Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Myeloid but Not Lymphoid Bim Expression Is Required Suppress SLE-Like Disease.
Agrawal1, Hemant, Weber1, Evan, Misharin1, Alexander, Cuda1, Carla M., Haines2, G. Kenneth, Ramsey-Goldman1, Rosalind, Perlman1, Harris
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease of unknown etiology characterized by production of autoantibodies and extensive end organ damage. While it is clear that T and B cells are critical to SLE pathogenesis, intrinsic differences in myeloid cells, such as macrophages (Mj) and dendritic cells (DC), may influence the T and B cell phenotypes observed in patients with SLE. To date, few studies have focused on the loss of Bim, a pro-apoptotic member of the Bcl-2 family, specifically in monocytes/Mj and its non-apoptotic roles such as activation, cytokine production, and presentation and their relationship to the pathogenesis of lupus.
Peripheral blood from aged and sex matched healthy controls and patients with inactive (SLAM <2) or active SLE (SLAM >10) were analyzed for monocyte expression of Bim and markers of activation. Additionally, mice lacking Bim specifically in T cells (CreCD4Bimflox/flox), B cells (CreCD19Bimflox/flox) and monocytes/Mj (CreLysMBimflox/flox) using the Cre-loxP system were generated and the deletion of Bim was verified by real time PCR. Bimflox/flox (Bim intact) mice were used as controls. Young (<2 mon) and aged mice (>6 mon) were phenotyped using histological and flow cytometric analyses. Luminex based assays and ELISAs were performed to detect antibody isotypes, autoantibodies, cytokines/chemokines, and activation of kinases. A pathologist blinded to the study scored all tissues for SLE-like disease.
SLE patients with active disease displayed reduced expression of Bim in monocytes but not in lymphocytes or granulocytes, which was associated with increased expression of HLA-DR, CCR2, CD62L, and CCR5 but not CD163. To further understand the importance of the reduction of Bim in monocytes, we studied mice lacking Bim in monocytes/Mj. Young and aged CreLysMBimflox/flox mice showed severe splenomegaly compared to Bimflox/flox, CreCD4Bimflox/flox and CreCD19Bimflox/flox mice. While both young and aged CreLysMBimflox/flox mice had increased numbers of activated splenic Mj and DC, only the aged CreLysMBimflox/flox mice had increased numbers of splenic Mj. Furthermore, young and aged CreLysMBimflox/flox mice showed increased accumulation of activated splenic B and T cells. Mj from young CreLysMBimflox/flox mice induced increased OT-II T-cell responses as compared to Bimflox/flox mice and displayed reduced phospho-AKT but increased phospho-cJun, and p38. Additionally, Mj from aged mice showed reduced caspase 3/7 activation. There were elevated levels of circulating autoantibodies (total IgM and isotypes of IgG) and cytokines (IL-12p70 and IL-17) in CreLysMBimflox/flox mice serum. Moreover, CreLysMBimflox/flox mice displayed severe renal damage as evident by increased glomerular size, cellular infiltration, retention of immune complexes, and high kidney disease scores.
These data demonstrate that reduction of Bim leads to a novel and non-apoptotic phenotype in monocytes/Mj and the loss or reduction of Bim in monocytes/Mj is sufficient to activate lymphocytes and SLE-like disease. Thus, the level of Bim in monocytes/Mj may be a biomarker of SLE-disease activity.
To cite this abstract, please use the following information:
Agrawal, Hemant, Weber, Evan, Misharin, Alexander, Cuda, Carla M., Haines, G. Kenneth, Ramsey-Goldman, Rosalind, et al; Myeloid but Not Lymphoid Bim Expression Is Required Suppress SLE-Like Disease. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :859