What is the classification of immunobullous disorders?

Classification of Immunobullous Disorders

Immunobullous disorders are classified into two major categories based on the level of blister formation: intraepidermal blistering diseases (pemphigus group) and subepidermal blistering diseases (pemphigoid group, epidermolysis bullosa acquisita, and dermatitis herpetiformis). 1, 2

Primary Classification Framework

The classification system uses a hierarchical "onion skin" approach that sequentially layers diagnostic information from basic to molecular levels 3:

Level 1: Site of Blister Formation

Intraepidermal Blistering Diseases (Pemphigus Group)

• Blisters form within the epidermis due to autoantibodies against desmosomal proteins including desmoglein 1, desmoglein 3, and plakin family members 4
• Characterized by acantholysis (loss of cell-to-cell adhesion) 2

Subepidermal Blistering Diseases

• Blisters form at or below the dermal-epidermal junction 1, 5
• This group includes:
  • Pemphigoid diseases (bullous pemphigoid, mucous membrane pemphigoid, linear IgA disease) 5
  • Epidermolysis bullosa acquisita 1
  • Dermatitis herpetiformis 2, 4

Level 2: Immunopathologic Characterization

For Subepidermal Diseases - Precise Localization:

• Bullous pemphigoid: Autoantibodies target BP180 (collagen XVII) and BP230 at the basement membrane zone, with linear IgG and C3 deposition on direct immunofluorescence 3, 6

• Epidermolysis bullosa acquisita: Autoantibodies bind to the dermal side on salt-split skin immunofluorescence, targeting collagen VII in the sublamina densa region 7

• Linear IgA disease: Linear IgA deposits along the basement membrane zone 5

• Dermatitis herpetiformis: Autoantibodies target transglutaminases 2 and 3, with granular IgA deposits in dermal papillae 4

Level 3: Molecular and Genetic Classification

For Inherited Epidermolysis Bullosa (Genetic Blistering Disorders):

The American Academy of Dermatology classifies inherited EB into four major types based on cleavage level 3, 8:

1. Epidermolysis Bullosa Simplex (EBS)

   • Suprabasal EBS: Blisters form in upper epidermal layers; mutations in transglutaminase 5, plakophilin 1, desmoplakin, or plakoglobin 3
   • Basal EBS: Blisters form within basal keratinocytes; mutations in keratins 5/14, plectin, BP230, exophilin 5, or kindlin-1 3

2. Junctional Epidermolysis Bullosa (JEB)

   • Blisters form within the lamina lucida of the basement membrane zone 3
   • Mutations in laminin-332, collagen XVII, α6β4 integrin, or α3 integrin 3, 8

3. Dystrophic Epidermolysis Bullosa (DEB)

   • Blisters form in the sublamina densa region (uppermost dermis) 3
   • Mutations in collagen VII (COL7A1 gene) 3, 8
   • Subdivided into dominant (DDEB) and recessive (RDEB) forms based on inheritance pattern 3

4. Kindler Syndrome

   • Mixed cleavage pattern at multiple levels within and beneath the basement membrane zone 3
   • Mutations in fermitin family homolog 1 (kindlin-1) 3

Diagnostic Algorithm for Classification

Step 1: Obtain perilesional skin biopsy for direct immunofluorescence - this is the diagnostic gold standard for autoimmune bullous diseases 4

Step 2: Determine blister level using:

• Direct immunofluorescence microscopy showing linear vs granular deposits and their location 3
• Salt-split skin immunofluorescence to distinguish roof-binding (epidermal side) vs floor-binding (dermal side) patterns 3, 7
• Transmission electron microscopy for precise ultrastructural localization in inherited forms 3

Step 3: Identify target antigens using:

• Indirect immunofluorescence on monkey esophagus and salt-split human skin 4
• ELISA for specific antigens (BP180, BP230, desmoglein 1/3) 3
• Immunofluorescence antigen mapping with monoclonal antibodies against basement membrane zone components 3

Step 4: For inherited forms, pursue molecular analysis:

• Immunohistochemistry to identify absent or reduced structural proteins 3, 8
• Genetic testing to identify specific mutations and inheritance pattern 3, 8

Critical Clinical Distinctions

Age and presentation patterns matter for classification:

• Bullous pemphigoid typically affects elderly patients with tense blisters on erythematous skin 3
• Inherited epidermolysis bullosa presents at birth or early childhood with skin fragility 8
• Drug-induced bullous pemphigoid should be suspected when symptoms begin weeks to months after starting medications like gliptins, furosemide, or spironolactone 6

Mucosal involvement helps narrow diagnosis:

• Extensive mucosal involvement suggests pemphigus vulgaris or mucous membrane pemphigoid 3
• Minimal mucosal involvement is typical of bullous pemphigoid 3

Scarring patterns provide diagnostic clues:

• Scarring occurs in dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita 3
• Absence of scarring suggests bullous pemphigoid or epidermolysis bullosa simplex 3

Common Diagnostic Pitfalls

Do not rely solely on clinical appearance - autoimmune bullous diseases overlap significantly in morphology and require immunopathologic confirmation 3

Ensure proper biopsy handling - direct immunofluorescence specimens must be snap-frozen in liquid nitrogen or transported in Michel's medium; saline transport requires processing within 24-48 hours 3

Consider drug-induced disease - obtain detailed medication history in all elderly patients presenting with bullous pemphigoid, as approximately 50% of drug-induced cases persist despite drug withdrawal and require standard treatment 6

Recognize that ELISA alone is insufficient - while BP180 ELISA has high sensitivity, false-positive results occur in 7.4% of cases; immunofluorescence studies remain the gold standard 3