Skip to main content
SpringerLink
Log in

Anatomical evidence for ileal Peyer’s patches innervation by enteric nervous system: a potential route for prion neuroinvasion?

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

We have examined the innervation of the gut-associated lymphoid system of the sheep ileum, with a view to identifying potential sites for neuroinvasion by pathogens, such as prions (PrPSc). Special attention has been paid to the follicles of Peyer’s patches (PPs), which are major sites of PrPSc accumulation during infection. Evidence exists that the enteric nervous system, together with the parasympathetic and sympathetic pathways projecting to the intestine, are important for PrPSc entry into the central nervous system. Thus, PrPSc might move from PPs to the neurons and nerve fibres that innervate them. We investigated, by immunohistochemistry and retrograde tracing (DiI) from the follicles, the distribution and phenotype of enteric neurons innervating the follicles. Antibodies against protein gene product 9.5, tyrosine hydroxylase, dopamine β hydroxylase, choline acetyltransferase, calbindin (CALB), calcitonin gene-related peptide (CGRP), and nitric oxide synthase were used to characterise the neurons. Immunoreactivity for each of these was observed in fibres around and inside PP follicles. CGRP-immunoreactive fibres were mainly seen at the follicular dome. Retrograde tracing revealed submucosal neurons that contributed to the innervation of PPs, including Dogiel type II neurons and neurons immunoreactive for CALB and CGRP. The major source of the adrenergic fibres are the sympathetic ganglia. Our results thus suggest that enteric and sympathetic neurons are involved during the first stage of neuroinvasion, with neurons connecting to them acting as potential carriers of PrPSc to the central nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aguzzi A, Heikenwalder M (2006) Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4:765–775

    Article  PubMed  CAS  Google Scholar 

  • Aguzzi A, Polymenidou M (2004) Mammalian prion biology: one century of evolving concepts. Cell 116:313–327

    Article  PubMed  CAS  Google Scholar 

  • Balemba OB, Mbassa GK, Semuguruka WD, Assey RJ, Kahwa CK, Hay-Schmidt A, Dantzer V (1999) The topography, architecture and structure of the enteric nervous system in the jejunum and ileum of cattle. J Anat 195:1–9

    Article  PubMed  Google Scholar 

  • Beekes M, McBride PA (2007) The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies. FEBS J 274:588–605

    Article  PubMed  CAS  Google Scholar 

  • Bienenstock J, Croitoru K, Ernst PB, Stead RH, Stanisz A (1989) Neuroendocrine regulation of mucosal immunity. Immunol Invest 18:69–76

    Article  PubMed  CAS  Google Scholar 

  • Brehmer A, Schrödl F, Neuhuber W, Tooyama I, Kimura H (2006) Co-expression pattern of neuronal nitric oxide synthase and two variants of choline acetyltransferase in myenteric neurons of porcine ileum. J Chem Neuroanat 27:33–41

    Article  CAS  Google Scholar 

  • Carucci JA, Ignatius R, Wei Y, Cypess AM, Schaer DA, Pope M, Steinman RM, Mojsov S (2000) Calcitonin gene-related peptide decreases expression of HLA-DR and CD86 by human dendritic cells and dampens dendritic cell-driven T cell-proliferative responses via the type I calcitonin gene-related peptide receptor. J Immunol 164:3494–3499

    PubMed  CAS  Google Scholar 

  • Chiocchetti R, Grandis A, Bombardi C, Clavenzani P, Lalatta-Costerbosa G, Lucchi ML, Furness JB (2004) Characterisation of neurons expressing calbindin immunoreactivity in the ileum of the unweaned and mature sheep. Cell Tissue Res 318:289–303

    Article  PubMed  CAS  Google Scholar 

  • Chiocchetti R, Clavenzani P, Mazzoni M, Albanese V, Di Guardo G, De Grossi L, Bortolami R, Lalatta-Costerbosa G (2005) The sheep enteric nervous system after scrapie (PrPSc) infection. Autonomic Neurosci 119:144–145

    Google Scholar 

  • Chiocchetti R, Grandis A, Bombardi C, Lucchi ML, Tadini Dal Lago D, Bortolami R, Furness JB (2006) Extrinsic and intrinsic sources of calcitonin gene-related peptide immunoreactivity in the lamb ileum. A morphometric and neurochemical investigation. Cell Tissue Res 323:183–196

    Article  PubMed  CAS  Google Scholar 

  • Defaweux V, Dorban G, Demonceau C, Piret J, Jolois O, Thellin O, Thielen C, Heinen E, Antoine N (2005) Interfaces between dendritic cells, other immune cells, and nerve fibres in mouse Peyer’s patches: potential sites for neuroinvasion in prion diseases. Microsc Res Tech 6:1–9

    Article  CAS  Google Scholar 

  • Defaweux V, Dorban G, Antoine N, Piret J, Gabriel A, Jacqmot O, Falisse-Poirier N, Flandroy S, Zorzi D, Heinen E (2007) Neuroimmune connections in jejunal and ileal Peyer’s patches at various bovine ages: potential sites for prion neuroinvasion. Cell Tissue Res 329:35–44

    Article  PubMed  Google Scholar 

  • Driessen A, Creemers J, Gebos K (1992) The innervation of the lymphoid tissue at the ileocolonic transition: an enzyme and immunohistochemical study. Acta Anat (Basel) 144:304–310

    CAS  Google Scholar 

  • Falck B, Nystedt T, Rosengren E, Stenflo J (1964) Dopamine and mast cells in ruminants. Acta Pharmacol Toxicol 21:51–58

    Article  CAS  Google Scholar 

  • Feher E, Fodor M, Burnstock G (1992) Distribution of somatostatin-immunoreactive nerve fibres in Peyer’s patches. Gut 33:1195–1198

    Article  PubMed  CAS  Google Scholar 

  • Felten DL, Felten SY, Carlson SL, Olschowaka JA, Livnat S (1985) Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol 135:755S–765S

    PubMed  CAS  Google Scholar 

  • Felten DL, Felten SY, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, Olschowki JA, Livnat S (1987) Noradrenergic sympathetic neural interactions with the immune system. Structure and function. Immunol Rev 100:225–260

    Article  PubMed  CAS  Google Scholar 

  • Felten SY, Felten DL, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, Olschowka JA, Livnat S (1988) Noradrenergic sympathetic innervation of lymphoid organs. Prog Allergy 43:14–36

    PubMed  CAS  Google Scholar 

  • Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton AL, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK (2001) Catecholamines in murine bone marrow derived mast cells. J Neuroimmunol 119:231–238

    Article  PubMed  CAS  Google Scholar 

  • Furness JB (2006) The enteric nervous system. Blackwell, Oxford, pp 64–66

    Google Scholar 

  • Furness JB, Robbins HL, Xiao J, Stebbing MJ, Nurgali K (2004)Projections and chemistry of Dogiel type II neurons in the mouse colon.Cell Tissue Res 317:1–12

    Article  PubMed  CAS  Google Scholar 

  • Gerber HA, Morris B, Trevella W (1986) The role of gut-associated lymphoid tissues in the generation of immunoglobulin-bearing lymphocytes in sheep. Aust J Exp Biol Med Sci 64:201–203

    Article  PubMed  Google Scholar 

  • Glatzel M, Heppner FL, Albers KM, Aguzzi A (2001) Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25–34

    Article  PubMed  CAS  Google Scholar 

  • Gonzales-Ariki S, Husband AJ (2000) Ontogeny of IgA+ cells in lamina propria: effects of sympathectomy. Dev Comp Immunol 24:61–69

    Article  Google Scholar 

  • Goode T, O’Connell J, Ho WZ, O’Sullivan GC, Collins JK, Douglas SD, Shanahan F (2000) Differential expression of neurokinin-1 receptor by human mucosal and peripheral lymphoid cells. Clin Diagn Lab Immunol 7:371–376

    Article  PubMed  CAS  Google Scholar 

  • Green T, Dockray GJ (1987) Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neurosci Lett 76:151–156

    Article  PubMed  CAS  Google Scholar 

  • Green BT, Lyte M, Kulkarni-Narla A, Brown DR (2003) Neuromodulation of enteropathogen internalization in Peyer’s patches from porcine jejunum. J Neuroimmunol 141:74–78

    Article  PubMed  CAS  Google Scholar 

  • Haïk S, Faucheux BA, Sazdovitch V, Privat N, Kemeny JL, Perret-Liaudet A, Hauw JJ (2003) The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease. Nat Med 9:1121–1129

    Article  PubMed  CAS  Google Scholar 

  • Heggebø R, Gonzales L, Press CM, Gunnes G, Espenes A, Jeffrey M (2003) Disease associated PrP in the enteric nervous system of scrapie-affected sheep. J Gen Virol 84:1327–1338

    Article  PubMed  CAS  Google Scholar 

  • Hens J, Schrödl F, Brehmer A, Adriaensen D, Neuhuber W, Scheuermann DW, Schemann M, Timmermans JP (2000) Mucosal projections of enteric neurons in the porcine small intestine. J Comp Neurol 421:429–436

    Article  PubMed  CAS  Google Scholar 

  • Hens J, Vanderwinden JM, De Laet MH, Scheuermann DW, Timmermans JP (2001)Morphological and neurochemical identification of enteric neurones with mucosal projections in the human small intestine. J Neurochem 76:464-471

    Article  PubMed  CAS  Google Scholar 

  • Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A (2001) Transepithelial prion transport by M cells. Nat Med 7:976–977

    Article  PubMed  CAS  Google Scholar 

  • Holzer P, Wachter C, Heinemann A, Jocic M, Lippe IT, Herbert MK (1995) Diverse interactions of calcitonin gene related peptide and nitric oxide in the gastric and cutaneous microcirculation. Can J Physiol Pharmacol 73:991–994

    PubMed  CAS  Google Scholar 

  • Huntley JF, Haig DM, Irvine J, Inglis L, MacDonald A, Rance A, Moqbel R (1992) Characterisation of ovine mast cells derived from in vitro culture of haemopoietic tissue. Vet Immunol Immunopathol 32:47–64

    Article  PubMed  CAS  Google Scholar 

  • Ichikawa S, Sreedharan SP, Goetzl EJ, Owen RL (1994) Immunohistochemical localization of peptidergic nerve fibres and neuropeptide receptors in Peyer’s patches of the cat ileum. Regul Pept 54:385-395

    Article  PubMed  CAS  Google Scholar 

  • Krammer HJ, Kühnel W (1993) Topography of the enteric nervous system in Peyer’s patches of the porcine small intestine. Cell Tissue Res 272:267–272

    Article  PubMed  CAS  Google Scholar 

  • Kulkarni-Narla A, Beitz AJ, Brown DR (1999) Catecholaminergic, cholinergic and peptidergic innervation of gut-associated lymphoid tissue in porcine jejunum and ileum. Cell Tissue Res 298:275–286

    Article  PubMed  CAS  Google Scholar 

  • Lalatta-Costerbosa G, Mazzoni M, Clavenzani P, Di Guardo G, Mazzuoli G, Marruchella G, De Grossi L, Agrimi U, Chiocchetti R (2007) NOS-immunoreactivity and NADPH-d histochemistry in the enteric nervous system of Sarda breed sheep with different PrP genotypes in wholemount and cryostat preparations. J Histochem Cytochem 55:387–401

    Article  PubMed  CAS  Google Scholar 

  • Landsverk T, Halleraker M, Aleksandersen M, McClure S, Hein W, Nicander L (1991) The intestinal habitat for organized lymphoid tissues in ruminants; comparative aspects of structure, function and development. Vet Immunol Immunopathol 28:1–16

    Article  PubMed  CAS  Google Scholar 

  • Ma B, Wasielewski R von, Lindenmaier W, Dittmar KEJ (2007) Immmunohistochemical study of the blood and lymphatic vasculature and the innervation of mouse gut and gut-associated lymphoid tissue. Anat Histol Embryol 36:62–74

    Article  PubMed  CAS  Google Scholar 

  • Mabbott NA, MacPherson GG (2006) Prions and their lethal journey to the brain. Nat Rev Microbiol 4:201–211

    Article  PubMed  CAS  Google Scholar 

  • Mao Y, Wang B, Kunze W (2006) Characterization of myenteric sensory neurons in the mouse small intestine. J Neurophysiol 96:998–1010

    Article  PubMed  Google Scholar 

  • Marruchella G, Ligios C, Albanese V, Cancedda MG, Madau L, Lalatta-Costerbosa G, Mazzoni M, Clavenzani P, Chiocchetti R, Sarli G, De Grossi L, Agrimi U, Aguzzi A, Di Guardo G (2007) Enteroglia and neuron involvement without apparent neuronal loss in ileal enteric nervous system plexi from scrapie-affected sheep. J Gen Virol 88:2899–2904

    Article  PubMed  CAS  Google Scholar 

  • Mazzuoli G, Mazzoni M, Albanese V, Clavenzani P, Lalatta-Costerbosa G, Lucchi ML, Furness JB, Chiocchetti R (2007) Morphology and neurochemistry of descending and ascending myenteric plexus neurons of sheep ileum. Anat Rec 290:1480–1491

    Article  CAS  Google Scholar 

  • Ottaway CA, Lewis DL, Asa SL (1987) Vasoactive intestinal peptide-containing nerves in Peyer’s patches. Brain Behav Immun 1:148–158

    Article  PubMed  CAS  Google Scholar 

  • Pascual DW, Kiyono H, McGhee JR (1994) The enteric nervous system: interactions for mucosal immunity and inflammation. Immunomethods 5:56–72

    Article  PubMed  CAS  Google Scholar 

  • Payan DG, McGillis JP, Renold FK, Mitsuhashi M, Goetzl EJ (1987) Neuropeptide modulation of leukocyte function. Ann N Y Acad Sci 496:182–191

    Article  PubMed  CAS  Google Scholar 

  • Pfannkuche H, Schemann M, Gäbel G (2002) Ruminal muscle of sheep is innervated by non-polarized pathways of cholinergic and nitrergic myenteric neurones. Cell Tissue Res 309:347–354

    Article  PubMed  CAS  Google Scholar 

  • Pfoch M, Unsicker K (1972) Electron microscopic study on the innervation of Peyer’s patches of the Syrian hamster. Z Zellforsch Mikrosk Anat 123:425–429

    Article  PubMed  CAS  Google Scholar 

  • Powley TL (2000) Vagal input to the enteric nervous system. Gut 47:iv30–iv32

    Article  PubMed  Google Scholar 

  • Press CM, Heggebø R, Espenes A (2004) Involvement of gut-associated lymphoid tissue of ruminants in the spread of transmissible spongiform encephalopathies. Adv Drug Deliv Rev 56:885–899

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383

    Article  PubMed  CAS  Google Scholar 

  • Reynaud CA, Mackay CR, Muller RG, Weill JC (1991) Somatic generation of diversity in a mammalian primary lymphoid organ: the sheep ileal Peyer’s patches. Cell 64:995–1005

    Article  PubMed  CAS  Google Scholar 

  • Sharkey KA (1992) Substance P and calcitonin gene-related peptide (CGRP) in gastrointestinal inflammation. Ann N Y Acad Sci 664:425–442

    Article  PubMed  CAS  Google Scholar 

  • Sharkey KA, Lomax AEG, Bertrand PP, Furness JB (1998) Electrophysiology, shape and chemistry of intestinofugal neurons projecting from guinea pig distal colon to inferior mesenteric ganglia. Gastroenterology 115:909–918

    Article  PubMed  CAS  Google Scholar 

  • Shtylik AV, Otellin VA, Nozdrachev AD (1998) Innervation of grouped lymphoid nodules (Peyer’s patches) by the enteric nervous system and the topography of their interior neural elements in the rat. Morfologiia 114:34–39

    PubMed  CAS  Google Scholar 

  • Stead RH (1992) Innervation of mucosal immune cells in the gastrointestinal tract. Reg Immunol 4:91–99

    PubMed  CAS  Google Scholar 

  • Tooyama I, Kimura H (2000) A protein encoded by an alternative splice variant of choline acetyltransferase mRNA is localized preferentially in peripheral nerve cells and fibers. J Chem Neuroanat 17:217–226

    Article  PubMed  CAS  Google Scholar 

  • Vulchanova L, Casey MA, Crabb GW, Kennedy WR, Brown DR (2007) Anatomical evidence for enteric neuroimmune interactions in Peyer’s patches. J Neuroimmunol 185:64–74

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi K, Schoefl GI (1983) Blood vessels of the Peyer’s patches in the mouse. I. Topographical studies. Anat Rec 206:391–401

    Article  PubMed  CAS  Google Scholar 

  • Young HM, Anderson CR, Furness JB (2000) Nitric oxide in the peripheral autonomic nervous system. In: Steinbusch HWM, De Vente J, Vincent SR, Björklund A, Hökfelt T (eds) Handbook of chemical neuroanatomy, vol 17. Elsevier Science, Amsterdam, pp 215–226

    Google Scholar 

Download references

Acknowledgements

The careful technical assistance of Caterina Mongardi-Fantaguzzi is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Veterinary Morphophysiology and Animal Productions, University of Bologna, 40064 Ozzano Emilia, Bologna, Italy

    Roberto Chiocchetti, Gemma Mazzuoli, Maurizio Mazzoni, Paolo Clavenzani, Giovanna Lalatta-Costerbosa & Maria L. Lucchi

  2. Department of Comparative Biomedical Sciences, University of Teramo, 64100, Teramo, Italy

    Valeria Albanese, Giovanni Di Guardo & Giuseppe Marruchella

  3. Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia

    Valeria Albanese & John B. Furness

Authors
  1. Roberto Chiocchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gemma Mazzuoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valeria Albanese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maurizio Mazzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paolo Clavenzani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giovanna Lalatta-Costerbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria L. Lucchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giovanni Di Guardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Marruchella
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John B. Furness
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Chiocchetti.

Additional information

This study was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR, PRIN 2006), from the Fondazione del Monte di Bologna e Ravenna and from the National Health and Medical Research Council of Australia (grant no. 400020).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chiocchetti, R., Mazzuoli, G., Albanese, V. et al. Anatomical evidence for ileal Peyer’s patches innervation by enteric nervous system: a potential route for prion neuroinvasion?. Cell Tissue Res 332, 185–194 (2008). https://doi.org/10.1007/s00441-008-0583-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-008-0583-y

Keywords

Search

Navigation