The immuno-inhibitory adaptor protein SLy2 - a potential therapeutic target for pneumococcal infections

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Dokumentart: PhDThesis
Date: 2014-12-11
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Beer-Hammer, Sandra (PD Dr.)
Day of Oral Examination: 2014-12-03
DDC Classifikation: 570 - Life sciences; biology
610 - Medicine and health
Keywords: Infektion , Immunregulation , Immunglobulin M
Other Keywords: Adaptorprotein
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The present work describes the experimental investigation of the SH3 Lymphocyte protein 2 (SLy2) in the mammalian immune system. SLy2 is an adaptor protein which is physiologically expressed in hematopoietic tissues as well as in heart, brain and placenta. SLy2 is located on human chromosome 21 and was reported to be amongst a particular group of genes, which were amplified in Down syndrome (DS) patients and which were proposed to contribute to DS phenotypes. Aside from congenital heart defects and mental retardation, susceptibility to infections with Streptococcus pneumoniae is a common immunological problem in DS patients. Notably, these infections represent the major cause of mortality in a Swedish DS cohort. In this work, the immunological role of SLy2 was examined with the help of a tg-SLy2 animal model, that over-expresses SLy2 in B and T lymphocytes. The investigations unraveled a novel intracellular mechanism by which abundance of B-1 lymphocytes and their capacity to produce pneumococcal polysaccharide-specific antibodies were inhibited following SLy2 over-expression, suggesting that SLy2 amplification in human DS might contribute to a general susceptibility to S. pneumoniae infections. This hypothesis was supported by additional data from BALB/c and SLy2-/- mice. As previously reported, BALB/c mice were resistant to S. pneumoniae infections, and SLy2-deficient mice generally showed improved adaptive immunity. Here we proved that BALB/c mice share important immunological phenotypes with SLy2-/- mice, including a massive down-regulation of SLy2 in splenic B cells and increased peritoneal B-1 cell abundance. In conclusion, the presented data strongly propose SLy2 as an immuno-inhibitory adaptor protein, which might represent a potential future therapeutic target for prevention of pneumococcal infections.

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