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• W2071207381 abstract "extracellular matrix epidermal nerve fiber junctional epidermolysis bullosa mast cell protein gene product 9.5 peripheral nervous system recessive dystrophic epidermolysis bullosa subepidermal neural plexus TO THE EDITOR Chronic pain and itch are substantial quality-of-life obstacles for patients with the genetic skin disorder recessive dystrophic epidermolysis bullosa (RDEB). RDEB is caused by loss-of-function mutations in the anchoring fibril protein type VII collagen. Extreme skin fragility leads to chronic wounds and inflammation that are accompanied by significant pain and itch. Itchy skin has been consistently rated as the highest burden in RDEB patients (van Scheppingen et al., 2008van Scheppingen C. Lettinga A.T. Duipmans J.C. et al.Main problems experienced by children with epidermolysis bullosa: a qualitative study with semi-structured interviews.Acta Derm Venereol. 2008; 88: 143-150Crossref PubMed Scopus (82) Google Scholar; Danial et al., 2014Danial C. Adeduntan R. Gorell E.S. et al.Prevalence and characterization of pruritus in epidermolysis bullosa.Pediatr Dermatol. 2014https://doi.org/10.1111/pde.12391Google Scholar), and another study found that 93% of dystrophic EB patients experienced itch symptoms (Snauwaert et al., 2014Snauwaert J.J. Yuen W.Y. Jonkman M.F. et al.Burden of itch in epidermolysis bullosa.Br J Dermatol. 2014; 171: 73-78Crossref PubMed Scopus (38) Google Scholar). Compounding the burden of itching in RDEB, scratching can be associated with new lesions and secondary infection, exacerbating the disease’s symptoms and undermining treatment. The second-highest burden in RDEB is pain (van Scheppingen et al., 2008van Scheppingen C. Lettinga A.T. Duipmans J.C. et al.Main problems experienced by children with epidermolysis bullosa: a qualitative study with semi-structured interviews.Acta Derm Venereol. 2008; 88: 143-150Crossref PubMed Scopus (82) Google Scholar; Danial et al., 2014Danial C. Adeduntan R. Gorell E.S. et al.Prevalence and characterization of pruritus in epidermolysis bullosa.Pediatr Dermatol. 2014https://doi.org/10.1111/pde.12391Google Scholar). Fifty percent of RDEB patients rated their daily pain level as at least a 5 on a scale of 0–10, and only 5% of patients were without pain (Goldschneider & Lucky, 2010Goldschneider K.R. Lucky A.W. Pain management in epidermolysis bullosa.Dermatol Clin. 2010; 28 (ix): 273-282Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Pain symptoms in RDEB are often extreme and resistant to first-line analgesics. More potent opioid analgesics are effective against moderate to severe pain, but can exacerbate itch (Goldschneider & Lucky, 2010Goldschneider K.R. Lucky A.W. Pain management in epidermolysis bullosa.Dermatol Clin. 2010; 28 (ix): 273-282Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), making them potentially unbearable or unacceptable treatments. Here, we describe distinct peripheral nerve morphology and mast cell accumulation in RDEB skin. These findings are an important step toward understanding the mechanisms of pain and itch in dystrophic EB, which should point the way toward more effective analgesics and antipruritics. We first characterized the epidermal nerve fiber (ENF) density, a widely used metric for peripheral neuropathy, in six RDEB patients in comparison with six healthy control subjects (all samples were obtained with written, informed patient consent, following a protocol approved by the Institutional Review Board of the University of Minnesota and University of Puerto Rico, and compliant with the Helsinki Guidelines). All RDEB patients rated itch and pain as at least a 4 (“very bothersome”) on the 5-point Likert scale (Danial et al., 2014Danial C. Adeduntan R. Gorell E.S. et al.Prevalence and characterization of pruritus in epidermolysis bullosa.Pediatr Dermatol. 2014https://doi.org/10.1111/pde.12391Google Scholar), with an average itch rating of 4.5±0.55 and an average pain rating of 4±0 (Supplementary Tables SI-II online). Skin biopsies taken from perilesional sites on individuals with RDEB or from healthy controls were stained with antibodies against protein gene product 9.5 (PGP9.5), a pan-neuronal marker commonly used to identify ENFs (Kennedy et al., 1996Kennedy W.R. Wendelschafer-Crabb G. Johnson T. Quantitation of epidermal nerves in diabetic neuropathy.Neurology. 1996; 47: 1042-1048Crossref PubMed Scopus (366) Google Scholar; Chiang et al., 2011Chiang L.Y. Poole K. Oliveira B.E. et al.Laminin-332 coordinates mechanotransduction and growth cone bifurcation in sensory neurons.Nat Neurosci. 2011; 14: 993-1000Crossref PubMed Scopus (48) Google Scholar). PGP9.5-positive nerves within the epidermis were traced in three-dimensional confocal images (Kennedy et al., 1996Kennedy W.R. Wendelschafer-Crabb G. Johnson T. Quantitation of epidermal nerves in diabetic neuropathy.Neurology. 1996; 47: 1042-1048Crossref PubMed Scopus (366) Google Scholar). Download .pdf (.18 MB) Help with pdf files Supplementary Material RDEB patients had significantly fewer ENFs compared with healthy control subjects. Epidermal innervation decreases with age (Panoutsopoulou et al., 2014Panoutsopoulou I.G. Luciano C.A. Wendelschafer-Crabb G. et al.Epidermal innervation in healthy children and adolescents.Muscle Nerve. 2014https://doi.org/10.1002/mus.24329Google Scholar); thus, ENF density for each patient was plotted against his or her age. As epidermal separation during tissue processing is common in RDEB skin, we confirmed that age-dependent ENF densities were reduced in RDEB skin both when considering only unblistered skin regions (Figure 1a) and when including all regions (Figure 1b). All RDEB patients also had marked dermal nerve disorganization. Two patients lacked more than 75% of nerve density in the subepidermal neural plexus (SNP) (Figure 1c) and all patients lacked normal SNP morphology (Figure 1d) and bundled nerve structures in the deep dermis fibers (Supplementary Figure S1 online). Total PGP9.5 immunofluorescence in the dermis of RDEB patients was significantly reduced over control skin both as a group (Figure 1e) and as a function of age (Supplementary Figure S2 online). The critical next step is to understand how these morphological peripheral nervous system (PNS) changes arise and impact a patient’s sensory experience. In atopic dermatitis, lesional keratinocytes make more nerve growth factor and less of the axonal repellant semaphorin 3A, causing greater ENF densities and itch sensitivity (Tominaga & Takamori, 2014Tominaga M. Takamori K. Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications.J Dermatol. 2014; 41: 205-212Crossref PubMed Scopus (141) Google Scholar). Although other pruritic and painful conditions have subnormal numbers of ENFs (Kennedy et al., 1996Kennedy W.R. Wendelschafer-Crabb G. Johnson T. Quantitation of epidermal nerves in diabetic neuropathy.Neurology. 1996; 47: 1042-1048Crossref PubMed Scopus (366) Google Scholar; Maddison et al., 2011Maddison B. Parsons A. Sangueza O. et al.Retrospective study of intraepidermal nerve fiber distribution in biopsies of patients with nummular eczema.Am J Dermatopathol. 2011; 33: 621-623Crossref PubMed Scopus (24) Google Scholar; Schuhknecht et al., 2011Schuhknecht B. Marziniak M. Wissel A. et al.Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis skin as a potential sign of subclinical cutaneous neuropathy.Br J Dermatol. 2011; 165: 85-91Crossref PubMed Scopus (90) Google Scholar; Caro & Winter, 2014Caro X.J. Winter E.F. Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications.Arthritis Rheumatol. 2014; 66: 1945-1954Crossref PubMed Scopus (86) Google Scholar), the mechanisms are less well understood. Extended periods of inactivity and systemic opioid analgesia in RDEB may be factors. Abnormal innervation could be associated with fibrotic changes present in RDEB skin. Itching is common in fibrotic scar tissue, and, although increased innervation has been described in hypertrophic scars and animal models (Zhang & Laato, 2001Zhang L.Q. Laato M. Innervation of normal and hypertrophic human scars and experimental wounds in the rat.Ann Chir Gynaecol. 2001; 90: 29-32PubMed Google Scholar; Liang et al., 2004Liang Z. Engrav L.H. Muangman P. et al.Nerve quantification in female red Duroc pig (FRDP) scar compared to human hypertrophic scar.Burns. 2004; 30: 57-64Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar), another study found fewer ENFs in itchy keloids (Tey et al., 2012Tey H.L. Maddison B. Wang H. et al.Cutaneous innervation and itch in keloids.Acta Derm Venereol. 2012; 92: 529-531Crossref PubMed Scopus (14) Google Scholar). Alternatively, the epidermal hypoinnervation in RDEB, in combination with the lack of visible scarring at the biopsy sites, might be indicative of an intrinsic axonal guidance dysfunction. In support of this hypothesis, proteomic analysis of RDEB extracellular matrix (ECM) has revealed decreased matrix metalloproteinase-2 activity (Kuttner et al., 2013Kuttner V. Mack C. Rigbolt K.T. et al.Global remodelling of cellular microenvironment due to loss of collagen VII.Mol Syst Biol. 2013; 9: 657Crossref PubMed Scopus (82) Google Scholar), which is involved in neuronal growth cone formation (Tominaga et al., 2009Tominaga M. Kamo A. Tengara S. et al.In vitro model for penetration of sensory nerve fibres on a Matrigel basement membrane: implications for possible application to intractable pruritus.Br J Dermatol. 2009; 161: 1028-1037Crossref PubMed Scopus (24) Google Scholar), and decreased basement membrane proteins, including several laminin chains. Laminin-332, the protein absent in the junctional form of EB (JEB), has been shown to inhibit nerve branching as well as neuronal graded potentials in vitro, which is consistent with an increase in ENFs in JEB patients (Chiang et al., 2011Chiang L.Y. Poole K. Oliveira B.E. et al.Laminin-332 coordinates mechanotransduction and growth cone bifurcation in sensory neurons.Nat Neurosci. 2011; 14: 993-1000Crossref PubMed Scopus (48) Google Scholar). Therefore, perturbations in ECM homeostasis caused by loss of type VII collagen may dictate sensory pathology in a systemic, developmental manner rather than through secondary skin injury. Cutaneous mast cells (MCs) are significant sources of neurotrophic factors such as nerve growth factor, and MC-derived tumor necrosis factor-α was found to be required for epidermal hyperinnervation in a rodent model of atopic dermatitis (Kakurai et al., 2006Kakurai M. Monteforte R. Suto H. et al.Mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice.Am J Pathol. 2006; 169: 1713-1721Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). MC degranulation alone can trigger pain responses (Drummond, 2004Drummond P.D. The effect of cutaneous mast cell degranulation on sensitivity to heat.Inflamm Res. 2004; 53: 309-315Crossref PubMed Scopus (21) Google Scholar; Chatterjea et al., 2012Chatterjea D. Wetzel A. Mack M. et al.Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice.Biochem Biophys Res Commun. 2012; 425: 237-243Crossref PubMed Scopus (51) Google Scholar), and MCs are the most significant source of histamine and other pruritic compounds such as tryptase. To consider their role in RDEB, we quantified MCs in patient biopsies using tryptase immunostaining. Four out of six RDEB biopsies contained significantly more MCs, especially in the upper dermis (Figure 2a and b), and half also contained higher amounts of free MC granules (Figure 2c), which were more localized to the lower dermis (Figure 2a), in comparison with control skin. Given these findings, an MC stabilizer such as sodium cromolyn (sodium cromoglycate) may be effective for treatment of pain or itch in some patients. In summary, all RDEB patients in this study had significant peripheral nerve pathology, and 67% (4/6) had increased dermal MC numbers and degranulation. To our knowledge both the pattern of PNS pathology and MC activity in RDEB have not been reported previously, and can serve as a platform for rational identification of effective analgesic and antipruritic treatments in a disease for which they are desperately needed. Teresa Kivisto Bekkala, Meghan Flesher, and Marna Ericson provided valuable assistance with sample collection and management. This work was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers R01 AR059947-01A1 and R01 AR063070. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Department of Defense (USAMRAA/DOD Department of the Army W81XWH-12-1-0609 and USAMRAA/DOD W81XWH-10-1-0874), DebRA, the Jackson Gabriel Silver Fund, the Epidermolysis Bullosa Medical Research Fund, and the Children‘s Cancer Research Fund, Minnesota. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid" @default.
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• W2071207381 title "Peripheral Neuro-Immune Pathology in Recessive Dystrophic Epidermolysis Bullosa" @default.
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