The loss of a protein called Bim in macrophages leads to the development of lupus-like disease in mice, Northwestern Medicine scientists have shown. The finding suggests that Bim may be a novel therapeutic target for lupus in humans.
“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. The idea now is to parlay that into patient material,"
said Harris Perlman, PhD, chief of Rheumatology in the Department of Medicine. He and Carla M. Cuda, PhD, research assistant professor of Medicine in the Division of Rheumatology, were co-senior authors of the study.
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 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. But therapies that have tried to target T- and B-cells cells have all failed. So, we suggested maybe it’s something else,"
explained Perlman, also the Mabel Greene Myers Professor of Medicine.
Bim And Lupus
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. Among other future research directions, the team is also investigating if the same system is involved in neuropsychiatric lupus, a major comorbidity.
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, Harris Perlman Bim suppresses the development of SLE by limiting myeloid inflammatory responses Journal of Experimental Medicine Dec 2017, 214 (12) 3753-3773; DOI: 10.1084/jem.20170479
Image: Odra Noel, Wellcome Images