Junctional basement membrane anomalies of skin and mucosa in lipoid proteinosis (hyalinosis cutis et mucosae)

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Summary

Background

Excessive basement membrane (BM) deposition in skin and mucosa is characteristic for lipoid proteinosis (LP; hyalinosis cutis et mucosae), an inherited disease caused by extracellular matrix protein 1 (ECM1) mutations. According to ultrastructure there are striking differences between junctional and microvascular BM.

Objective

Distinct analysis of the junctional zone in epidermis and oral mucosa, contrasting concentric BM arrays in the microvasculature; evaluation of impact on epithelial histogenesis and differentiation, and specifically on adhesion structures to BM (hemidesmosomes).

Methods

LP-epithelia were analyzed for alterations in differentiation, BM composition and texture, and hemidesmosomal components by indirect immunofluorescence (IIF), electron microscopy (EM), and immunoelectron microscopy (ImEM).

Results

Most striking was the irregular deposition of collagen IV and VII, BM-laminin, and laminin-5 at the junctional zone, accompanied by lamellate or punctuated structures below BM (IIF), whereas integrin α6β4 and bullous pemphigoid antigen-1 and -2 (BPAG-1/-2) were regularly aligned. Also integrins α2β1 and α3β1 remained restricted to the epidermal basal layer, while the tissue-specific differentiation markers keratin K1/10 (mucosa, additionally K4/13) appeared delayed indicating mild hyperplasia, further confirmed by focal K6/16 expression. Ultrastructure (EM) disclosed abundance of extended basal cell protrusions and junctional aberrations like exfoliating excessive BM material. Hemidesmosomes were complete, but ImEM indicated weakened interactions between their components (BPAG-1, -2, and HD1). Confirming IIF, collagen IV and VII, and laminin-5 appeared extensively scattered, the latter two probably remaining associated.

Conclusions

Subtle defects in anchorage assembly, spanning the entire BM zone, apparently compromise epithelial-matrix adhesion, which may provoke (mechanical stress-induced) erroneous BM repair.

Introduction

Lipoid proteinosis (LP; hyalinosis cutis et mucosae; OMIM 247100) is an autosomal recessive condition displaying multiple systemic manifestations. Mainly affected are skin, mucosa of the upper aerodigestive tract, and the local microvasculature. Typical clinical symptoms are a hoarse voice, itching bullous skin eruptions healing with atrophic scars, and generalized yellowish infiltrations of skin and mucosae (reviewed by [1], [2]). Main characteristics of LP-histology are hyaline deposits within the interstitial connective tissue and abnormal small blood vessels with extensively thickened vessel walls. Common ultrastructural features are irregular multiplications of basement membrane (BM) structures at the dermo-epidermal junction and onion shell-like BM arrays around microvessels ([3], [4] and references therein). Accordingly, excessive deposition of BM constituents, like type IV collagen, BM-laminin [5] and other major BM molecules [4], has been found by indirect immunofluorescence (IIF). The tissue-specific defects in LP-tissue may relate to differences in composition and cellular source of BM molecules. Whereas vascular endothelial cells produce their entire BM complement, for the junctional BM keratinocytes synthesize all major components except nidogen, which is provided by the neighboring fibroblasts. Crucial for firm anchorage in skin are type VII collagen and epithelial-specific laminin-5, both interconnected within the BM zone [6], [7]. The markedly enhanced type IV collagen synthesis in fibroblast cultures, derived from LP-skin [8], could imply a particular role of this cell type for the junctional aberrations in the disease.

Mutations in the extracellular matrix protein 1 (ECM1) are the common cause of LP [2], [9], [10]. While the type of mutation, leading to partial or complete ECM1 loss-of-function (depending on the affected splice variants), largely determines the clinical symptoms; there is considerable variation among patients with identical mutations [9], [10]. Thus, the individual microenvironment modulates the degree of disturbance in the balance of BM synthesis and turnover, presumably involving interactions with other matrix components. In addition, the differences between BM anomalies of skin or mucous epithelia and on the other hand the microvasculature raise further questions for the tissue-specific function of ECM1 in regulatory events and molecular interactions.

In our biopsy material from LP-patients the overall epithelial structure (skin, mucosa) appeared largely normal, besides some lesions in exposed areas and general mild hyperplasia. The existence of multiple BM arrays, seen by EM, was corroborated by large deposits of nidogen, BM-laminin, type IV collagen, and perlecan (IIF, in part immuno-EM), consisting with previous reports on LP-skin [5] and its microvasculature especially [4]. Herein we have focused on the correlation of BM alterations with the fate of junctional complexes, not explicitly addressed in earlier studies. While in our specimens molecular arrays responsible for dermal anchorage of BM (type VII collagen, laminin-5) were more visibly affected than the intracellular hemidesmosomal constituents, both together may alter adhesive properties and thus, provoke erroneous, unscheduled BM repair processes.

Section snippets

Biopsy material

Biopsies from skin or small flaps of oral mucosa removed at tooth extraction were taken with LP-patients’ (parents’) consent on occasion of medical examination. As common clinical symptoms, patients were suffering from pronounced hoarseness, infiltrations within the oral cavity and the larynx, and skin lesions at exposed areas like elbow, forearm, and back of hands. Patient 1 was a 28-year-old Turkish female, one of two affected siblings [3]. Biopsy material from axilla and face (near the

Clinical picture and histopathology (light microscopy)

Comparable to the other patients, the affected skin of patient 2 (Fig. 1a) revealed scarring (elbow) and small reddish papules (forearm, and back of the hand). In addition, physical examination had disclosed long-standing varicella-like atrophic scars and hyperpigmentation on face and limbs. Histological sections of LP-skin (Fig. 1b) and oral mucosa (shown elsewhere [4]) generally revealed a mild epithelial hyperplasia and serrated contours at the cell–matrix junction. Numerous microvessels

Discussion

Irregular deposition and accumulations of basement membrane (BM) represent special features of lipoid proteinosis (LP), affecting skin, mucous epithelia and especially small blood vessels. This could be due to lack of feedback control in synthesis, processing, secretion or assembly but also reduced turnover. The primary cause are mutations in the ECM1 gene, abolishing ECM1 synthesis or leading to partial loss-of-function [1], [2], [9], [10] and accordingly autoantibodies against ECM1 (lichen

Acknowledgments

We like to thank Anke Wollschläger, Regina Beck, and Renate Ayubi for skillful technical assistance as well as the photo department at the DKFZ for continuous support. This investigation was in part supported by the Deutsche Forschungsgemeinschaft (D.B.) and an industrial grant (N.M.; Aventis Pharma Deutschland/Aventis-Sanofi).

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