Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often it...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1095830/full |
| _version_ | 1827997125398495232 |
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| author | Marina A. Korn Marie Steffensen Carolin Brandl Dmytro Royzman Dmytro Royzman Christoph Daniel Thomas H. Winkler Lars Nitschke |
| author_facet | Marina A. Korn Marie Steffensen Carolin Brandl Dmytro Royzman Dmytro Royzman Christoph Daniel Thomas H. Winkler Lars Nitschke |
| author_sort | Marina A. Korn |
| collection | DOAJ |
| description | Systemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often its etiology remains unknown. Existing efforts to determine this etiology have focused on SLE in mouse models revealing not only that mutations in specific genes lead to SLE development, but also that epistatic effects of several gene mutations significantly amplify disease manifestation. Genome-wide association studies for SLE have identified loci involved in the two biological processes of immune complex clearance and lymphocyte signaling. Deficiency in an inhibitory receptor expressed on B lymphocytes, Siglec-G, has been shown to trigger SLE development in aging mice, as have mutations in DNA degrading DNase1 and DNase1l3, that are involved in clearance of DNA-containing immune complexes. Here, we analyze the development of SLE-like symptoms in mice deficient in either Siglecg and DNase1 or Siglecg and DNase1l3 to evaluate potential epistatic effects of these genes. We found that germinal center B cells and follicular helper T cells were increased in aging Siglecg-/- x Dnase1-/- mice. In contrast, anti-dsDNA antibodies and anti-nuclear antibodies were strongly increased in aging Siglecg-/- x Dnase1l3-/- mice, when compared to single-deficient mice. Histological analysis of the kidneys revealed glomerulonephritis in both Siglecg-/- x Dnase1-/- and Siglecg-/- x Dnase1l3-/- mice, but with a stronger glomerular damage in the latter. Collectively, these findings underscore the impact of the epistatic effects of Siglecg with DNase1 and Dnase1l3 on disease manifestation and highlight the potential combinatory effects of other gene mutations in SLE. |
| first_indexed | 2024-04-10T05:23:36Z |
| format | Article |
| id | doaj.art-64c20df68051432f9f311146a4f6e232 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T05:23:36Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-64c20df68051432f9f311146a4f6e2322023-03-08T05:02:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-03-011410.3389/fimmu.2023.10958301095830Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosusMarina A. Korn0Marie Steffensen1Carolin Brandl2Dmytro Royzman3Dmytro Royzman4Christoph Daniel5Thomas H. Winkler6Lars Nitschke7Division of Genetics, Department of Biology, University of Erlangen, Erlangen, GermanyDivision of Genetics, Department of Biology, University of Erlangen, Erlangen, GermanyDivision of Genetics, Department of Biology, University of Erlangen, Erlangen, GermanyDivision of Genetics, Department of Biology, University of Erlangen, Erlangen, GermanyDepartment of Immune Modulation, University Hospital of Erlangen, Erlangen, GermanyDepartment of Nephropathology, University Hospital of Erlangen, Erlangen, GermanyDivision of Genetics, Department of Biology, University of Erlangen, Erlangen, GermanyDivision of Genetics, Department of Biology, University of Erlangen, Erlangen, GermanySystemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often its etiology remains unknown. Existing efforts to determine this etiology have focused on SLE in mouse models revealing not only that mutations in specific genes lead to SLE development, but also that epistatic effects of several gene mutations significantly amplify disease manifestation. Genome-wide association studies for SLE have identified loci involved in the two biological processes of immune complex clearance and lymphocyte signaling. Deficiency in an inhibitory receptor expressed on B lymphocytes, Siglec-G, has been shown to trigger SLE development in aging mice, as have mutations in DNA degrading DNase1 and DNase1l3, that are involved in clearance of DNA-containing immune complexes. Here, we analyze the development of SLE-like symptoms in mice deficient in either Siglecg and DNase1 or Siglecg and DNase1l3 to evaluate potential epistatic effects of these genes. We found that germinal center B cells and follicular helper T cells were increased in aging Siglecg-/- x Dnase1-/- mice. In contrast, anti-dsDNA antibodies and anti-nuclear antibodies were strongly increased in aging Siglecg-/- x Dnase1l3-/- mice, when compared to single-deficient mice. Histological analysis of the kidneys revealed glomerulonephritis in both Siglecg-/- x Dnase1-/- and Siglecg-/- x Dnase1l3-/- mice, but with a stronger glomerular damage in the latter. Collectively, these findings underscore the impact of the epistatic effects of Siglecg with DNase1 and Dnase1l3 on disease manifestation and highlight the potential combinatory effects of other gene mutations in SLE.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1095830/fullB cell signalingmouse modelsinhibitory receptorslymphocytesautoimmunity |
| spellingShingle | Marina A. Korn Marie Steffensen Carolin Brandl Dmytro Royzman Dmytro Royzman Christoph Daniel Thomas H. Winkler Lars Nitschke Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus Frontiers in Immunology B cell signaling mouse models inhibitory receptors lymphocytes autoimmunity |
| title | Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus |
| title_full | Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus |
| title_fullStr | Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus |
| title_full_unstemmed | Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus |
| title_short | Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus |
| title_sort | epistatic effects of siglec g and dnase1 or dnase1l3 deficiencies in the development of systemic lupus erythematosus |
| topic | B cell signaling mouse models inhibitory receptors lymphocytes autoimmunity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1095830/full |
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