This dissertation, "Induction and Regulation of Autoimmune Responses by Dendritic Cells Upon Interaction With Dying Cells in Murine Models" by Liang, Ma, 馬亮, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author.
Abstract:
Abstract of thesis entitled Induction and regulation of autoimmune responses by dendritic cells upon interaction with dying cells in murine models
Submitted by Liang Ma
for the degree of Doctor of Philosophy at The University of Hong Kong in August 2005
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the loss of immunological tolerance to a multitude of self-antigens. Production of autoantibodies against nuclear antigens (ANA), anti-double-stranded DNA antibodies (anti-dsDNA) in particular, is a classical hallmark of the disease, the mechanism underlying their induction remains unclear. Dendritic cells (DCs) are professional antigen-presenting cells (APC) that play important roles in the initiation and regulation of immune responses. Emerging evidence indicates that abnormally regulated DC functions may result in a break of peripheral tolerance leading to autoimmunity. DCs have been shown to take up dying cells and process antigens derived from the dying cells for antigen presentation. Importantly, the interactions between DCs and dying cells in return also modulate DC functions. The present study was therefore designed to investigate whether and how DCs may interact with dying cells to induce the ANA responses leading to autoimmune disease.
The results showed that mouse bone marrow-derived DCs took up both necrotic and apoptotic cells rapidly and efficiently in vitro. After injection of the DCs that had taken up necrotic (DC/nec) cells, strong anti-dsDNA responses (IgG) were observed in both the lupus-prone and normal control mice. Injection of DC/nec not only accelerated the disease progression in the MRL/lpr lupus-prone mice, but also induced a lupus-like disease in the MRL/+ wild type control strain. Glomerular hypercellularity and immune complex deposition were readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/+ mice that had received DC/nec but not DC/apo developed a 'butterfly' facial lesion mirroring vividly a cardinal feature of human SLE. In contrast, injection of DCs that had taken up apoptotic cells (DC/apo) induced significantly lower levels of the autoantibodies with no or minimal disease activity. Moreover, injection of DC/apo into young MRL/lpr (lupus-prone) was also found to exert tolerogenic effects on both the spontaneous and DC/nec-induced disease activities. These included the suppressed anti-dsDNA antibody responses, reduced proteinuria and decreased mortality.
The DC/nec-induced clinical manifestations of lupus were evident however only in the susceptible mouse strains (MRL/lpr, MRL/+) and not in the normal C57BL/6 strain. This was found to be closely correlated with the ability of DC/nec from these different mouse strains to induce a Th1 type of responses in vitro and in vivo, including the increased IFN-γ and decreased IL-10 activities and, more importantly, the preferential induction of pathogenic IgG2a anti-dsDNA antibodies. Taken together, the present study demonstrates that interactions of DCs with necrotic and apoptotic cells differentially regulate DC functions. The abnormally regulated DC activities may result in the activation of self reactive lymphocytes leading to autoimmunity. In particular, it suggests that a Th1-type of responses induced by DC/nec may play a crucial role in the pathogenesis of lupus disea