Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel

Christine Moelzer; Yi-Hsia Liu; Elizabeth Muckersie; Izabela Klaska; Richard J. Cornall; Heather Wilson; Lucia Kuffova; John Forrester

doi:10.1038/s41598-022-27018-9

Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel

Christine Moelzer, Yi-Hsia Liu, Elizabeth Muckersie, Izabela Klaska, Richard J. Cornall, Heather Wilson, Lucia Kuffova, John Forrester^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina crossed with 3A9 mice expressing a transgenic HEL-specific TCR spontaneously develop uveoretinitis at post-partum day (P)20/21. Double transgenic (dTg TCR/HEL) mice also spontaneously develop clinical signs of colitis at ~ P30 with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show increased histological LP cell infiltration but no bowel shortening and diarrhoea. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide complexes (MHCII-HEL), not only in the inflamed retina but also in the colon and have the potential for antigen presentation. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye can activate colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feedback to amplify IOI.

Original language	English
Article number	1256
Number of pages	14
Journal	Scientific Reports
Volume	13
DOIs	https://doi.org/10.1038/s41598-022-27018-9
Publication status	Published - 23 Jan 2023

Bibliographical note

Acknowledgements
This work was funded by Fight for Sight, The Eye Charity [CSO project grant award: 3031-3032; grant code: RG14602-10], and The Development Trust of the University of Aberdeen (Saving Sight in Grampian) [grant codes: RG-12663, and RG-14251]. We thank the Iain Fraser Flow Cytometry core facility1 and the Microscopy and Histology core facility2 of the University of Aberdeen, and the NHS Grampian Pathology Department3, particularly Andrea Holme1, Ailsa Laird1, Gillian Milne2, Debbie Wilkinson2, Lucy Wight2, Linda Davidson3 and Jacqueline Strachan3. We thank Petruta Morvay (University of Exeter, Exeter, UK) for her valuable assistance with the preparation of bowel Swiss rolls.

Data Availability Statement

The dataset generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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title = "Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel",

abstract = "Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina crossed with 3A9 mice expressing a transgenic HEL-specific TCR spontaneously develop uveoretinitis at post-partum day (P)20/21. Double transgenic (dTg TCR/HEL) mice also spontaneously develop clinical signs of colitis at ~ P30 with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show increased histological LP cell infiltration but no bowel shortening and diarrhoea. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide complexes (MHCII-HEL), not only in the inflamed retina but also in the colon and have the potential for antigen presentation. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye can activate colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feedback to amplify IOI.",

author = "Christine Moelzer and Yi-Hsia Liu and Elizabeth Muckersie and Izabela Klaska and Cornall, {Richard J.} and Heather Wilson and Lucia Kuffova and John Forrester",

note = "Acknowledgements This work was funded by Fight for Sight, The Eye Charity [CSO project grant award: 3031-3032; grant code: RG14602-10], and The Development Trust of the University of Aberdeen (Saving Sight in Grampian) [grant codes: RG-12663, and RG-14251]. We thank the Iain Fraser Flow Cytometry core facility1 and the Microscopy and Histology core facility2 of the University of Aberdeen, and the NHS Grampian Pathology Department3, particularly Andrea Holme1, Ailsa Laird1, Gillian Milne2, Debbie Wilkinson2, Lucy Wight2, Linda Davidson3 and Jacqueline Strachan3. We thank Petruta Morvay (University of Exeter, Exeter, UK) for her valuable assistance with the preparation of bowel Swiss rolls.",

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T1 - Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel

AU - Moelzer, Christine

AU - Liu, Yi-Hsia

AU - Muckersie, Elizabeth

AU - Klaska, Izabela

AU - Cornall, Richard J.

AU - Wilson, Heather

AU - Kuffova, Lucia

AU - Forrester, John

N1 - Acknowledgements This work was funded by Fight for Sight, The Eye Charity [CSO project grant award: 3031-3032; grant code: RG14602-10], and The Development Trust of the University of Aberdeen (Saving Sight in Grampian) [grant codes: RG-12663, and RG-14251]. We thank the Iain Fraser Flow Cytometry core facility1 and the Microscopy and Histology core facility2 of the University of Aberdeen, and the NHS Grampian Pathology Department3, particularly Andrea Holme1, Ailsa Laird1, Gillian Milne2, Debbie Wilkinson2, Lucy Wight2, Linda Davidson3 and Jacqueline Strachan3. We thank Petruta Morvay (University of Exeter, Exeter, UK) for her valuable assistance with the preparation of bowel Swiss rolls.

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N2 - Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina crossed with 3A9 mice expressing a transgenic HEL-specific TCR spontaneously develop uveoretinitis at post-partum day (P)20/21. Double transgenic (dTg TCR/HEL) mice also spontaneously develop clinical signs of colitis at ~ P30 with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show increased histological LP cell infiltration but no bowel shortening and diarrhoea. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide complexes (MHCII-HEL), not only in the inflamed retina but also in the colon and have the potential for antigen presentation. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye can activate colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feedback to amplify IOI.

AB - Undifferentiated uveitis (intraocular inflammation, IOI) is an idiopathic sight-threatening, presumed autoimmune disease, accountable for ~ 10% of all blindness in the developed world. We have investigated the association of uveitis with inflammatory bowel disease (IBD) using a mouse model of spontaneous experimental autoimmune uveoretinitis (EAU). Mice expressing the transgene (Tg) hen egg lysozyme (HEL) in the retina crossed with 3A9 mice expressing a transgenic HEL-specific TCR spontaneously develop uveoretinitis at post-partum day (P)20/21. Double transgenic (dTg TCR/HEL) mice also spontaneously develop clinical signs of colitis at ~ P30 with diarrhoea, bowel shortening, oedema and lamina propria (LP) inflammatory cell infiltration. Single (s)Tg TCR (3A9) mice also show increased histological LP cell infiltration but no bowel shortening and diarrhoea. dTg TCR/HEL mice are profoundly lymphopenic at weaning. In addition, dTg TCR/HEL mice contain myeloid cells which express MHC Class II-HEL peptide complexes (MHCII-HEL), not only in the inflamed retina but also in the colon and have the potential for antigen presentation. In this model the lymphopenia and reduction in the absolute Treg numbers in dTg TCR/HEL mice is sufficient to initiate eye disease. We suggest that cell-associated antigen released from the inflamed eye can activate colonic HEL-specific T cells which, in a microbial micro-environment, not only cause colitis but feedback to amplify IOI.

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DO - 10.1038/s41598-022-27018-9

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SN - 2045-2322

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JO - Scientific Reports

JF - Scientific Reports

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Colitis in a transgenic mouse model of autoimmune uveitis may be induced by neoantigen presentation in the bowel

Abstract

Bibliographical note

Data Availability Statement

UN SDGs

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