The long-term goal of this proposal is to understand the mechanism of salivary gland disease and develop novel therapies to prevent this tissue destruction. HIV-associated salivary gland disease (HIV-SGD) is a similar entity to Sjogren's syndrome (SS) clinically and histologically. A retroviral association with HIV-SGD is well-established, although the role of the virus in HIV-SGD is unclear. Recent reports showing the presence of serum antibodies to the AIDS-associated p24 gag protein in patients with SS provide a compelling argument for the role of a retrovirus in autoimmune disorders. Viruses are known to affect intracellular events such as gene transcription, and protein synthesis and targeting. Our laboratory work has focused on investigating the causes of salivary gland destruction by TEM, immunohistochemistry, and in situ hybridization. Our results show increased levels of a laminin-like protein in ductal epithelium of diseased salivary glands, but normal levels of fibronectin, another basement membrane protein. The mechanism for this abnormality is unknown, but it occurs prior to lymphocytic infiltration and glandular destruction. Our hypothesis is that this abnormality, associated with damage to the basement membrane, is due to a virally-induced increase in laminin expression, which could account for the cellular infiltration and destruction.
The aims of the present study are to quantify laminin expression in SS and determine the effects of HIV on laminin expression in vitro using the following experiments: 1) quantify increased laminin expression in SS and control salivary glands using reverse transcription- polymerase chain reaction (RT-PCR) amplification: 2) determine if HIV infection increases laminin expression in cultured salivary gland cells, using a combination of northern blotting and RT-PCR amplification. These studies will provide the basis for investigating the effects of drugs and viruses on gene expression and regulation of protein levels in vitro.
|Daniels, P J; Gustafson, S A; French, D et al. (2000) Interferon-mediated block in cell cycle and altered integrin expression in a differentiated salivary gland cell line (HSG) cultured on Matrigel. J Interferon Cytokine Res 20:1101-9|
|Daniels, P J; McArthur, C P; Heruth, D P et al. (1999) Cytokine-mediated stimulation of laminin expression and cell-growth arrest in a human submandibular gland duct-cell line (HSG). Arch Oral Biol 44:603-15|
|McArthur, C P; Daniels, P J; Kragel, P et al. (1997) Sjogren's syndrome salivary gland immunopathology: increased laminin expression precedes lymphocytic infiltration. J Autoimmun 10:59-65|