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      NERVE GROWTH FACTOR, NEUROPEPTIDES AND CUTANEOUS NERVES IN ATOPIC DERMATITIS

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          Abstract

          Introduction:

          Neurogenic components, as neurotrophic factors and neuropeptides, are probably involved in the pathogenesis of atopic dermatitis (AD) with the neuroimmunocutaneous system as they modify the functions of immunoactive cells in the skin. Nerve growth factor (NGF) is the best-characterized member of the neurotrophin family. Both NGF and neuropeptides (NPs) may be associated with the disease pathogenesis.

          Aim:

          This study aims to evaluate the plasma level of NGF and NPs in AD patients and correlate them with the disease activity and nerve changes in the skin by electron microscopy.

          Materials and Methods:

          Plasma levels of NGF and vasoactive intestinal peptide (+VIP) were measured by an immunoenzymatic assay while plasma levels of calcitonine gene related peptide (CGRP) and neuropeptide Y (NPY) were measured by radioimmunoassay in 30 AD patients in comparison to 10 normal non-atopic controls. Electron microscopic study was done in 10 AD patients.

          Results:

          It has been found that there is significant increase of plasma levels of NGF and NPs in AD patients compared with controls. There is a positive correlation between the plasma levels of NGF and disease activity (correlation coefficient = 0.750, P<0.005). There is a significant correlation between the number of Schwann axon complex, evidenced by electron microscopic examination and plasma level of NGF in AD patients.

          Conclusion:

          It has been concluded that these neurogenic factors; NGF and NPs modulate the allergic response in AD, probably through interactions with cells of the immune-inflammatory component. NGF might be considered as a marker of the disease activity.

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          Most cited references28

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          Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia.

          1. Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones. 2. To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene-related peptide (CGRP) in the L4 dorsal root ganglion 48 h post CFA injection. 3. The effects of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drug on the levels of NGF and IL-1 beta in inflamed tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones. 4. Systemic dexamethasone (120 micrograms kg-1 per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg-1 daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg-1 daily was required to reduce significantly mechanical and thermal hypersensitivity. 5. The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL-1 beta whereas indomethacin had an effect only at the higher dose. 6. The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes. 7. Intraplantar injections of IL-1 beta (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL-1 receptor antagonist (IL-1 ra) (0.625 microgram, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL-1 beta (1 ng) was prevented by administration of a polyclonal neutralizing anti-NGF serum. 8. IL-1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA-induced elevation in NGF levels. Anti-NGF pretreatment substantially reduced CFA-induced mechanical and thermal hyperalgesia without reducing the elevation in IL-1 beta. 9. Intraplantar NGF (0.02, 0.2 and 2 microg) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL-1beta levels in the hindpaw skin.10. Our results demonstrate that IL-1beta contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.
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            Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide.

            Several observations suggest interactions between the immune and nervous systems. Psoriasis and atopic dermatitis may worsen with anxiety and have been associated with anomalous neuropeptide regulation. Neurotransmitters affect lymphocyte function and lymphoid organs are innervated. Calcitonin gene-related peptide (CGRP) is a neuropeptide and vasodilator that modulates some macrophage functions, including antigen presentation in vitro. CGRP is associated with Langerhans cells (LC) in oesophageal mucosa, particularly during inflammation, is present in epidermal nerves and is associated with Merkel cells. We examined the ability of CGRP to modulate LC antigen-presenting function and asked if CGRP-containing nerves impinge on LC. We report here that CGRP-containing nerve fibres are intimately associated with LC in human epidermis and CGRP is found at the surface of some LC. In three functional assays CGRP inhibited LC antigen presentation. These findings indicate that CGRP may have immunomodulatory effects in vivo and suggest a locus of interaction between the nervous system and immunological function.
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              Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema.

              The association between mast cells and sensory nerves and the distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) were studied immunohistochemically in lesional and nonlesional skin of 26 atopic dermatitis (AD) and 23 nonatopic nummular eczema (NE) patients. Mast cell-nerve contacts were counted morphometrically and confirmed by confocal laser scanning microscopy. Neuropeptide positivity was assessed semiquantitatively. Dermal contacts between mast cells and nerves were increased in number in both lesional and nonlesional samples of AD and NE when compared to those in normal controls, although only the values in lesional AD reached statistical significance ( P<0.05). Nerve-mast cell contacts in the basement membrane zone were seen practically only in lesional NE. SP and CGRP fibres were prominently increased in lesional samples when compared to their nonlesional controls both in AD and NE in the epidermis and in the papillary dermis. In both AD and NE, only small differences were found regarding VIP positivity in lesional and nonlesional biopsies. The epidermis was devoid of VIP positivity. In conclusion, SP and CGRP but not VIP fibres were more frequent in lesional than in nonlesional papillary dermis of both AD and NE. Since mast cells are also increased in number in lesions of AD and NE, they are able to maintain neurogenic inflammation through activation by SP and CGRP. The increased SP/CGRP nerves in the epidermis of AD and NE lesions may stimulate keratinocytes to release cytokines which affect various cell types enhancing inflammation.
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                Author and article information

                Journal
                Indian J Dermatol
                IJD
                Indian Journal of Dermatology
                Medknow Publications (India )
                0019-5154
                1998-3611
                Apr-Jun 2010
                : 55
                : 2
                : 135-139
                Affiliations
                Departement of Dermatology and and Venereology, Tanta University, Egypt.
                [1 ] Departement of Clinical Pathology, Tanta University, Egypt.
                [2 ] Departement of Histology, Tanta University, Egypt.
                Author notes
                Address for Correspondence: Dr. Abeer Hodeib, Tanta University, Egypt Tanta Egypt. E-mail: abeerhodeib@ 123456hotmail.com
                Article
                IJD-55-135
                10.4103/0019-5154.62735
                2887515
                20606880
                13c3d87e-0a1a-4a1d-ac25-9d32c1600d67
                © Indian Journal of Dermatology

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : June 2008
                : November 2009
                Categories
                Basic Research

                Dermatology
                neuropeptides,nerve growth factor,atopic dermatitis
                Dermatology
                neuropeptides, nerve growth factor, atopic dermatitis

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