Showing papers by "Per A. Peterson published in 2000"

Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.

Abstract: Tangier disease (TD) and familial HDL deficiency (FHA) have recently been linked to mutations in the human ATP-binding cassette transporter 1 (hABCA1), a member of the ABC superfamily. Both diseases are characterized by the lowering or lack of high-density lipoprotein cholesterol (HDL-C) and low serum cholesterol. The murine ABCA1−/− phenotype corroborates the human TD linkage to ABCA1. Similar to TD in humans, HDL-C is virtually absent in ABCA1−/− mice accompanied by a reduction in serum cholesterol and lipid deposition in various tissues. In addition, the placenta of ABCA1−/− mice is malformed, resulting in severe embryo growth retardation, fetal loss, and neonatal death. The basis for these defects appears to be altered steroidogenesis, a direct result of the lack of HDL-C. By 6 months of age, ABCA1−/− animals develop membranoproliferative glomerulonephritis due to deposition of immunocomplexes followed by cardiomegaly with ventricular dilation and hypertrophy, ultimately succumbing to congestive heart failure. This murine model of TD will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them.

T cells can use either T cell receptor or CD28 receptors to absorb and internalize cell surface molecules derived from antigen-presenting cells.

Abstract: At the site of contact between T cells and antigen-presenting cells (APCs), T cell receptor (TCR)–peptide–major histocompatibility complex (MHC) interaction is intensified by interactions between other molecules, notably by CD28 and lymphocyte function-associated antigen 1 (LFA-1) on T cells interacting with B7 (B7-1 and B7-2), and intracellular adhesion molecule 1 (ICAM-1), respectively, on APCs. Here, we show that during T cell–APC interaction, T cells rapidly absorb various molecules from APCs onto the cell membrane and then internalize these molecules. This process is dictated by at least two receptors on T cells, namely CD28 and TCR molecules. The biological significance of T cell uptake of molecules from APCs is unclear. One possibility is that this process may allow activated T cells to move freely from one APC to another and eventually gain entry into the circulation.

Human cytomegalovirus immediate early glycoprotein US3 retains MHC class I molecules by transient association.

Abstract: Human cytomegalovirus (HCMV) interferes with major histocompatibility complex (MHC) class I antigen presentation by a sequential multistep process to escape T cell surveillance. During the immediate early phase of infection, the glycoprotein US3 prevents intracellular transport of MHC class I molecules. Interestingly, US3 displays a significantly shorter half-life than US3-retained MHC class I molecules. Here we show that US3 associates only transiently with MHC class I molecules, exits the ER, and is inefficiently retrieved from the Golgi. US3 was degraded in a post-Golgi compartment, most likely lysosomes, because: i) Brefeldin A treatment prolonged the half-life of US3; and ii) US3 co-localized with the lysosomal marker protein LAMP in chloroquine-treated cells. In contrast, MHC class I molecules remained stable in the ER. Upon inhibition of protein synthesis MHC class I molecules were released suggesting that a continuous supply of newly synthesized US3 molecules is required for inhibition of transport. Thus, US3 does not seem to retain MHC class I molecules by a retrieval mechanism. Instead, our observations are consistent with US3 preventing MHC class I trafficking by blocking forward transport.

The major histocompatibility complex-encoded HFE in iron homeostasis and immune function.

Abstract: HFE is a non-classical major histocompatibility complex class I molecule that complexes with a β2-microglobulin. A functional link between HFE and iron metabolism has been established by the discovery of aphysical association between HFE and the transferrin receptor. By inhibiting transferrin receptor internalization, HFE functions as a negative modulator of transferrin receptor function. In addition, HFE appears to be an iron sensor that directly or indirectly communicates the body’s iron status to T cells, which then use cytokines as feedback modulators to achieve iron homeostasis. A working model for the feedback regulatory mechanism between iron metabolism and immune function is proposed.

Atp-binding cassette transporter (abc1) modified transgenic mice

Abstract: A transgenic mouse with alterations in an abc1 gene is prepared by introduction of an altered abc1 gene into a host animal The resulting transgenic mice do not produce functional ABC1 protein molecules Cells and cell lines derived from these animals also contain the altered abc1 gene

Methods for Producing B cells and antibodies from H2-O modified transgenic mice

Abstract: A transgenic animal with alterations in an H2-O gene is prepared by introduction of an altered H2-O gene into a host animal. The resulting transgenic animals produce a substantially greater frequency of high affinity antibodies compared to H2-O wild type animals. A method for the production of high affinity antibodies is disclosed.