Übersicht — Neue Konzepte Paraneurone anstatt APUD-System? — Überlegungen zur Nomenklatur des diffusen neuroendokrinen Systems (DNES) der Haut

  • W. M. Herbst


Bereits 1975 schlug der Japaner Fujita die Bezeichnung Paraneuron anstelle des mittlerweile überholten Begriffs „APUD-System“ vor. Der Begriff Paraneuron bezeichnet Zellen, die auf ein definiertes Signal (z.B. Neuropeptid) nach Besetzung des jeweiligen Rezeptors sekretorisch aktiv werden und durch charakteristische funktionelle und biochemische Gemeinsamkeiten gekennzeichnet sind. Auch in der Dermatologie und besonders in der Neuroendokrinologie findet dieses neuroparakrine Konzept zunehmend Anwendung bei der Aufklärung der neuronalen Plastizität und Interaktion typischer Paraneurone wie Merkel- und Mastzellen im Rahmen der Erforschung der peripheren Biokommunikation. In der vorliegenden Arbeit wird die Relevanz dieser Nomenklatur für die Haut anhand neuerer morphologischer und biochemischer Daten überprüft.


In order to improve the nomenclature of the APUD-system, the Japanese Fujita introduced the term paraneuron in 1975. Paraneurons are receptor-secretory cells which produce substances identical or related to neuronal secretions, store them in neurosecretion-like and/or synaptic vesicle-like granules, and release them in response to adequate stimuli. The relevance of this optional classification is considered by critical analysis of potential paraneurons of the skin and adjacent mucosa.


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  1. 1.
    Alroy, J, Leav, I, DeLellis, R A, Weinstein, R S: Distinctive intestinal mast cell neoplasms of domestic cats. Lab. Invest. 33, 159–167 (1975)PubMedGoogle Scholar
  2. 2.
    Blois, M S, Kallman, R F: Incorporation of 14C from 3,4-dihydroxyphenylanine-2′-14C into the melanin of mouse melanomas. Cancer Res. 24, 863–868 (1964)PubMedGoogle Scholar
  3. 3.
    Cutz, E, Chan, W, Track, N S, Goth, A, Said, S I: Release of vasoactive intestinal polypeptide in mast cells by histamine liberators. Nature (Lond.) 275, 661–662 (1978)CrossRefGoogle Scholar
  4. 4.
    Dalsgaard, C J, Rydh, M, Haegerstrand, A: Cutaneous innervation in man visualized with protein gene product 9.5 antibodies. Histochemistry 92, 385–390 (1989)PubMedCrossRefGoogle Scholar
  5. 5.
    Dyer, R F: Endoneurial mast cells in peripheral nerves of the armadillo dermis. Cell Tiss. Res. 192, 97–105 (1978)CrossRefGoogle Scholar
  6. 6.
    Falck, B, Jacobson, S, Olivecrona, H: Fluorescent dopa reaction of nevi and melanomas. Arch. Derm. (Chicago) 94, 363 (1966)CrossRefGoogle Scholar
  7. 7.
    Fewtrell, C M S, Foreman, J C, Jordan, C C, Oehme, P, Renner, H, Stewart, J M: The effects of substance P on histamine and 5-hydroxytryptamine release in the rat. J. Physiol. 330, 393–411 (1982)PubMedGoogle Scholar
  8. 8.
    Feyrter, F: Über diffuse endokrine epitheliale Organe. Zbl. Inn. Med. 545, 561 (1938)Google Scholar
  9. 9.
    Foreman, J C: Receptor-secretion coupling in mast cells. Trends Pharmacol. Sci. 2, 460–462 (1980)CrossRefGoogle Scholar
  10. 10.
    Foreman, J C, Garland, L G, Mongar, J L: The role of calcium in secretory processes: model studies in mast cells. In: Duncan, C J (ed) Calcium in biological systems (30th Symp. Soc. for Experimental Biology). Cambridge: Cambridge University Press 1976, pp. 193–218Google Scholar
  11. 11.
    Fuß, R, Oshima, N: Control of chromatophore movements in teleost fishes. Zool. Sci. 3, 13–47 (1986)Google Scholar
  12. 12.
    Fujita, T, Kobayashi, S: Paraneurons: new sisters of neurons (in Japanese). Igaku no Ayumi 94, 638–640 (1975)Google Scholar
  13. 13.
    Fujita, T: Insulo-acinar portal system in the horse pancreas. Arch. Histol. Jpn. 35, 161–171 (1973)PubMedCrossRefGoogle Scholar
  14. 14.
    Fujita, T: The gastro-enteric endocrine cell and its paraneuronic nature. In: Fujita, T, Coupland, R E (eds) Chromaffin, enterochromaffin and related cells. Amsterdam, Oxford, New York: Elsevier 1976, pp. 191–208Google Scholar
  15. 15.
    Fujita, T: Present status of paraneuron concept. Arch. Histol. Cytol. 52, Suppl., 1–8 (1989)PubMedCrossRefGoogle Scholar
  16. 16.
    Fujita, T, Kanno, T, Kobayashi, S: The paraneuron. Tokyo, Berlin, Heidelberg, New York: Springer 1988, pp. 228–234, 254–287CrossRefGoogle Scholar
  17. 17.
    Gould, V E, Moll, R, Moll, I, Lee, I, Franke, W W: Biology of disease. Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab. Invest. 52, 334–353 (1985)PubMedGoogle Scholar
  18. 18.
    Hartschuh, W, Grube, D: The Merkel cell — a member of the APUD cell system? Fluorescence and electron microscopic contribution to the neurotransmitter function of the Merkel cell granules. Arch. derm. Res. 265, 115–122 (1979)PubMedCrossRefGoogle Scholar
  19. 19.
    Hartschuh, W, Weihe, E, Buchler, M, Helmstaedter, V, Feurle, G E, Forssmann, W G: Met-enkephalin-like immunoreactivity in Merkel cells. Cell Tiss. Res. 201, 343–348 (1979)CrossRefGoogle Scholar
  20. 20.
    Hartschuh, W, Weihe, E, Yanaihara, N, Reinecke, M: Immunohistochemical localization of vasoactive intestinal polypeptide (VIP) in Merkel cells of various mammals: evidence for a neuromodulator function of the Merkel cell. J. invest. Derm. 81, 361–364 (1983)PubMedCrossRefGoogle Scholar
  21. 21.
    Hartschuh, W, Reinecke, M, Weihe, E, Yanaihara, N: VIP-immunoreactivity in the skin of various mammals: immunohistochemical, radioimmunological and experimental evidence for a dual localization in cutaneous nerves and Merkel cells. Peptides 5, 239–245 (1984)PubMedCrossRefGoogle Scholar
  22. 22.
    Harvima, I T, Naukkarinen, A, Harvima, R J, Fräki, J E: Immunoperoxidase and enzyme-histochemical demonstration of human skin tryptase in cutaneous mast cells in normal and mastocytoma skin. Arch. derm. Res. 280, 363–370 (1988)PubMedCrossRefGoogle Scholar
  23. 23.
    Hashimoto, K: The ultrastructure of the skin of human embryos. X. Merkel tactile cells in the finger and nail. J. Anat. 111, 99–120 (1972)PubMedGoogle Scholar
  24. 24.
    Heine, H, Förster, F J: Relationships between mast cells and preterminal nerve fibres. Z. mikr.-anat. Forsch. 89, 934–937 (1975)PubMedGoogle Scholar
  25. 25.
    Herbst, W M, Kummer, W, Hofmann, W J, Otto, H F, Heym, C: Carcinoid tumors of the thymus: an immunohistochemical study. Cancer (Philad.) 60, 2465–2470 (1987)CrossRefGoogle Scholar
  26. 26.
    Herbst, W M, Heym, C: Der Enddarm als endokrines Organ. Z. Phlebol. Proktol. 18, 288–291 (1989)Google Scholar
  27. 27.
    Herbst, W M, Gotzmann, W, Zöbe, A: Kongenitales solitäres Mastozytom. In: Fortschritte der operativen Dermatologie. Heidelberg, Berlin, New York, Tokyo: Springer 1990 (im Druck)Google Scholar
  28. 28.
    Herbst, W M, Kummer, W, Heym, C: VIP-receptor like immunoreactivity in human salivary glands. Neuropeptides 1991 (im Druck)Google Scholar
  29. 29.
    Hökfelt, T, Holets, V R, Staines, W, Meister, B, Melander, T, Schalling, M, Schultzberg, M et al: Coexistence of neuronal messengers — an overview. In: Hökfelt, T, Fuxe, K, Pernow, B (eds) Progress in brain research, Vol 68. Amsterdam: Elsevier 1986, pp. 33–70CrossRefGoogle Scholar
  30. 30.
    Horai, T, Nishihara, H, Hattori, S, Tateishi, R: Malignant melanoma producing serotonin. Cancer (Philad.) 43, 294–298 (1979)CrossRefGoogle Scholar
  31. 31.
    Hui, W M, Lui, H C, Lam, S K, Koo, A: Histamine containing cells in gastric fundus of dogs. Cell. molec. Biol. 33, 747–754 (1987)Google Scholar
  32. 32.
    Isaacson, P: Mast cells in benign nerve sheath tumors. J. Pathol. 119, 193–196 (1976)PubMedCrossRefGoogle Scholar
  33. 33.
    Iwanaga, T, Fujita, T, Takeda, N, Endo, Y, Lederis, K: Urotensin I-like immunoreactivity in the midgut endocrine cells of the insects Gryllus bimaculatus and Periplaneta americana. Cell Tiss. Res. 244, 565–568 (1986)CrossRefGoogle Scholar
  34. 34.
    Johnson, A R, Erdös, E G: Release of histamine from mast cells by vasoactive peptides. Proc. Soc. exp. Biol. Med. 142, 1252–1256 (1973)PubMedGoogle Scholar
  35. 35.
    Kirschner, N: Biosynthesis of the catecholamines. In: Greep, R O, Astwood, E B (eds) Adrenal gland (Handbook of Physiology 7/VI). Washington, DC: Am. Physiol. Soc. 1975, pp. 341–355Google Scholar
  36. 36.
    Kitamura, Y, Shimada, M, Hatanaka, K, Miyano, Y: Development of mast cells from grafted bone marrow cells in irradiated mice. Nature (Lond.) 268, 442–443 (1977)CrossRefGoogle Scholar
  37. 37.
    Kurose, M, Saeki, K: Histamine release induced by neurotensin from rat peritoneal mast cells. Eur. J. Pharmakol. 76, 129–136 (1981)CrossRefGoogle Scholar
  38. 38.
    Kurosumi, K: Paraneuronic and related cells in the mammalian skin. In: Coupland, R E, Fujita, T: Chromaffin, enterochromaffin and related cells. Amsterdam, Oxford, New York: Elsevier 1976, pp. 171–189Google Scholar
  39. 39.
    Kusumoto, Y: The effects of local anesthetic on the degranulation of rat peritoneal mast cells. Biomed. Res. 1, 237–241 (1981)Google Scholar
  40. 40.
    Kummer, W, Herbst, W M, Heym, C: Immunohistochemical localization of VIP-receptor-like immunoreactivity in human sweat glands. Neurosci. Letters 110, 239–243 (1990)CrossRefGoogle Scholar
  41. 41.
    Lagunoff, D, Benditt, E P: Histochemical examinations of chymotrypsin-like esterases. Nature (Lond.) 192, 1198–1199(1961)CrossRefGoogle Scholar
  42. 42.
    Lundberg, J M, Hamberger, B, Schultzberg, M, Hökfelt, T, Granber, P O, Efendic, S, Terenius, L, Goldstein, M, Luft, R: Enkephalin- and somatostatin-like immunoreactivities in human adrenal medulla and pheochromocytoma. Proc. nat. Acad. Sci. USA 76, 4079–4083 (1979)PubMedCrossRefGoogle Scholar
  43. 43.
    Maul, G G, Brumbaugh, J A: On the possible function and coated vesicles in melanogenesis of the regenerating fowl feather. J. Cell Biol. 48, 41–48 (1971)PubMedCrossRefGoogle Scholar
  44. 44.
    Merkel, F: Tastzellen und Tastkörperchen bei den Haustieren und beim Menschen. Arch. Mikrosk. Anat. 11, 636–652 (1875)CrossRefGoogle Scholar
  45. 45.
    Merkel, F: Über die Endigungen der sensiblen Nerven in der Haut der Wirbeltiere. Rostock: H. Schmidt 1880Google Scholar
  46. 46.
    Mihara, M, Hashimoto, K, Ueda, K, Kumakiri, M: The specialized junctions between Merkel cell and neurite: an electron microscope study. J. invest. Derm. 73, 325–334 (1979)PubMedCrossRefGoogle Scholar
  47. 47.
    Mishima, Y: New technic for comprehensive demonstration of melanin, premelanin and tyrosinase site. J. invest. Derm. 34, 355–360 (1969)Google Scholar
  48. 48.
    Nakajima, T, Kameya, T, Watanabe, S, Hirota, T, Shimosato, Y, Isobe, T: S-100 protein distribution in normal and neoplastic tissues. In: Delellis, R A (ed) Advances in immunohistochemistry. Chicago: Masson 1984, pp. 141–158Google Scholar
  49. 49.
    Parrat, J R, West, G B: 5-hydroxytryptamine and tissue mast cells. J. Physiol. 137, 169–178 (1957)Google Scholar
  50. 50.
    Pearse, A G E: The cytochemistry and ultrastructure of polypeptide hormone-producing cells in the APUD series and the embryologic, physiologic and pathologic implications of the concept. J. Histochem. Cytochem. 17, 303–313 (1969)PubMedCrossRefGoogle Scholar
  51. 51.
    Pearse, A G E: The endocrine division of the nervous system: a logical extension of the APUD concept. Fol. anat. iugoslav. 4, 5–20 (1975a)Google Scholar
  52. 52.
    Pearse, A G E: Neurocristopathy, neuroendocrine pathology and the APUD concept. Z. Krebsforsch. 84, 1–18 (1975b)CrossRefGoogle Scholar
  53. 53.
    Pearse, A G E, Polak, J M: Endocrine tumors of neural crest origIn: neuromas, apudomas and the APUD concept. Med. Biol. 52, 3–18 (1974)PubMedGoogle Scholar
  54. 54.
    Pearse, A G E, Welbourn, R B: The apudomas. Gr. J. Hosp. Med. 1973, 617–624Google Scholar
  55. 55.
    Pinkus, F: Über Hautsinnesorgane neben dem menschlichen Haar (Haarscheiben) und ihre vergleichend-anatomische Bedeutung. Arch. mikr. Anat. Entw.-Gesch. 65, 121–180 (1905)CrossRefGoogle Scholar
  56. 56.
    Rost, F W D, Polak, J M; Pearse, A G E: The melanocyte: its cytochemical and immunological relationship to cells of the endocrine polypeptide (APUD) series. Virchows Arch. Abt. B Zellpath. 4, 93–101 (1969)Google Scholar
  57. 57.
    Schultzberg, M, Hökfelt, T, Lundberg, J M: Peripheral peptide-containing neurons. In: Miyoshi, A (ed) Gut peptides, secretion, function and clinical aspects. Tokyo: Kodansha; Amsterdam, New York, Oxford: Elsevier 1979, pp. 281–292Google Scholar
  58. 58.
    Seiji, M, Fitzpatrick, T B, Birbeck, M S: The melanosome: a distinctive subcellular particle of mammalian melanocytes and the site of melanogenesis. J. invest. Derm. 36, 243–252 (1961)PubMedGoogle Scholar
  59. 59.
    Sidhu, G S: The entodermal origin of digestive and respiratory tract APUD cells. Am. J. Pathol. 96, 5–17 (1979)PubMedGoogle Scholar
  60. 60.
    Sziji, I, Csapó, Z, László, F A, Kovács, K: Medullary cancer of the thyroid gland associated with hypercorticism. Cancer (Philad.) 24, 167–173 (1969)CrossRefGoogle Scholar
  61. 61.
    Tachybana, T, Nawa, T: Merkel cell differentiation in the labial mucous epithelium of the rabbit. J. Anat. 131, 145–155 (1980)Google Scholar
  62. 62.
    Toker, C: Trabecular carcinoma of the skin. Arch. Derm. (Chicago) 105, 107–110 (1972)CrossRefGoogle Scholar
  63. 63.
    Varndell, I M, Tapia, F J, De Mey, J, Rush, R A, Bloom, S R, Polak, J M: Electron immunocytochemical localization of enkephalin-like material in catecholamine-containing cells of the carotid body, the adrenal medulla, and in pheochromocytomas of man and other mammals. J. Histochem. Cytochem. 30, 682–690 (1982)PubMedCrossRefGoogle Scholar
  64. 64.
    Warner, T F C S, Uno, H, Hafez, R, Burgess, J, Bolles, C, Lloyd, R V, Oka, M: Merkel cells and Merkel cell tumors: ultrastructure, immunocytochemistry and review of the literature. Cancer (Philad.) 52, 238–245 (1983)CrossRefGoogle Scholar
  65. 65.
    Wesley, J R, Vinik, A J, O’Dorisio, T M, Glaser, B, Fink, A: A new syndrome of symptomatic cutaneous mastocytoma producing vasoactive intestinal polypeptide. Gastroenterology 82, 963–967 (1982)PubMedGoogle Scholar
  66. 66.
    Weichert, R F: The neural ectodermal origin of the peptide-secreting endocrine glands. Am. J. Med. 49, 232–241 (1970)PubMedCrossRefGoogle Scholar
  67. 67.
    Wiedenmann, B, Franke, W: Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 47, 1017–1028 (1985)CrossRefGoogle Scholar
  68. 68.
    Winkelmann, R K, Breathnach, A S: The Merkel cell. J. invest. Derm. 60, 2–15 (1973)PubMedCrossRefGoogle Scholar
  69. 69.
    Yamasaki, H, Fujita, T, Ohara, Y, Komoto, S: Electron microscope studies on the release of histamine from rat peritoneal mast cells. Arch. Histol. Jpn. 31, 393–408 (1970)PubMedCrossRefGoogle Scholar
  70. 70.
    Yoshida, Y, Takei, T, Hattori, A, Kaku, T, Yokokawa, K, Mori, M: Merkel cell tumor of the skIn: ultrastructural and immunohistochemical study. Acta path. jap. 34, 1433–1440 (1984)PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • W. M. Herbst
    • 1
  1. 1.Dermatologische KlinikUniversität Erlangen-NürnbergDeutschland

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