Year: 2010
Type: dissertation
Abstract: Analysing apoptotic cell death it has been observed that late apoptotic cells expose internal membranes with heavily altered glycocalyx. The latter is the target for a plethora of sugar-epitope recognizing proteins such as pentraxins, collectins, galectins, and, less physiological, plant lectins. These lectins bind to late apoptotic as well as to primary and secondary necrotic cells. Strong binding to late apoptotic cells with intact membranes was observed for the plant lectins Narcissus pseudonarcissus (NPn) and Griffonia simplicifolia (GSL II). Within this thesis the C-type lectins CLEC4L/DC-SIGN, CLEC9A/DNGR1, CLEC7A/Dectin-1 and their role in recognition, uptake of apoptotic and necrotic cells and/or their influence on the immunogenicity of dead and dying cells has been investigated. Enhanced binding for CLEC4L/DC-SIGN and CLEC9A/DNGR1 to late apoptotic cells was observed. CLEC9A/DNGR1 binding, which until now was only reported for necrotic cells, could also be demonstrated for late apoptotic PMN endowed with intact membranes. CLEC9A/DNGR1 could, therefore, act as recognition receptor of dying cells at the edge of late apoptosis and secondary necrosis. Its physiological role is yet unkown, but might become clear, when CLEC9A/DNGR1 ligands are revealed. For CLEC7A/Dectin-1 no direct binding to apoptotic or necrotic cells was observed. However, a co-operation with other receptors is proposed, since phagocytosis assays revealed differences in uptake and/or degradation in the absence or presence of CLEC7A/Dectin-1 receptor. In vivo studies revealed an attenuated immune response in the presence of CLEC7A/Dectin-1 against dead and dying cells. This thesis points out that the role of lectin receptors in the clearance process seems to be much more important than assumed. The anti-inflammatory PS-dependent clearance of early apoptotic cells is well characterized. Hence, if apoptotic cells escape clearance, the recognition of their altered surface glycosylation pattern with exposed modified autoantigens by C-type lectin receptors on professional phagocytes and antigen presenting cells is very likely. The role of C-type lectins in immune stimulation in co-operation with other phagocytic receptors is subject to deeper investigation. If involved in the clearance process of late apopotic cells, as the data in this thesis indicate, C-type lectins might be targets for a therapeutic concept for the chronic inflammatory autoimmune diseases SLE, which is linked with clearance deficiencies.
Author: Connie Hesse
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
Award: G4243619321
OpenAlex ID: W3155671700