HISTOPATHOLOGY OF IMMUNOBULLOUS DISORDERS

1
HISTOPATHOLOGY OF IMMUNOBULLOUS DISORDERS

• DR.SHUBHA

2
INTRAEPIDERMAL BULLOUS DISORDERS
3
TARGET ANTIGENS

• Located in the desmosomes the most prominent
  adhesion junction in stratified squamous
  epithelium.
• Desmosome complex contains desmogleins and
  desmocollins as transmembrane components and
  desmoplakins , phakoglobins as intracellular
  components.

4
(No Transcript)
5
PEMPHIGUS VULGARIS

• Autoimmune disease characterised by large flaccid
  blisters primarily in older individuals .
• Scalp, face, flexures, groin and pressure points.
• Lesions characteristically involves the oral
  mucosa.
• It is important that early blisters preferably
  smaller ones are selected for biopsy.

6

• Greek pemphix-blister or bubble
• Disruption of intercelular cementing substance
• Most common 80
• Fourth to sixth decade
• 50-70 mucosal lesions
• Bullae rupture spontaneously, no tendency to heal
  spontaneously
• Nikolskys sign (Asboe-Hansen sign)

7
(No Transcript)
8
(No Transcript)
9
HISTOPATHOLOGY

• Target antigen is desmoglein 3 which is 130 kD
  localised in spinous layer and in mucus
  membrane.Early blisters smaller in size
  selected.
• Earliest change spongiosis in lower epidermis.
  Acantholysis is suprabasal ,may extend into the
  adenexa.
• Basal keratinocytes though seperated from one
  another remain attached to the basement membrane
  Row of tombstones appearance.

10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
IMMUNOFLOURESCENCE

• DIF -Edge of the blister with intact sorrounding
  skin is selected transported in michaels
  medium.
• Very sensitive and reliable test esp. in oral
  lesions.
• Squamous intercellular or cell surface IgG
  deposition seen in 95 of cases.
• IDF IgG antibodies in 80 of cases using
  monkey oesophagus as substrate.

16
(No Transcript)
17
PEMPHIGUS VEGETANS

• Rare variant of pemphigus vulgaris .
• Vegetating lesions in flexures.
• Initially bullae or pustule
• Two types Neumann and Hallopeau.
• Antibodies against Pemphigus vulgaris antigens
  130 KDa.

18
(No Transcript)
19
HISTOPATHOLOGY

• Vegetating lesions are acanthotic ,
  hyperkeratotic and papillomatous.
• Suprabasal clefts contain acantholytic cells and
  eosinophils. Intraepidermal eosinophilic
  abscesses seen in older lesions.
• Hallopeau lesions pustules on normal skin with
  acantholysis and small suprabasal clefts.
• Dermis heavy infiltrate of lymphocytes and
  eosinophils with few neutrophils.

20
(No Transcript)
21
IMMUNOFLOURESCENCE

• DIRECT -Intercellular deposition of IgG in all
  reported cases.
• INDIRECT -Positive in most of the patients.
• Differential diagnosis Pyoderma vegetans seen
  in association with inflammatory bowel disease.
  Neutrophils are more common . Eosinophilic
  abscesses and acantholytic cells are rare.Mimicks
  pemphigus vegetans clinically and histologically.

22
PEMPHIGUS FOLIACEOUS

• Subcorneal blister
• Ig G antibodies against desmoglein 1
• Les severe, crusted moist, scaly lesions in
  seborrheic distribution
• Very transient
• Better prognosis

23

• Early lesions Vacoulation in intracellular
  spaces in the upper level of epidermis which
  coalesce to form clefts and bullae in granular
  layer or immediately beneath the stratum corneum.
• Bullae contain fibrin , acantholytic cells and
  neutrophils.
• Dyskeratotic cells in granular layer important.
• Dermis shows mixed infiltrate of eosinophils and
  neutrophils .

24
(No Transcript)
25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
IMMUNOFLOURESCENCE

• DIRECT - Intercellular IgG and C3 deposition
  throughout the epidermis or restricted to upper
  part of epidermis.
• INDIRECT Positive in 85 of sera.
• Pemphigus foliaceous antibody DESMOGLEIN 1 is
  expressed more in the upper layers of epidermis.
• Staphylococcal scalded skin syndrome

29
DIFFERENTIAL DIAGNOSIS

• Marked dyskeratosis distinguishes pemphigus
  foliaceous from p.vulgaris.ultrastructurally ,
  there is early loss of intercellular cement
  substance in lower half of epidermis, perinuclear
  homogenisation of tonofilaments in mid epidermis.
• Impetigo
• Subcorneal pustular dermatosis
• SSSS.

30
PEMPHIGUS ERYTHEMATOSUS

• Senear Usher syndrome
• Variant of pemphigus foliaceous.
• Clinically resembles lupus erythematosus
  erythematous plaques and patches in butterfly
  distribution .
• HPE Light microscpic changes similar to P.
  foliaceous. Rarely interface dermatitis in older
  lesions.
• Direct immunoflourescence squamous
  intercellular deposition of IgG , granular IgG
  and IgM at dermoepidermal junction.ANA positive
  in 30 80 of cases.

31
IgA pemphigus

• Pruritic pustular eruption in middle aged and
  elderly characterised by intercellular IgA
  deposition and intraepidermal neutrophils.
• Two types 1. Subcorneal pustular dermatosis
  type subcorneal vesicles and
  pustules with minimal acantholysis.2.
  intraepidermal neutrophilic dermatosis
• Antibodies against Desmocollin -1 in SCPD type
  and Desmoglein 2 in latter type.

32
(No Transcript)
33
PARANEOPLASTIC PEMPHIGUS

• Most common neoplasm Nonhodgkins lymphoma , CLL
  , castlemans tumour ,thymomas and sarcomas.
• Histological pitcure depends on various clinical
  presentations unique combination of erythema
  multiforme like , lichen planus like , pemphigus
  vulgaris like and pemphigoid like features.

34
(No Transcript)
35
HISTOPATHOLOGY

• Suprabasal acantholysis.
• Basal apoptosis
• Interface dermatitis (erythema multiforme like )
• With or without lichenoid inflammation.
• desmoplakin

36
IMMUNOFLOURESCENCE

• DIRECT Squamous intercellular deposition of IgG
  in perilesional skin At dermoepidermal junction
  linear deposition of C3 and IgG seen.
• IgG antibodies directed against desmoplakins ,
  envoplakins and desmogleins.

37

• Endemic P.Foliaceous
• Bite of black fly
• Drug
• Penicillamine,captopril, penicillin,rifampicin
• Neonatal pemphigus
• Transplacental transfer, resolves in 2 weeks

38

• Treatment
• Systemic steroids
• DCP
• Dapsone
• Methotrexate
• Azathioprine
• Ciclosporine
• plasmapheresis

39
SUBEPIDERMAL BLISTERING DISORDERS

• BULLOUS PEMPHIGOID
• Elderly
• Preceded by pruritis by 2-3 weeks
• Tense bullae on flexures
• Face and scalp relatively spared
• Heals spontaneously with PIH
• Nikolsky negative
• Mucosa rare

40

• Underlying malignancy-gastric carcinoma
• DM, RA, psoriasis
• Better prognosis than pemphigus
• Topical and systemic steroids

41

• Antibodies react with two antigens 230
  kD(BPAg1) , 180kD (BPAg2).
• Blister is subepidermal with intact and often
  viable epidermis forming the roof.
• Early lesions show papillary edema with cell rich
  or cell poor perivascular lymphocytes and
  eosinophilic infiltrate. Eosinophilic spongiosis
  or microabscesses may be seen.
• Blister lumen contains inflammatory cells .

42
(No Transcript)
43
(No Transcript)
44

45
(No Transcript)
46
IMMUNOFLOURESCENCE

• Direct -Linear C3 deposition at dermo epidermal
  junction in 100 of cases and IgG in 65 95
  .IgG is located within lamina lucida and
  specifically bound to hemidesmosomes.
• Salt split technique IgG at roof or floor of
  artificially induced blister.
• Indirect circulating IgG antibodies to
  basement membrane zone in 70 80 .

47
(No Transcript)
48
(No Transcript)
49
(No Transcript)
50
MUCUS MEMBRANE PEMPHIGOID

• Subepidermal blister that may extend down the
  adenexa.
• Neutrophils , lymphocytes and histiocytes
  predominate in the infiltrate with less
  eosinophils.
• Late lesions Lamellar fibrosis is the hallmark.
• Mucosal lesions show cell rich lichenoid
  infiltrate.

51
(No Transcript)
52
(No Transcript)
53
HERPES GESTATIONALIS

• non viral auto immune
• 21-28 weeks of pregnancy, 1st post natal
• Severe pruritis with urticaria, wheals
• Peri umbilical, lower abdomen, thigh
• Rarely mucosa
• Recurs with OCP, pregnancies, premenstrually

54

• Early urticated lesions show marked edema of
  papillary dermis with foci of eosinophilic
  spongiosis.
• Blister is subepidermal with split at lamina
  lucida.
• DIF linear deposition of C3 and IgG at basement
  membrane zone. Split skin binding at epidermal
  side of the blister.

55
EPIDERMOLYSIS BULLOSA AQUISITA

• Acquired autoimmune
• Trauma induced sub epidermal blistering
• Mucosal lesions

56

• Two forms 1. Bullous pemphigoid like eruption
  heavy inflammatory infiltrate mainly neutrophils
  and lymphocytes., heals with scarring,
  mechanobullous type, dystrophic nails
• 2.classical form with sparse infiltrate.
• DIF Linear C3 deposition at basement membrane
  IgG in some cases.
• Salt split Abs bind to lamina densa (type V11
  collagen) and hence seen at floor of blister.

57
(No Transcript)
58
(No Transcript)
59
BULLOUS SLE

• Three histological patterns 1.striking basal
  cell vacuolization with subepidermal blister
  formation. 2.vasulitis with subepidermal blister
  formation. 3. dermatitis herpetiformis like
  lesion.
• Neutrophils prominent in blister cavity and
  superficial dermis.
• DIF IgG and C3 at basement membrane zone
  (linear or granular band like ).
• Salt split localization at floor.

60

• Treatment
• Steroids
• Dapsone
• Immunosuppresive therapy

61
(No Transcript)
62
(No Transcript)
63
DERMATITIS HERPETIFORMIS

• Prutitic , chronic, recurrent, papulovesicular
  lesions extensors, buttocks , shoulders
• Gluten sensitivity
• HLA-B8
• 20-55 years
• MC males
• Oral lesions
• Provocation of lesions with iodides

64

• Typically seen in erythematous skin adjacent to
  the early blisters.
• Characteristic dermal papillary neutrophilic
  microabscesses which separate the tips of
  papillae from epidermis to form multilocular
  blisters.
• Papillary dermis beneath intense infiltrate of
  neutrophils and some eosinophils

65
(No Transcript)
66
(No Transcript)
67
(No Transcript)
68
(No Transcript)
69
IMMUNOFLOURESCENCE

• DIF Granular IgA deposition in papillary dermis
  in both lesional and perilesional skin.
• IgA is exclusively IgA1 , both monomeric and
  polymeric with J chain and secretory components ,
  associated with microfibrils.
• IIF Antiendomysial antibodies (smooth muscle )
  , antireticulin , antigliadin antibodies.
• Antibodies against Trans-glutaminase II.

70
(No Transcript)
71

• Treatment
• Dapsone 100-200 mg/day
• Gluten free diet

72
LINEAR IgA DERMATOSES

• Two types 1.adult linear IgA dermatoses.
  2.chronic benign bullous dermatoses of childhood.
• Adult similar to dermatitis herpetiformis
  i.e.papillary neutrophilic abscesses or
  neutrophils along dermoepidermal junction.
• Children string of pearl appearance.-urticarial
  plaques blistering at edge

73
(No Transcript)
74
IMMUNOFLOURESCENCE

• DIF linear deposition of IgA along basement
  membrane zone.
• Salt split at lamina lucida majority bind to
  upper part of blister , few combined and few to
  lower .
• IIF more positivity in children.
• Drug induced most common to vancomycin ,
  diclofenac , lithium and captopril.

75
(No Transcript)
76
(No Transcript)
77
Disease Direct IMF Isotype Target antigens Antigens Location
Pemphigus vulgaris Intercell-ular IgG, IgM Desmoglein3 130 Desmosomes
Vegetans Intercell-ular IgG Desmoglein1 160 Desmosomes
Foliaceus Intercell-ular IgG Desmoglein1 160 Desmosomes
Paraneoplastic pemphigus Intercell-ular and subepidermal IgG plakins 230,250 Desmosomes,BMZ
78
Disease Direct IMF Isotype Binding to split skin Target Antigens Location Structure
Bullous Pemphigoid Linear BMZ IgG Epidermal BP230 BP180 Hemidesmosome Dense plaque
Mucous membrane pemphigoid Linear BMZ IgG Epidermal BP180, BP230 Lamina lucida Anchoring Filament
Pemphigoid gestationis Linear BMZ IgG Epidermal BP180, BP230 Hemidesmosome Dense plaque
Linear IgA disease Linear BMZ IgA Epidermal Dermal BP180 Collagen VII Hemidesmosome
Epidermolysis bullosa acquistia Linear BMZ IgG Dermal Collagen VII Lamina Densa Anchoring Fibril
Bullous SLE Linear BMZ IgG,IgA Dermal Collagen VII Lamina Densa Anchoring Fibril
79
Linear IgA disease Linear BMZ IgA Epidermal Dermal BP180 Collagen VII Hemidesmosome
Epidermolysis bullosa acquistia Linear BMZ IgG Dermal Collagen VII Lamina Densa Anchoring Fibril
Bullous SLE Linear BMZ IgG,IgA Dermal Collagen VII Lamina Densa Anchoring Fibril
80

• THANK YOU