Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus
While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). T...
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| Format: | Article |
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1499551/full |
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| author | Diana F. Alzamareh Nida Meednu Neha Nandedkar-Kulkarni Daria Krenitsky Jennifer Barnard Ken Yasaka Wesley Durrett Juilee Thakar Juilee Thakar Javier Rangel-Moreno Jennifer H. Anolik Jennifer L. Barnas |
| author_facet | Diana F. Alzamareh Nida Meednu Neha Nandedkar-Kulkarni Daria Krenitsky Jennifer Barnard Ken Yasaka Wesley Durrett Juilee Thakar Juilee Thakar Javier Rangel-Moreno Jennifer H. Anolik Jennifer L. Barnas |
| author_sort | Diana F. Alzamareh |
| collection | DOAJ |
| description | While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target. Here, we compare the matched bone marrow (BM) and peripheral blood (PBL) plasma cell (PC) compartments of SLE and healthy donors (HD). We show a similar distribution of CD138- and CD138+ PC, including putative LLPC (CD19- CD138+ CD38+), between SLE and HD BM. For both SLE and HD, CD138+ PC are at a higher frequency in BM than PBL. Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression. Transcriptomic analysis identifies an interferon (IFN) gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. BM PC and B cells phosphorylate STAT1 in response to type I IFN stimulation in vitro, but with decreased fold change compared to those from the PBL. While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Anti-nuclear autoantibodies (ANA) are found in the BM supernatant and PBL serum of SLE patients. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE. |
| format | Article |
| id | doaj-art-8ee342eb63d14ea9bfe5a0289c4e06ea |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-8ee342eb63d14ea9bfe5a0289c4e06ea2025-08-20T02:46:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14995511499551Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosusDiana F. Alzamareh0Nida Meednu1Neha Nandedkar-Kulkarni2Daria Krenitsky3Jennifer Barnard4Ken Yasaka5Wesley Durrett6Juilee Thakar7Juilee Thakar8Javier Rangel-Moreno9Jennifer H. Anolik10Jennifer L. Barnas11Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, United StatesWhile durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target. Here, we compare the matched bone marrow (BM) and peripheral blood (PBL) plasma cell (PC) compartments of SLE and healthy donors (HD). We show a similar distribution of CD138- and CD138+ PC, including putative LLPC (CD19- CD138+ CD38+), between SLE and HD BM. For both SLE and HD, CD138+ PC are at a higher frequency in BM than PBL. Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression. Transcriptomic analysis identifies an interferon (IFN) gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. BM PC and B cells phosphorylate STAT1 in response to type I IFN stimulation in vitro, but with decreased fold change compared to those from the PBL. While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Anti-nuclear autoantibodies (ANA) are found in the BM supernatant and PBL serum of SLE patients. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1499551/fullplasma cell (PC)lupus (SLE)transitional B cellbone marrowinterferonB cell |
| spellingShingle | Diana F. Alzamareh Nida Meednu Neha Nandedkar-Kulkarni Daria Krenitsky Jennifer Barnard Ken Yasaka Wesley Durrett Juilee Thakar Juilee Thakar Javier Rangel-Moreno Jennifer H. Anolik Jennifer L. Barnas Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus Frontiers in Immunology plasma cell (PC) lupus (SLE) transitional B cell bone marrow interferon B cell |
| title | Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus |
| title_full | Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus |
| title_fullStr | Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus |
| title_full_unstemmed | Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus |
| title_short | Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus |
| title_sort | interferon activation in bone marrow long lived plasma cells in systemic lupus erythematosus |
| topic | plasma cell (PC) lupus (SLE) transitional B cell bone marrow interferon B cell |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1499551/full |
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