Immunobullous Disorders😊

Immunobullous Disorders

Introduction

• Vesicles and bullae from immune process
• Mainly pemphigus and pemphigoid groups

Mechanism

• Antibodies target:
• Keratinocyte connections (desmosomes)
• Epidermis-dermis link (basement membrane zone)

• Weakening leads to:
• Separation
• Fluid accumulation:
• Vesicles
• Bullae

Classification

• Intraepidermal: Split within epidermis (between keratinocytes)

• Subepidermal: Split at basement membrane zone

Intraepidermal Disorders (Pemphigus Group)

• Cause: Keratinocyte separation

• Structures affected: Desmosomes (complex structures in stratum spinosum)
• Components: desmoplakins, desmogleins, desmocollins

Types based on Antigen

Desmoglein Compensation Theory

• Mechanism: Presence of Dsg1 & Dsg3 affects lesion distribution
• Compensation occurs if both present at a site.

• Tissue Dsg distribution:
• Skin = Dsg1
• Dsg1 throughout (more in upper)
• Dsg3 in lower layers only
• Mucous membranes = Dsg3
• Predominantly Dsg3 > Dsg1

Antibody effects:

Pemphigus Vulgaris (Common Type)

• Mnemonic:
• Vulgur base (suprabasal split) & oral (oral lesions) → Dessi (desmoglein) girl on Net (Fish net pattern) → Kandapo tomb (tomb stone app) ayi
• Vulgur → spread (bulla spread sign) via nikkar (nikolsky sign)

Antigen: 

• Primarily Dsg3 > Dsg1

Clinical Features:

• Mucosal:
• Almost always present (oral, genital)
• Non-healing, painful, erythematous erosions
• Oral bullae rupture quickly

• Skin:
• Split: Suprabasal
• Flaccid, clear-fluid bullae, spread
• Rupture in 3-4 days (Leaves → erosions/crusting)
• Bullae usually not painful (oral lesions are)

• Sites: 
• Trunk, flexures; any area

Treatment

• Pulse steroids

Pemphigus Foliaceus

• Antigen: Dsg1 only

Clinical Features:

• Mucosal: 
• Absent (Dsg3 compensation)

• Skin:
• Split: Subcorneal (just below the stratum corneum)
• No visible bullae (very fragile)
• Crusted erosions in seborrheic distribution

Pemphigus Differentiation Table

Diagnostic Tests for Pemphigus Group:

Nikolsky's Sign:

• Shearing force near bulla/erosion causes skin to split

• Positive in intraepidermal disorders

• Negative in subepidermal disorders

• Monitors disease activity

True Nikolsky:

• Acantholysis
• SSSS - Dsg1 antigen
• Pemphigus Vulgaris

Pseudo Nikolsky:

• SJS/TEN due to epidermal necrosis

False Nikolsky:

• Subepidermal cleavage when pulling blister roof

Bulla Spread Sign:

• Pressure on small bulla spreads it peripherally

Uniform/dome-shaped in

• subepidermal disorders → BP

Angular spread in

• intraepidermal disorders → PV

Tzanck Smear:

• Acantholysis:
• Keratinocytes separate
• Separated cells: Acanthocytes / Acantholytic cells / Tzanck cells

• Smear shows
• Multinucleated Giant cell
• Peripheral cytoplasm condensation

Histopathology/Biopsy:

Pemphigus Foliaceus:

• Subcorneal split

Pemphigus Vulgaris:

• Suprabasal split

• Acantholytic cells present

• "Row of tombstone" appearance of basal cells (Pemphigus Vulgaris)

• Some inflammatory cells

Direct Immunofluorescence (DIF):

• Gold standard test

• Antigen-antibody binding between keratinocytes

• Typical "fishnet" fluorescence

Variants of Pemphigus:

• Endemic Pemphigus Foliaceus (Wildfire/Fogo Selvagem):
• Localised to South America (e.g., Brazil, Colombia)
• Aggravating factor: Arthropod bite (blackfly, Simuliidae)
• Predominantly head and neck
• No mucosal involvement
• Histologically/immunologically identical to sporadic Pemphigus Foliaceus

• Paraneoplastic Pemphigus:



• Associated with neoplasm (most common: Non-Hodgkin's lymphoma)
• Multiple antigens (Dsg1&3, desmoplakin, envoplakin, periplakin, BP230)
• Most severe type of pemphigus
• Intraepidermal and subepidermal bullae, lichenoid lesions
• Involvement of all mucosas
• Anhalt’s criteria for diagnosis
• Severe, extensive, paronychia may be present
• Mnemonic: Mothathil (all involved) Halt (anhalt) ayi → NH il (NHL)

• IgA Pemphigus:



• Antigen: Desmocollin
• Circinate lesions (annular, circular vesicles/bullae)
• Mnemonic: A (IgA) → Callgirl (desmocollin) → Circumcised

Treatment for Pemphigus Group Disorders:

• Steroids (daily/pulse)

• Adjuvants/Immunosuppressants: (started with steroids, then weaned)
• Azathioprine
• Mycophenolate mofetil
• Cyclophosphamide
• Dapsone (for IgA Pemphigus)

• Newer Agent: Rituximab (anti-CD20 biological)

• Lichen Planus and Pemphighus has similar treatment

Subepidermal Disorders (Pemphigoid Group & Others)

• General Characteristics:
• Tense blisters
• Nikolsky's sign is negative

Dermo-Epidermal Junction (DEJ) Antigens:

Salt Split Test:

• Tissue under 1 molar NaCl, splits at lamina lucida

• Differentiates



1. Bullous Pemphigoid (BP)
• Hemidesmosome
• Immunofluorescence on roof of split
2. Epidermolysis Bullosa Acquisita (EBA)
• Sublamina Densa
• Immunofluorescence on floor of split

Important Antigens and Associated Disorders:

Order of Disorders from Top to Bottom (Level of Split/Antigen):

• Mnemonic: FIRST WE PRAY THEN CAN EAT

F	Pemphigus Foliaceus	Dsg 1
W	Pemphigus Vulgaris	Dsg 3 >> 1
P	Bullous Pemphigoid	BP 180/ BP 230
Can	Cicatricial Pemphigoid	BP 180
Eat	EBA /Bullous SLE	Collagen 7

Bullous Pemphigoid (Prototype)

• Buzzword:
• Tense, Linear IgG, C3

• Mnemonic:
• “goiD, Dermatitis herp = deep”
• Bull () with headset (headset like cell → eosinophil infiltration) → deshyam vann
• Line (linear deposit of IgG and C3) varachitt → Hemisection (hemidesmosome) aakki
• Nicotine () vachitt → 4 piece (tetracycline) aaki → ennnitt Dab (dapsone) cheyth

• Antigens: BP antigen 1 (BP 230) and BP antigen 2 (BP 180)

• Bulla Type: Subepidermal bulla

Characteristic Features:

• Preceded by itchy urticarial lesions (pre-bulla stage)

• Eosinophil infiltration

• Seen in elderly (60-80 years)

• Tense, hemorrhagic bulla on trunk and limbs

• Heal with crusted erosions

• Mucosal Involvement: Not common (30%)

• Nikolsky's Sign: Negative

• Bulla Spread Sign: Positive (uniform or round spread)

• Tzanck Smear: Negative

Histopathology/Biopsy:

• Subepidermal split

• Significant inflammatory infiltrate, mainly eosinophils

Direct Immunofluorescence (DIF):

• No fishnet pattern

• Linear deposition of IgG and C3 along DEJ

Treatment for Bullous Pemphigoid:

• Pulse steroids

• Mild cases: Topical corticosteroids

• Severe cases: Oral corticosteroids

• Other options:
• Dapsone >>>
• tetracyclines
• nicotinamides
• immunosuppressants

Differentiation: Pemphigus and Pemphigoid

Pemphigoid Gestationis (Herpes Gestationis):

• Bullous pemphigoid in pregnancy
• (misnomer, no herpes)

• Also seen in females with trophoblastic tumors

• "Herpes gestation (HG) factor" binds to BP-180

• Antibody: C3 > IgG

• Classical area: Periumbilical

• Initially itchy urticarial lesions, then tense bullae

• Treatment: Steroids (safest in pregnancy)

Linear IgA Disease (LAD):

• Antibody: IgA

• Antigens: BP 180 and LAD1

• Characteristic:
• "String of pearls" appearance
• tense bullae in string configuration
• Vesicles are arranged in an annular pattern around lesion

• Primarily adults

• DIF shows linear IgA deposition

• Treatment: Dapsone

Chronic Bullous Disease of Childhood (CBDC/CLDC):

• Similar to linear IgA disease in children

• "String of pearls" appearance

• Common perioral involvement

• Rx: Dapsone

Dermatitis Herpetiformis (DH):

• Subepidermal, but not pemphigoid group

• Antigen: Epidermal tissue transglutaminase

• Important Features:
• No typical vesicles or bullae
• A/w gluten-sensitive enteropathy
• HLA association: DQ2 and BA

• Cutaneous Features:
• Mainly extensor surfaces
• Itchy, excoriated papules (persistent, not like eczema/scabies)

Biopsy:

• Papillary tip microabscesses

DIF:

• Papillary tip immunofluorescence

Treatment:

• Avoid gluten

• Dapsone

• Allowed: Maize, Rice

• Gluten free pure uncontaminated Oats is safest

Gluten Avoidance:

• Avoid: Barley, Rice, Oats, Wheat