Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients
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Formalin-fixed, paraffin-embedded skin tissue sections were collected from a matched cohort of 63 fibromyalgia syndrome (FMS) patients and 49 volunteers from the general population with both alpha1-antitrypsin (AAT) normal and deficiency variants. These tissues were examined for the expression of the broad-spectrum inhibitor AAT, the serine proteinases elastase and tryptase, the proinflammatory cytokines MCP-1 and TNFα, the endothelium biomarker VEGF, and the inflammation/nociception-related receptor PAR2. The most relevant finding of the study was a significantly increased number of mast cells (MCs) in the papillary dermis of all FMS patients (greater than or equal to five to 14 per microscopic high power field) compared to zero to one in controls (p < 0.001). MCs strongly stained with tryptase, AAT and PAR2 antibodies, exhibited a spindle-like shape and were uniformly distributed around blood vessels and appendages. MCP-1 and VEGF expressed weak/moderate positivity in most samples, with a higher expression in controls than in FMS patients (p < 0.001 and 0.051, respectively). No differences in elastase and TNFα were found between both groups. Moreover, no histological differences were found between samples from AAT deficiency and normal AAT phenotypes. Our results indicate that FMS is a MC-associated condition. MCs are present in skin and mucosal surfaces throughout the human body, and are easily stimulated by a number of physical, psychological, and chemical triggers to degranulate, releasing several proinflammatory products which are able to generate nervous peripheral stimuli causing CNS hypersensitivity, local, and systemic symptoms. Our findings open new avenues of research on FMS mechanisms and will benefit the diagnosis of patients and the development of therapeutics.
KeywordsAlpha 1-antitrypsin Fibromyalgia Mast cell Skin biopsy Tryptase
We would like to thank every patient and volunteer who participated in this study, providing us with their clinical data and biopsy samples. We also acknowledge the technical work for the preparation of the paraffin-embedded tissues samples by Dr. Francisco Domínguez and laboratory technicians at the Valle del Nalón Hospital, Asturias, Spain; and the immunohistochemical work performed by Ms. Mercedes Acha (Cabueñes Hospital, Gijón, Spain). Furthermore, we are indebted to Dr. Eleftherios P. Diamandis (Mount Sinai Hospital, Toronto) for sharing vital reagents and ideas for the completion of this work. Finally, we are grateful to Ms. Jimena Blanco Fueyo (UNESCO; MA/BA Université de Genève) for the English editing of this manuscript. This study has been endorsed by the Spanish National Health Institute Carlos III and the Biohealth Research Office (OIB) of the Principado de Asturias, Spain (IB and VC). KO is a recipient of an Alberta Heritage Foundation for Medical Research (AHFMR) Postdoctoral Fellowship for whom operating funds were provided by a grant to MDH by the Canadian Institutes of Health Research.
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