Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity
Abstract Objectives B cells drive the production of autoreactive antibody‐secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long‐term organ damage. Current treatments for antibody‐mediated autoimmune diseases target B cells...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | Clinical & Translational Immunology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cti2.1470 |
| _version_ | 1797372166926237696 |
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| author | Jack Polmear Lauren Hailes Moshe Olshansky Maureen Rischmueller Elan L'Estrange‐Stranieri Anne L Fletcher Margaret L Hibbs Vanessa L Bryant Kim L Good‐Jacobson |
| author_facet | Jack Polmear Lauren Hailes Moshe Olshansky Maureen Rischmueller Elan L'Estrange‐Stranieri Anne L Fletcher Margaret L Hibbs Vanessa L Bryant Kim L Good‐Jacobson |
| author_sort | Jack Polmear |
| collection | DOAJ |
| description | Abstract Objectives B cells drive the production of autoreactive antibody‐secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long‐term organ damage. Current treatments for antibody‐mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre‐existing long‐lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI‐1 could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods Use of a BMI‐1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn−/− mice, a model of SLE, were treated with the BMI‐1 small molecule inhibitor PTC‐028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast‐based assay was established, and the impact of PTC‐028 on ASCs derived from Sjögren's syndrome patients was evaluated. Results BMI‐1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn−/− mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti‐DNA IgG. PTC‐028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age‐matched healthy donors. Conclusion These data provide evidence that inhibiting BMI‐1 can deplete ASC in a variety of contexts and thus BMI‐1 is a viable therapeutic target for antibody‐mediated autoimmune diseases. |
| first_indexed | 2024-03-08T18:31:59Z |
| format | Article |
| id | doaj.art-a2cc8dc41eea467d987f4c8b9f2b2986 |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-03-08T18:31:59Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-a2cc8dc41eea467d987f4c8b9f2b29862023-12-30T01:50:27ZengWileyClinical & Translational Immunology2050-00682023-01-011210n/an/a10.1002/cti2.1470Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunityJack Polmear0Lauren Hailes1Moshe Olshansky2Maureen Rischmueller3Elan L'Estrange‐Stranieri4Anne L Fletcher5Margaret L Hibbs6Vanessa L Bryant7Kim L Good‐Jacobson8Department of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaThe Queen Elizabeth Hospital and Basil Hetzel Institute Woodville South SA AustraliaDepartment of Immunology, Alfred Research Alliance Monash University Melbourne VIC AustraliaDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaDepartment of Immunology, Alfred Research Alliance Monash University Melbourne VIC AustraliaImmunology Division Walter & Eliza Hall Institute Parkville VIC AustraliaDepartment of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaAbstract Objectives B cells drive the production of autoreactive antibody‐secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long‐term organ damage. Current treatments for antibody‐mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre‐existing long‐lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI‐1 could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods Use of a BMI‐1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn−/− mice, a model of SLE, were treated with the BMI‐1 small molecule inhibitor PTC‐028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast‐based assay was established, and the impact of PTC‐028 on ASCs derived from Sjögren's syndrome patients was evaluated. Results BMI‐1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn−/− mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti‐DNA IgG. PTC‐028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age‐matched healthy donors. Conclusion These data provide evidence that inhibiting BMI‐1 can deplete ASC in a variety of contexts and thus BMI‐1 is a viable therapeutic target for antibody‐mediated autoimmune diseases.https://doi.org/10.1002/cti2.1470antibodyautoimmunityB cellsBMI‐1Sjögren's syndromeSystemic Lupus Erythematosus |
| spellingShingle | Jack Polmear Lauren Hailes Moshe Olshansky Maureen Rischmueller Elan L'Estrange‐Stranieri Anne L Fletcher Margaret L Hibbs Vanessa L Bryant Kim L Good‐Jacobson Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity Clinical & Translational Immunology antibody autoimmunity B cells BMI‐1 Sjögren's syndrome Systemic Lupus Erythematosus |
| title | Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity |
| title_full | Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity |
| title_fullStr | Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity |
| title_full_unstemmed | Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity |
| title_short | Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity |
| title_sort | targeting bmi 1 to deplete antibody secreting cells in autoimmunity |
| topic | antibody autoimmunity B cells BMI‐1 Sjögren's syndrome Systemic Lupus Erythematosus |
| url | https://doi.org/10.1002/cti2.1470 |
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