Abstract
BackgroundCathepsin D is a well-characterized aspartic protease expressed ubiquitously in lysosomes. Cathepsin D deficiency is associated with a spectrum of pathologies leading ultimately to death. Cathepsin D is expressed at high levels in many cells of the immune system, but its role in immune function is not well understood. This study examines the reconstitution and function of the immune system in the absence of cathepsin D, using bone marrow radiation chimaeras in which all haematopoietic cells are derived from cathepsin D deficient mice.ResultsCathepsin D deficient bone marrow cells fully reconstitute the major cellular components of both the adaptive and innate immune systems. Spleen cells from cathepsin D deficient chimaeric mice contained an increased number of autofluorescent granules characteristic of lipofuscin positive lysosomal storage diseases. Biochemical and ultrastructural changes in cathepsin D deficient spleen are consistent with increased autolysosomal activity. Chimaeric mice were immunised with either soluble (dinitrophenylated bovine gamma globulin) or particulate (sheep red blood cells) antigens. Both antigens induced equivalent immune responses in wild type or cathepsin D deficient chimaeras.ConclusionAll the parameters of haematopoietic reconstitution and adaptive immunity which were measured in this study were found to be normal in the absence of cathepsin D, even though cathepsin D deficiency leads to dysregulation of lysosomal function.
Highlights
Cathepsin D is a well-characterized aspartic protease expressed ubiquitously in lysosomes
No significant differences in numbers of T cells or B cells or granulocytes were observed between unirradiated control mice, or chimaeras generated from bone marrow taken from cathepsin D deficient (CCDD) or cathepsin D wild type (CCDWT) mice
Levels of cathepsin D in spleen of chimaeric cathepsin D deficient (CCDD) chimaeras were less than 10% of those found in spleens of Chimaeric cathepsin D wild type (CCDWT) chimaeras, confirming that most or all the spleen haematopoietic cells were derived from donor precursors, and did not represent the selective outgrowth of a small minority of surviving host precursor cells
Summary
Cathepsin D is a well-characterized aspartic protease expressed ubiquitously in lysosomes. Cathepsin D deficiency is associated with a spectrum of pathologies leading to death. Cathepsin D is expressed at high levels in many cells of the immune system, but its role in immune function is not well understood. This study examines the reconstitution and function of the immune system in the absence of cathepsin D, using bone marrow radiation chimaeras in which all haematopoietic cells are derived from cathepsin D deficient mice. Cathepsin D, the first cathepsin to be identified, is an aspartic proteinase which is ubiquitously expressed in lysosomes of most eukaryotic cells. Cathepsin D has been implicated in cell growth and apoptosis, though it remains unclear whether these functions require the proteolytic activity of the enzyme, or involve some separate ligand/receptor interaction [2]. The precise link between cathepsin D deficiency and pathology remains unclear, but bulk proteolysis by cathepsin D deficient fibroblasts was found to be normal
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