Abstract
We analyzed the activation and function of dendritic cells (DCs) in the spleens of diseased, lupus-prone NZM2410 and NZB-W/F1 mice and age-matched BALB/c and C57BL/6 control mice. Lupus DCs showed an altered ex vivo costimulatory profile, with a significant increase in the expression of CD40, decreased expression of CD80 and CD54, and normal expression of CD86. DCs from young lupus-prone NZM2410 mice, before the development of the disease, expressed normal levels of CD80 and CD86 but already overexpressed CD40. The increase in CD40-positive cells was specific for DCs and involved the subset of myeloid and CD8α+ DCs before disease onset, with a small involvement of plasmacytoid DCs in diseased mice. In vitro data from bone marrow-derived DCs and splenic myeloid DCs suggest that the overexpression of CD40 is not due to a primary alteration of CD40 regulation in DCs but rather to an extrinsic stimulus. Our analyses suggest that the defect of CD80 in NZM2410 and NZB-W/F1 mice, which closely resembles the costimulatory defect found in DCs from humans with systemic lupus erythematosus, is linked to the autoimmune disease. The increase in CD40 may instead participate in disease pathogenesis, being present months before any sign of autoimmunity, and its downregulation should be explored as an alternative to treatment with anti-CD40 ligand in lupus.
Highlights
Dendritic cells (DCs) initiate and maintain immune responses, and evidence suggests that they have an active role in the pathogenesis of lupus: human dendritic cells (DCs) progressively disappear from the blood of patients with lupus [1], possibly because they are sequestered in the secondary lymphoid organs; they show an abnormal costimulatory profile [2], with a specific defect of expression of CD80 [3,4]; and sera from patients with lupus have been shown to induce differentiation of peripheral blood mononuclear cells into DCs, with a mechanism dependent on type I IFN-α [5], a cytokine produced in large amounts by plasmacytoid DCs [6]
Our analyses suggest that the defect of CD80 in NZM2410 and NZB-W/F1 mice, which closely resembles the costimulatory defect found in DCs from humans with systemic lupus erythematosus, is linked to the autoimmune disease
Dendritic cells (DCs) initiate and maintain immune responses, and evidence suggests that they have an active role in the pathogenesis of lupus: human DCs progressively disappear from the blood of patients with lupus [1], possibly because they are sequestered in the secondary lymphoid organs; they show an abnormal costimulatory profile [2], with a specific defect of expression of CD80 [3,4]; and sera from patients with lupus have been shown to induce differentiation of peripheral blood mononuclear cells into DCs, with a mechanism dependent on type I IFN-α [5], a cytokine produced in large amounts by plasmacytoid DCs [6]
Summary
Dendritic cells (DCs) initiate and maintain immune responses, and evidence suggests that they have an active role in the pathogenesis of lupus: human DCs progressively disappear from the blood of patients with lupus [1], possibly because they are sequestered in the secondary lymphoid organs; they show an abnormal costimulatory profile [2], with a specific defect of expression of CD80 [3,4]; and sera from patients with lupus have been shown to induce differentiation of peripheral blood mononuclear cells into DCs, with a mechanism dependent on type I IFN-α [5], a cytokine produced in large amounts by plasmacytoid DCs (pDCs) [6]. DCs accumulate both in T cell areas [7] and B cell areas [8] in the lymph nodes and spleens of lupus-prone MRL/lpr (Fas-deficient) and NZBW/F1 mice; in the latter strain, the accumulation has been attributed to high levels of Flt-3L [9], which is increased in patients with lupus [10]. The antigenpresenting capability of DCs in lupus-prone mice requires further characterization, because normal [9], defective [13], and excessive [14] antigen-presenting cell functions have all been reported in different murine models of lupus. A recent report describes the phenotype of DCs in C57BL/6.Sle mice, a congenic strain of mice in which one of the NZM2410-derived
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