Damage of cutaneous peripheral nervous system evolves differently according to the disease phase and subset of systemic sclerosis

Manneschi, Lidia Ibba; Rosso, Angela Del; Milia, Anna Franca; Tani, Akio; Nosi, D.; Pignone, Alberto Moggi; Generini, Sergio; Giacomelli, Roberto; Cerinic, M. Matucci

doi:10.1093/rheumatology/keh559

Cited by 15 publications

(24 citation statements)

References 21 publications

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“…In advanced dcSSc, telocytes are almost completely disappeared. Thus, as previously shown for the modifications of skin innervation and microcirculation , the progression in telocyte reduction occurs earlier and is more severe in dcSSc than in lcSSc. Moreover, this progressive reduction in telocytes occurs in parallel with the severity of their ultrastructural abnormalities.…”

Section: Discussionsupporting

confidence: 75%

Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis

Manetti

Guiducci

Ruffo

et al. 2013

J Cellular Molecular Medi

141

170

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Telocytes, a peculiar type of stromal cells, have been recently identified in a variety of tissues and organs, including human skin. Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease characterized by fibrosis of the skin and internal organs. We presently investigated telocyte distribution and features in the skin of SSc patients compared with normal skin. By an integrated immunohistochemical and transmission electron microscopy approach, we confirmed that telocytes were present in human dermis, where they were mainly recognizable by their typical ultrastructural features and were immunophenotypically characterized by CD34 expression. Our findings also showed that dermal telocytes were immunophenotypically negative for CD31/PECAM-1 (endothelial cells), α-SMA (myofibroblasts, pericytes, vascular smooth muscle cells), CD11c (dendritic cells, macrophages), CD90/Thy-1 (fibroblasts) and c-kit/CD117 (mast cells). In normal skin, telocytes were organized to form three-dimensional networks distributed among collagen bundles and elastic fibres, and surrounded microvessels, nerves and skin adnexa (hair follicles, sebaceous and sweat glands). Telocytes displayed severe ultrastructural damages (swollen mitochondria, cytoplasmic vacuolization, lipofuscinic bodies) suggestive of ischaemia-induced cell degeneration and were progressively lost from the clinically affected skin of SSc patients. Telocyte damage and loss evolved differently according to SSc subsets and stages, being more rapid and severe in diffuse SSc. Briefly, in human skin telocytes are a distinct stromal cell population. In SSc skin, the progressive loss of telocytes might (i) contribute to the altered three-dimensional organization of the extracellular matrix, (ii) reduce the control of fibroblast, myofibroblast and mast cell activity, and (iii) impair skin regeneration and/or repair.

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Section: Discussionsupporting

confidence: 75%

Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis

Manetti

Guiducci

Ruffo

et al. 2013

J Cellular Molecular Medi

141

170

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“…32 More recently, ultrastructural changes in nerve morphology have been noted to progress from early to late phases of scleroderma-associated peripheral neuropathy. 33 Although the prevalence of perineural inflammation in morphea (84%) may seem surprisingly high, this can be explained by the methodology adopted that we believe is one of the strengths of our study. If only routinely stained sections had been used, we would have identified perineural inflammation in 46 of the 80 cases (57.50%).…”

Section: Discussionmentioning

confidence: 83%

“…Perineural and intraneural infiltration by lymphocytes, plasma cells and mast cells have been observed along with changes involving mesenchymal elements of dermal nerves in morphea . More recently, ultrastructural changes in nerve morphology have been noted to progress from early to late phases of scleroderma‐associated peripheral neuropathy …”

Section: Discussionmentioning

confidence: 99%

Perineural inflammation in morphea (localized scleroderma): systematic characterization of a poorly recognized but potentially useful histopathological feature

2013

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The association between morphea and perineural inflammation has been reported sporadically but never studied systematically. To assess the prevalence and nature of perineural inflammation in various clinicopathologic stages of morphea and a cohort of other inflammatory dermatoses, 80 morphea and 36 control skin biopsies were studied using hematoxylin/eosin and S100 stains. Perineural inflammation was semiquantitatively analyzed (scored), which along with the pattern (concentric vs. marginal) and cellular composition was compared in the two groups. Perineural inflammation was identified in 84% and 61% of morphea and control cases, respectively. Examination of only routinely stained sections could still detect this feature in 58% of morphea and 33% of control biopsies. Mean perineural inflammation score in morphea (0.65) was significantly higher than in the control group (0.23) (p < 0.0001) and the inflammation tended to show a concentric pattern with plasma cell neurotropism. Intraneural inflammation was limited to four morphea cases. Although perineural inflammation is common in morphea, it is not unusual to find this feature in other inflammatory conditions. Nevertheless, perineural inflammation can serve as an important diagnostic adjunct in difficult cases of morphea if one considers its greater intensity, predominantly concentric pattern and the tendency to show plasma cell neurotropism.

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“…Histopathologic hallmarks of SSc are perivascular infiltrates, reduced capillary density, and accumulation of extracellular matrix proteins (2). The earliest histologic evidence of vascular involvement in SSc is edematous concentric proliferation of the intima with hypertrophic endothelial cells (ECs) (3–5). In the early phase, altered permeability induces increased passage of both plasma and mononuclear cells, with formation of perivascular infiltrates (5, 6) in which T lymphocytes predominate (7, 8).…”

mentioning

confidence: 99%

“…The earliest histologic evidence of vascular involvement in SSc is edematous concentric proliferation of the intima with hypertrophic endothelial cells (ECs) (3–5). In the early phase, altered permeability induces increased passage of both plasma and mononuclear cells, with formation of perivascular infiltrates (5, 6) in which T lymphocytes predominate (7, 8). In advanced phases, intimal thickening, delamination, vessel narrowing or obliteration, and perivascular fibrosis are present (9, 10).…”

mentioning

confidence: 99%

Differential expression of stromal cell–derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications

Cipriani¹,

Milia²,

Liakouli³

et al. 2006

Arthritis & Rheumatism

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Objective. Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc.Methods. We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcriptionpolymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting.Results. SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function.Conclusion. Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation in SSc.

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Damage of cutaneous peripheral nervous system evolves differently according to the disease phase and subset of systemic sclerosis

Cited by 15 publications

References 21 publications

Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis

Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis

Perineural inflammation in morphea (localized scleroderma): systematic characterization of a poorly recognized but potentially useful histopathological feature

Differential expression of stromal cell–derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications

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