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

Dept Med/Div Rheumatology, Northwestern University
Yale University

Purpose:

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.

Method:

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.

Summary:

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.

Conclusion:

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
DOI: 10.1002/art.28627

Abstract Supplement

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