoskeleton to the extracellular matrix Affects the shape, polarity, adhesion, proliferation, and motility of keratinocytes 80 Image source: Bolognia, J., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology. Philadelphia: Elsevier Saunders.
81 Study Pearl Know not only the genetic defects, but also the functions of the proteins mutated in genodermatosis
82 Thank you Best of lucky and happy studying!
Index. derm.theclinics.com. Note: Page numbers of article titles are in boldface type.
Note: Page numbers of article titles are in boldface type. A Adhesion and migration, the diverse functions of the laminin a3 subunit, 79 87 Alopecia in epidermolysis bullosa, 165 169 Amblyopia and inherited
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