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Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
Stefan Lüth, … , Johannes Herkel, Ansgar W. Lohse
Stefan Lüth, … , Johannes Herkel, Ansgar W. Lohse
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3403-3410. https://doi.org/10.1172/JCI32132.
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Research Article

Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs

Abstract

Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25– T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-β–dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.

Authors

Stefan Lüth, Samuel Huber, Christoph Schramm, Thorsten Buch, Stefan Zander, Christine Stadelmann, Wolfgang Brück, David C. Wraith, Johannes Herkel, Ansgar W. Lohse

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Is it possible to induce oral tolerance using a non-myelin peripheral nerve antigen?

Submitter: Colin L. Crawford | clcraw13@hotmail.com

Imperial College of Medicine, UK

Published December 18, 2008

In their article, Luth et al1 found that expression of myelin basic protein (MBP) in the liver induced protection from allergic encephalomyelitis (EAE) and considered that this could be due to various cell types, such as Kuffner or hepatic cells. EAE can also be prevented by oral tolerance to MBP. 2 However, although oral tolerance to myelin antigens has been achieved in multiple sclerosis (MS) patients there was no beneficial effect to the patients. 3 Goubier et al4 that found that oral tolerance to egg ovalbumin also occurred in the liver, but was mediated specifically by plasmacytoid dendritic cells. This systemic tolerance involved delayed type hypersensitivity responses.

Plasmacytoid dendritic cells have not been demonstrated in EAE lesions. Plasma cells identified using the specific marker CD 138 are confined to the perivascular spaces in MS patients and are not present in the brain parenchyma.5 Cells in the parenchyma with extensive rough endoplasmic reticulum, previously labelled as plasma cells are probably plasmacytoid dendritic cells but this needs confirmation using the specific marker CD123. 6,7

Skin lesions similar to those of non-lepromatous leprosy have been produced in rabbits using a homogenate of human sensory peripheral nerve plus adjuvant. 8 Some of these rabbits have developed a state of granulomatous hypersensitivity. ie Skin testing in sensitised rabbits, using various human non-myelin antigens produces plasma-like cells with extensive rough endoplasmic reticulum both in the dermis9 and also in the endoneurium with axonal damage and thinning of the myelin sheaths. 10 These plasma-like cells could be plasmacytoid dendritic cells.

The most active component is a deoxycholate extracted membrane fraction from the ‘nuclear pellet’ of sensory nerve after the myelin has been removed. 11 It may be possible to induce oral tolerance using this antigen. In order to confirm whether tolerance has occurred, there should be an absence of plasma-like cells in the endoneurium of dermal nerves with no axonal damage at skin-test sites, following challenge with this membrane fraction in sensitised rabbits. Systemic skin lesions should also be prevented if tolerance has occurred. 8 Although the antigen is effective in micrograms of protein, 11 further purification will be necessary in order to localise a similar antigen in the central nervous system.. Tolerance to this similar antigen in the central nervous system may then be possible, in which case a vaccine could be developed to prevent disability in MS.

References

  1. Luth, S., et al. 2008. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J. Clin. Invest. 118: 3403-3410.
  2. Song, F., et al. 2008. The peyer’s patch is a critical immunoregulatory site for mucosal tolerance in experimental autoimmune encephalomyelitis (EAE). J. Autoimmune. 30: 230-237.
  3. Faria, A.M., and Weiner, H.L. 2005. Oral tolerance. Immunol. Rev. 206: 232-259.
  4. Goubier, A., et al. 2008. Plasmacytoid dendritic cells mediate oral tolerance. Immunity. 29: 464-475.
  5. Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E., and Aloisi, F. 2004. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14: 164-174.
  6. Crawford, C.L., and Hardwicke, P.M.D . 2006. Characterizing the mechanisms and progression in multiple sclerosis: evidence and new hypotheses for future directions. Arch. Neurol. 63: 786-787.
  7. Crawford, C.L., and Hardwicke, P. Plasma or plasmacytoid cells in multiple sclerosis? Available at : http://www.jci.org/eletters/view/21357. Accessed 10 Dec 2008.
  8. Crawford, C.L., Evans, D.H.L., and Evans, E.M. 1974. Experimental allergic neuritis induced by sensory nerve myelin may provide a model for nonlepromatous leprosy. Nature. 251: 223-235.
  9. Crawford, C.L., Hardwicke, P.M.D., Evans, D.H.L., and Evans, E.M. 1977. Granulomatous hypersensitivity induced by sensory peripheral nerve. Nature. 265: 457-459.
  10. Crawford, C.L., and Hardwicke, P.M.D. 1979. Somatic unmyelinated degeneration in rabbits with granulomatous hypersensitivity produced by a non-myelin antigen in sensory peripheral nerve. Acta. Neuropath. 45: 1-7.
  11. Hardwicke, P.M.D., and Crawford, C.L. 1977. Nature of the antigen of human sensory nerve that induces granulomatous hypersensitivity. J. Neurochem. 30: 1609-1611.

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