Summary: A new study reports the loss of the Bim protein in macrophages leads to lupus-like symptoms in mice. The findings may help in the development of new treatments for the autoimmune disease in humans.
Source: Northwestern University.
Northwestern Medicine scientists have demonstrated that the loss of a protein called Bim in macrophages — a type of immune cell — leads to the development of lupus-like disease in mice. The findings, published in the Journal of Experimental Medicine, suggest that Bim may be a novel therapeutic target for lupus in humans.
Harris Perlman, PhD, chief of Rheumatology in the Department of Medicine, and Carla M. Cuda, PhD, research assistant professor of Medicine in the Division of Rheumatology, were co-senior authors of the study.
“Our study is the first to suggest an essential role for Bim in monocytes and macrophages in the development of lupus-like disease in mice,” Perlman said. “The idea now is to parlay that into patient material.”
Systemic lupus erythematosus, commonly called lupus, is a chronic inflammatory disorder in which the immune system mistakenly attacks its own healthy tissue, including internal organs. The cause of lupus is unknown.
A prevailing theory is that the systemic autoimmunity seen in lupus is induced by abnormalities in apoptosis — the process of programmed cell death — as well as in the clearance of these apoptotic cells.
The protein Bim, which is expressed in immune cells, is highly involved in the cell death pathway. Previous studies have demonstrated that mice lacking the gene for Bim develop a lupus-like disease within 12 months.
But it was unclear which type of immune cell was most important to the development of lupus.
“The original dogma suggested that it’s your lymphocytes — your T- and B-cells,” explained Perlman, also the Mabel Greene Myers Professor of Medicine. “But therapies that have tried to target T- and B-cells cells have all failed. So, we suggested maybe it’s something else.”
In the current study, the scientists investigated inactivating Bim in a different population: macrophages and their precursors, monocytes. Macrophages are a type of immune cell in tissue that recognize and digest target cells, as well as produce inflammatory cytokines.
The scientists discovered that when the Bim gene was removed in monocytes and macrophages, the mice developed a lupus-like disease — unlike when the same gene was knocked out in T- or B-cells.
The findings suggest for the first time that Bim may be involved in a non-cell death pathway, and may play a role in controlling macrophage function — which could be targeted for novel treatments.
The study also identified a gene signature indicative of lupus in kidney macrophages of mice. In future research, the team intends to investigate this same signature in humans. “The goal is to then determine if we can discover novel therapeutics that might be important for treating these patients,” said Perlman, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Among other future research directions, the team is also investigating if the same system is involved in neuropsychiatric lupus, a major comorbidity. “Lupus is extremely heterogeneous in terms of how many systems are affected and what symptoms patients present with,” Cuda explained. “So a major next step is to see how many other types of disease manifestations we can utilize this model for, in terms of understanding the impact of macrophage-specific Bim.”
Close collaborations with other Feinberg departments and divisions, including Nephrology and Pulmonary, will also help to further discovery in this area moving forward, Cuda and Perlman noted.
FuNien Tsai, PhD, a recent graduate of the Driskill Graduate Program in Life Sciences, was the first author of the paper. Other Feinberg co-authors include Scott Budinger, MD, chief of Pulmonary and Critical Care in the Department of Medicine, Christian Stehlik, PhD, the John P. Gallagher Research Professor of Rheumatology, Alexander Misharin, MD, PhD, assistant professor of Medicine in the Division of Pulmonary and Critical Care, Deborah Winter, PhD, assistant professor of Medicine in the Division of Rheumatology, Andrea Dorfleutner, PhD, research associate professor of Medicine in the Division of Rheumatology, and Hiam Abdala-Valencia, PhD, research assistant professor of Medicine in the Division of Rheumatology.
Funding: The study was supported by the American Heart Association grant PRE21410010, the National Institutes of Health grants K01AR064313, HL108795, AR050250, AR054796, AR064546 and AI092490, the United States-Israel Binational Science Foundation grant 2013247, the Rheumatology Research Foundation grant Agmt 05/06/14, and the Mabel Green Myers Chair of Medicine. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, which was purchased through the support of the National Institutes of Health grant 1S10OD011996-01. Flow cytometry and histology services were provided by the Northwestern University Lurie Cancer Center Flow Cytometry facility and Mouse Histology and Phenotyping Laboratory, which are supported by the National Cancer Institute grant P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
Source: Anna Williams – Northwestern University Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is in the public domain. Original Research:Abstract for “Bim suppresses the development of SLE by limiting myeloid inflammatory responses” by FuNien Tsai, Philip J. Homan, Hemant Agrawal, Alexander V. Misharin, Hiam Abdala-Valencia, G. Kenneth Haines, Salina Dominguez, Christina L. Bloomfield, Rana Saber, Anthony Chang, Chandra Mohan, Jack Hutcheson, Anne Davidson, G.R. Scott Budinger, Philippe Bouillet, Andrea Dorfleutner, Christian Stehlik, Deborah R. Winter, Carla M. Cuda, andHarris Perlman in Journal of Experimental Medicine. Published online November 7 2017 doi:10.1084/jem.20170479
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[cbtabs][cbtab title=”MLA”]Northwestern University “Investigating Protein’s Role in Lupus Development.” NeuroscienceNews. NeuroscienceNews, 5 December 2017. <https://neurosciencenews.com/lupus-bim-genetics-8109/>.[/cbtab][cbtab title=”APA”]Northwestern University (2017, December 5). Investigating Protein’s Role in Lupus Development. NeuroscienceNews. Retrieved December 5, 2017 from https://neurosciencenews.com/lupus-bim-genetics-8109/[/cbtab][cbtab title=”Chicago”]Northwestern University “Investigating Protein’s Role in Lupus Development.” https://neurosciencenews.com/lupus-bim-genetics-8109/ (accessed December 5, 2017).[/cbtab][/cbtabs]
Bim suppresses the development of SLE by limiting myeloid inflammatory responses
The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)–like disease that mirrors aged Bim−/− mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain–containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.
“Bim suppresses the development of SLE by limiting myeloid inflammatory responses” by FuNien Tsai, Philip J. Homan, Hemant Agrawal, Alexander V. Misharin, Hiam Abdala-Valencia, G. Kenneth Haines, Salina Dominguez, Christina L. Bloomfield, Rana Saber, Anthony Chang, Chandra Mohan, Jack Hutcheson, Anne Davidson, G.R. Scott Budinger, Philippe Bouillet, Andrea Dorfleutner, Christian Stehlik, Deborah R. Winter, Carla M. Cuda, andHarris Perlman in Journal of Experimental Medicine. Published online November 7 2017 doi:10.1084/jem.20170479