Protective role of commensal bacteria in Sjögren Syndrome
Mahira Zaheer, Changjun Wang, Fang Bian, Zhiyuan Yu, Humberto Hernandez, Rodrigo G de Souza, Ken T Simmons, Deborah Schady, Alton G Swennes, Stephen C Pflugfelder, Robert A Britton, Cintia S de Paiva, Mahira Zaheer, Changjun Wang, Fang Bian, Zhiyuan Yu, Humberto Hernandez, Rodrigo G de Souza, Ken T Simmons, Deborah Schady, Alton G Swennes, Stephen C Pflugfelder, Robert A Britton, Cintia S de Paiva
Abstract
CD25 knock-out (CD25KO) mice spontaneously develop Sjögren Syndrome (SS)-like inflammation. We investigated the role of commensal bacteria by comparing CD25KO mice housed in conventional or germ-free conditions. Germ-free CD25KO mice have greater corneal barrier dysfunction, lower goblet cell density, increased total lymphocytic infiltration score, increased expression of IFN-γ, IL-12 and higher a frequency of CD4+IFN-γ+ cells than conventional mice. CD4+ T cells isolated from female germ-free CD25KO mice adoptively transferred to naive immunodeficient RAG1KO recipients caused more severe Sjögren-like disease than CD4+ T cells transferred from conventional CD25KO mice. Fecal transplant in germ-free CD25KO mice reversed the spontaneous dry eye phenotype and decreased the generation of pathogenic CD4+IFN-γ+ cells. Our studies indicate that lack of commensal bacteria accelerates the onset and severity of dacryoadenitis and generates autoreactive CD4+T cells with greater pathogenicity in the CD25KO model, suggesting that the commensal bacteria or their metabolites products have immunoregulatory properties that protect exocrine glands in the CD25KO SS model.
Keywords: CD25KO; Dacryoadenitis; Dry eye; Fecal transplant; Germ-free; Microbiome; Sjögren Syndrome.
Conflict of interest statement
Conflict of interest
Baylor College of Medicine has filed a provisional patent. No other conflict of interest that could be perceived to bias the work.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Figures
![Figure 1. Germ-Free Environment Worsens Sjögren Syndrome…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6108910/bin/nihms976634f1.jpg)
Figure 2. Adoptive Transfer Recipients of Germ-free…
Figure 2. Adoptive Transfer Recipients of Germ-free CD25KO CD4 + T cells Develop SS-like Disease
CD4 +…
Figure 3. Fecal Microbiota Transplant in Germ-free…
Figure 3. Fecal Microbiota Transplant in Germ-free CD25KO Ameliorates the Autoimmune Phenotype
Germ-free (GF) CD25KO…
Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in…
Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in CD25KO mice
Wild-type (WT) and CD25KO mice were…
Figure 5. IL-12 Neutralization in Germ-free CD25KO…
Figure 5. IL-12 Neutralization in Germ-free CD25KO mice Improves Autoimmunity
A-Single cell suspensions were prepared…
- Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren's syndrome-like keratoconjunctivitis sicca in CD25KO mice.De Paiva CS, Hwang CS, Pitcher JD 3rd, Pangelinan SB, Rahimy E, Chen W, Yoon KC, Farley WJ, Niederkorn JY, Stern ME, Li DQ, Pflugfelder SC. De Paiva CS, et al. Rheumatology (Oxford). 2010 Feb;49(2):246-58. doi: 10.1093/rheumatology/kep357. Epub 2009 Dec 9. Rheumatology (Oxford). 2010. PMID: 20007286 Free PMC article.
- Deletion of interferon-γ delays onset and severity of dacryoadenitis in CD25KO mice.Pelegrino FS, Volpe EA, Gandhi NB, Li DQ, Pflugfelder SC, de Paiva CS. Pelegrino FS, et al. Arthritis Res Ther. 2012 Nov 1;14(6):R234. doi: 10.1186/ar4077. Arthritis Res Ther. 2012. PMID: 23116218 Free PMC article.
- Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice.Wang C, Zaheer M, Bian F, Quach D, Swennes AG, Britton RA, Pflugfelder SC, de Paiva CS. Wang C, et al. Int J Mol Sci. 2018 Feb 13;19(2):565. doi: 10.3390/ijms19020565. Int J Mol Sci. 2018. PMID: 29438346 Free PMC article.
- The gut-eye-lacrimal gland-microbiome axis in Sjögren Syndrome.Trujillo-Vargas CM, Schaefer L, Alam J, Pflugfelder SC, Britton RA, de Paiva CS. Trujillo-Vargas CM, et al. Ocul Surf. 2020 Apr;18(2):335-344. doi: 10.1016/j.jtos.2019.10.006. Epub 2019 Oct 20. Ocul Surf. 2020. PMID: 31644955 Free PMC article. Review.
- Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model.Hayashi T. Hayashi T. J Biomed Biotechnol. 2011;2011:407031. doi: 10.1155/2011/407031. Epub 2011 Jun 1. J Biomed Biotechnol. 2011. PMID: 21660135 Free PMC article. Review.
- Gastrointestinal microbiome and primary Sjögren's syndrome: a review of the literature and conclusions.Yao YF, Wang MY, Dou XY. Yao YF, et al. Int J Ophthalmol. 2022 Nov 18;15(11):1864-1872. doi: 10.18240/ijo.2022.11.19. eCollection 2022. Int J Ophthalmol. 2022. PMID: 36404958 Free PMC article. Review.
- Microbiome and immune-mediated dry eye: a review.Watane A, Raolji S, Cavuoto K, Galor A. Watane A, et al. BMJ Open Ophthalmol. 2022 Jun;7(1):e000956. doi: 10.1136/bmjophth-2021-000956. BMJ Open Ophthalmol. 2022. PMID: 36161855 Free PMC article. Review.
- Gut Dysbiosis and Fecal Microbiota Transplantation in Autoimmune Diseases.Belvoncikova P, Maronek M, Gardlik R. Belvoncikova P, et al. Int J Mol Sci. 2022 Sep 14;23(18):10729. doi: 10.3390/ijms231810729. Int J Mol Sci. 2022. PMID: 36142642 Free PMC article. Review.
- Ocular surface microbiota: Ophthalmic infectious disease and probiotics.Chiang MC, Chern E. Chiang MC, et al. Front Microbiol. 2022 Aug 19;13:952473. doi: 10.3389/fmicb.2022.952473. eCollection 2022. Front Microbiol. 2022. PMID: 36060740 Free PMC article. Review.
- Mucosal immunology of the ocular surface.de Paiva CS, St Leger AJ, Caspi RR. de Paiva CS, et al. Mucosal Immunol. 2022 Jun;15(6):1143-1157. doi: 10.1038/s41385-022-00551-6. Epub 2022 Aug 24. Mucosal Immunol. 2022. PMID: 36002743 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- CD4-Positive T-Lymphocytes / immunology
- CD4-Positive T-Lymphocytes / pathology
- Cornea / immunology*
- Cornea / pathology
- Dacryocystitis / genetics
- Dacryocystitis / immunology
- Dacryocystitis / microbiology*
- Dacryocystitis / pathology
- Disease Models, Animal
- Fecal Microbiota Transplantation
- Female
- Gastrointestinal Microbiome / immunology
- Gene Expression Regulation
- Germ-Free Life
- Goblet Cells / immunology
- Goblet Cells / pathology
- Homeodomain Proteins / genetics
- Homeodomain Proteins / immunology*
- Interferon-gamma / genetics
- Interferon-gamma / immunology
- Interleukin-12 / genetics
- Interleukin-12 / immunology
- Interleukin-2 Receptor alpha Subunit / deficiency
- Interleukin-2 Receptor alpha Subunit / genetics
- Interleukin-2 Receptor alpha Subunit / immunology*
- Lacrimal Apparatus / immunology*
- Lacrimal Apparatus / pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Permeability
- Sjogren's Syndrome / genetics
- Sjogren's Syndrome / immunology
- Sjogren's Syndrome / microbiology*
- Sjogren's Syndrome / pathology
- Symbiosis / immunology*
- Homeodomain Proteins
- IFNG protein, mouse
- Il2ra protein, mouse
- Interleukin-2 Receptor alpha Subunit
- RAG-1 protein
- Interleukin-12
- Interferon-gamma
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 2. Adoptive Transfer Recipients of Germ-free…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6108910/bin/nihms976634f2.jpg)
Figure 3. Fecal Microbiota Transplant in Germ-free…
Figure 3. Fecal Microbiota Transplant in Germ-free CD25KO Ameliorates the Autoimmune Phenotype
Germ-free (GF) CD25KO…
Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in…
Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in CD25KO mice
Wild-type (WT) and CD25KO mice were…
Figure 5. IL-12 Neutralization in Germ-free CD25KO…
Figure 5. IL-12 Neutralization in Germ-free CD25KO mice Improves Autoimmunity
A-Single cell suspensions were prepared…
- Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren's syndrome-like keratoconjunctivitis sicca in CD25KO mice.De Paiva CS, Hwang CS, Pitcher JD 3rd, Pangelinan SB, Rahimy E, Chen W, Yoon KC, Farley WJ, Niederkorn JY, Stern ME, Li DQ, Pflugfelder SC. De Paiva CS, et al. Rheumatology (Oxford). 2010 Feb;49(2):246-58. doi: 10.1093/rheumatology/kep357. Epub 2009 Dec 9. Rheumatology (Oxford). 2010. PMID: 20007286 Free PMC article.
- Deletion of interferon-γ delays onset and severity of dacryoadenitis in CD25KO mice.Pelegrino FS, Volpe EA, Gandhi NB, Li DQ, Pflugfelder SC, de Paiva CS. Pelegrino FS, et al. Arthritis Res Ther. 2012 Nov 1;14(6):R234. doi: 10.1186/ar4077. Arthritis Res Ther. 2012. PMID: 23116218 Free PMC article.
- Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice.Wang C, Zaheer M, Bian F, Quach D, Swennes AG, Britton RA, Pflugfelder SC, de Paiva CS. Wang C, et al. Int J Mol Sci. 2018 Feb 13;19(2):565. doi: 10.3390/ijms19020565. Int J Mol Sci. 2018. PMID: 29438346 Free PMC article.
- The gut-eye-lacrimal gland-microbiome axis in Sjögren Syndrome.Trujillo-Vargas CM, Schaefer L, Alam J, Pflugfelder SC, Britton RA, de Paiva CS. Trujillo-Vargas CM, et al. Ocul Surf. 2020 Apr;18(2):335-344. doi: 10.1016/j.jtos.2019.10.006. Epub 2019 Oct 20. Ocul Surf. 2020. PMID: 31644955 Free PMC article. Review.
- Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model.Hayashi T. Hayashi T. J Biomed Biotechnol. 2011;2011:407031. doi: 10.1155/2011/407031. Epub 2011 Jun 1. J Biomed Biotechnol. 2011. PMID: 21660135 Free PMC article. Review.
- Gastrointestinal microbiome and primary Sjögren's syndrome: a review of the literature and conclusions.Yao YF, Wang MY, Dou XY. Yao YF, et al. Int J Ophthalmol. 2022 Nov 18;15(11):1864-1872. doi: 10.18240/ijo.2022.11.19. eCollection 2022. Int J Ophthalmol. 2022. PMID: 36404958 Free PMC article. Review.
- Microbiome and immune-mediated dry eye: a review.Watane A, Raolji S, Cavuoto K, Galor A. Watane A, et al. BMJ Open Ophthalmol. 2022 Jun;7(1):e000956. doi: 10.1136/bmjophth-2021-000956. BMJ Open Ophthalmol. 2022. PMID: 36161855 Free PMC article. Review.
- Gut Dysbiosis and Fecal Microbiota Transplantation in Autoimmune Diseases.Belvoncikova P, Maronek M, Gardlik R. Belvoncikova P, et al. Int J Mol Sci. 2022 Sep 14;23(18):10729. doi: 10.3390/ijms231810729. Int J Mol Sci. 2022. PMID: 36142642 Free PMC article. Review.
- Ocular surface microbiota: Ophthalmic infectious disease and probiotics.Chiang MC, Chern E. Chiang MC, et al. Front Microbiol. 2022 Aug 19;13:952473. doi: 10.3389/fmicb.2022.952473. eCollection 2022. Front Microbiol. 2022. PMID: 36060740 Free PMC article. Review.
- Mucosal immunology of the ocular surface.de Paiva CS, St Leger AJ, Caspi RR. de Paiva CS, et al. Mucosal Immunol. 2022 Jun;15(6):1143-1157. doi: 10.1038/s41385-022-00551-6. Epub 2022 Aug 24. Mucosal Immunol. 2022. PMID: 36002743 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- CD4-Positive T-Lymphocytes / immunology
- CD4-Positive T-Lymphocytes / pathology
- Cornea / immunology*
- Cornea / pathology
- Dacryocystitis / genetics
- Dacryocystitis / immunology
- Dacryocystitis / microbiology*
- Dacryocystitis / pathology
- Disease Models, Animal
- Fecal Microbiota Transplantation
- Female
- Gastrointestinal Microbiome / immunology
- Gene Expression Regulation
- Germ-Free Life
- Goblet Cells / immunology
- Goblet Cells / pathology
- Homeodomain Proteins / genetics
- Homeodomain Proteins / immunology*
- Interferon-gamma / genetics
- Interferon-gamma / immunology
- Interleukin-12 / genetics
- Interleukin-12 / immunology
- Interleukin-2 Receptor alpha Subunit / deficiency
- Interleukin-2 Receptor alpha Subunit / genetics
- Interleukin-2 Receptor alpha Subunit / immunology*
- Lacrimal Apparatus / immunology*
- Lacrimal Apparatus / pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Permeability
- Sjogren's Syndrome / genetics
- Sjogren's Syndrome / immunology
- Sjogren's Syndrome / microbiology*
- Sjogren's Syndrome / pathology
- Symbiosis / immunology*
- Homeodomain Proteins
- IFNG protein, mouse
- Il2ra protein, mouse
- Interleukin-2 Receptor alpha Subunit
- RAG-1 protein
- Interleukin-12
- Interferon-gamma
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 3. Fecal Microbiota Transplant in Germ-free…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6108910/bin/nihms976634f3.jpg)
Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in…
Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in CD25KO mice
Wild-type (WT) and CD25KO mice were…
Figure 5. IL-12 Neutralization in Germ-free CD25KO…
Figure 5. IL-12 Neutralization in Germ-free CD25KO mice Improves Autoimmunity
A-Single cell suspensions were prepared…
- Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren's syndrome-like keratoconjunctivitis sicca in CD25KO mice.De Paiva CS, Hwang CS, Pitcher JD 3rd, Pangelinan SB, Rahimy E, Chen W, Yoon KC, Farley WJ, Niederkorn JY, Stern ME, Li DQ, Pflugfelder SC. De Paiva CS, et al. Rheumatology (Oxford). 2010 Feb;49(2):246-58. doi: 10.1093/rheumatology/kep357. Epub 2009 Dec 9. Rheumatology (Oxford). 2010. PMID: 20007286 Free PMC article.
- Deletion of interferon-γ delays onset and severity of dacryoadenitis in CD25KO mice.Pelegrino FS, Volpe EA, Gandhi NB, Li DQ, Pflugfelder SC, de Paiva CS. Pelegrino FS, et al. Arthritis Res Ther. 2012 Nov 1;14(6):R234. doi: 10.1186/ar4077. Arthritis Res Ther. 2012. PMID: 23116218 Free PMC article.
- Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice.Wang C, Zaheer M, Bian F, Quach D, Swennes AG, Britton RA, Pflugfelder SC, de Paiva CS. Wang C, et al. Int J Mol Sci. 2018 Feb 13;19(2):565. doi: 10.3390/ijms19020565. Int J Mol Sci. 2018. PMID: 29438346 Free PMC article.
- The gut-eye-lacrimal gland-microbiome axis in Sjögren Syndrome.Trujillo-Vargas CM, Schaefer L, Alam J, Pflugfelder SC, Britton RA, de Paiva CS. Trujillo-Vargas CM, et al. Ocul Surf. 2020 Apr;18(2):335-344. doi: 10.1016/j.jtos.2019.10.006. Epub 2019 Oct 20. Ocul Surf. 2020. PMID: 31644955 Free PMC article. Review.
- Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model.Hayashi T. Hayashi T. J Biomed Biotechnol. 2011;2011:407031. doi: 10.1155/2011/407031. Epub 2011 Jun 1. J Biomed Biotechnol. 2011. PMID: 21660135 Free PMC article. Review.
- Gastrointestinal microbiome and primary Sjögren's syndrome: a review of the literature and conclusions.Yao YF, Wang MY, Dou XY. Yao YF, et al. Int J Ophthalmol. 2022 Nov 18;15(11):1864-1872. doi: 10.18240/ijo.2022.11.19. eCollection 2022. Int J Ophthalmol. 2022. PMID: 36404958 Free PMC article. Review.
- Microbiome and immune-mediated dry eye: a review.Watane A, Raolji S, Cavuoto K, Galor A. Watane A, et al. BMJ Open Ophthalmol. 2022 Jun;7(1):e000956. doi: 10.1136/bmjophth-2021-000956. BMJ Open Ophthalmol. 2022. PMID: 36161855 Free PMC article. Review.
- Gut Dysbiosis and Fecal Microbiota Transplantation in Autoimmune Diseases.Belvoncikova P, Maronek M, Gardlik R. Belvoncikova P, et al. Int J Mol Sci. 2022 Sep 14;23(18):10729. doi: 10.3390/ijms231810729. Int J Mol Sci. 2022. PMID: 36142642 Free PMC article. Review.
- Ocular surface microbiota: Ophthalmic infectious disease and probiotics.Chiang MC, Chern E. Chiang MC, et al. Front Microbiol. 2022 Aug 19;13:952473. doi: 10.3389/fmicb.2022.952473. eCollection 2022. Front Microbiol. 2022. PMID: 36060740 Free PMC article. Review.
- Mucosal immunology of the ocular surface.de Paiva CS, St Leger AJ, Caspi RR. de Paiva CS, et al. Mucosal Immunol. 2022 Jun;15(6):1143-1157. doi: 10.1038/s41385-022-00551-6. Epub 2022 Aug 24. Mucosal Immunol. 2022. PMID: 36002743 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- CD4-Positive T-Lymphocytes / immunology
- CD4-Positive T-Lymphocytes / pathology
- Cornea / immunology*
- Cornea / pathology
- Dacryocystitis / genetics
- Dacryocystitis / immunology
- Dacryocystitis / microbiology*
- Dacryocystitis / pathology
- Disease Models, Animal
- Fecal Microbiota Transplantation
- Female
- Gastrointestinal Microbiome / immunology
- Gene Expression Regulation
- Germ-Free Life
- Goblet Cells / immunology
- Goblet Cells / pathology
- Homeodomain Proteins / genetics
- Homeodomain Proteins / immunology*
- Interferon-gamma / genetics
- Interferon-gamma / immunology
- Interleukin-12 / genetics
- Interleukin-12 / immunology
- Interleukin-2 Receptor alpha Subunit / deficiency
- Interleukin-2 Receptor alpha Subunit / genetics
- Interleukin-2 Receptor alpha Subunit / immunology*
- Lacrimal Apparatus / immunology*
- Lacrimal Apparatus / pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Permeability
- Sjogren's Syndrome / genetics
- Sjogren's Syndrome / immunology
- Sjogren's Syndrome / microbiology*
- Sjogren's Syndrome / pathology
- Symbiosis / immunology*
- Homeodomain Proteins
- IFNG protein, mouse
- Il2ra protein, mouse
- Interleukin-2 Receptor alpha Subunit
- RAG-1 protein
- Interleukin-12
- Interferon-gamma
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
![Figure 4. Antibiotic Treatment Worsens Dacryoadenitis in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6108910/bin/nihms976634f4.jpg)
Figure 5. IL-12 Neutralization in Germ-free CD25KO…
Figure 5. IL-12 Neutralization in Germ-free CD25KO mice Improves Autoimmunity
A-Single cell suspensions were prepared…
![Figure 5. IL-12 Neutralization in Germ-free CD25KO…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6108910/bin/nihms976634f5.jpg)
Source: PubMed