Hemidesmosomes Show Abnormal Association with the Keratin Filament Network in Junctional Forms of Epidermolysis Bullosa

Junctional epidermolysis bullosa is a group of hereditary bullous disorders resulting from defects in several hemidesmosome-anchoring filament components. Because hemidesmosomes are involved not only in keratinocyte-extracellular matrix adherence, but also in normal anchorage of keratin intermediate filaments to the basal keratinocyte membrane, we questioned whether this intracellular function of hemidesmosomes was also perturbed in junctional epidermolysis bullosa. We used quantitative electron microscopic methods to assess certain morphologic features of hemidesmosome–keratin intermediate filaments interactions in skin from normal subjects (n = 11) and from patients with different forms of junctional epidermolysis bullosa (n = 13). In addition, skin from patients with autosomal recessive epidermolysis bullosa simplex with plectin defects (n = 3) or with autosomal recessive dystrophic epidermolysis bullosa (n = 4) were included as controls. Values were expressed as a percentage of the total number of hemidesmosomes counted. In normal skin 83.3% ± 3.3 (SEM) hemidesmosomes were associated with keratin intermediate filaments and 90.1% ± 1.9 had inner plaques. In Herlitz junctional epidermolysis bullosa (laminin 5 abnormalities, n = 4) these values were reduced to 45.3% ± 11.5 (p < 0.001; analysis of variance) and 50.3% ± 12.8 (p < 0.001), respectively. In junctional epidermolysis bullosa with pyloric atresia (α6β4 abnormalities, n = 3) the values were also reduced [41.8% ± 7.0 (p < 0.001) and 44.5% ± 5.7 (p < 0.001), respectively]. In the non-Herlitz group (laminin 5 mutations, n = 3) the counts were 66.7% ± 7.1 (p > 0.05) and 70.5% ± 8.5 (p < 0.05), and in skin from patients with bullous pemphigoid antigen 2 mutations (n = 3) the counts were 54.3% ± 13.8 (p < 0.01) and 57.1% ± 13.9 (p < 0.01). In epidermolysis bullosa simplex associated with plectin mutations the values were 31.9% ± 8.9 (p < 0.001) for keratin intermediate filaments association and 39.9% ± 7.1 (p < 0.001) for inner plaques. Findings in recessive dystrophic epidermolysis bullosa patients’ skin were indistinguishable from normal control skin with inner plaques (90.5% ± 2.5) and keratin intermediate filaments attachment (86.3% ± 2.1). These findings suggest that the molecular abnormalities underlying different forms of junctional epidermolysis bullosa appear to affect certain critical intracellular functions of hemidesmosomes, such as the normal connections with keratin intermediate filaments. This may have important implications for the maintenance of basal keratinocyte integrity and resilience in junctional epidermolysis bullosa