The etiological role of viruses

In common with other autoimmune diseases, it is believed that polygenic genetic susceptibility factors interact with environmental factors to induce SS. Potential viral triggers include sialatropic and lym-photropic viruses such as the herpesviruses, in particular Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus type 6 (HHV-6). Evidence for involvement of any of these viruses has been conflicting, with some studies finding elevated titers of antibodies to all three viruses in patients with SS but others finding them normal. EBV has been detected in parotid and labial salivary glands by DNA hybridization techniques. Salivary epithelium can contain up to 50 copies of EBV DNA per cell in healthy people without inducing an immune response, suggesting that the gland is an important site of persistence. The extent of EBV infection load in salivary glands in SS is still controversial with conflicting reports. While these inconsistent data may reflect the different sensitivities and specificity of the methods or a bias introduced by studies based on small numbers of patients, a role for EBV and the other herpesviruses in the induction of Sjogren's syndrome remains unsubstantiated.

Retroviruses are known to infect cells of the immune system and can cause abnormalities of immune regulation including suppression, destruction or stimulation of T cells, excess antibody production and lymphomas. A subgroup of patients with human immunodeficiency virus (HIV) infection develop diffuse infiltrative lymphocytosis (DIES) of salivary glands and other organs with predominantly CD8+ T cells. They may present with a clinical picture almost indistinguishable from primary SS. In addition there is a high frequency of extraglandular disease including lymphocytic interstitial pneumonitis, lymphocytic hepatitis, lymphocytic interstitial nephritis and lymphocytic aseptic meningitis. In spontaneously occurring SS retroviral A-type particles were identified in lymphoblastoid cells cocul-tured with homogenates of salivary glands from SS patients but there has not been any further information such as sequence data to characterize the virus. A number of studies have detected antibodies to HIV- or human T lymphotropic virus type I (HTLV-I)-related gag sequences but these appeared to be broadly cross-reactive rather than indicating the presence of a specific retrovirus.

Animal models provide further support for the role of retroviruses in SS. Mice with the murine acquired immune deficiency syndrome (MAIDS) caused by the murine leukemia virus develop lymphocytic infiltrates of their salivary glands and other organs. The HTLV-I tax transgenic mouse develops a sialadenitis characterized by focal proliferation of ductal epithelial cells within the major and minor salivary glands followed by lymphocytic infiltration. Recently, a possible role for HTLV-I tax has been suggested in human disease. Using polymerase chain reaction (PGR) and in situ hybridization techniques, Mariette and coworkers detected HTLV-I tax but not gag, pol or env genes in labial salivary gland sections from two of nine patients with SS and none of nine control subjects. A Japanese study has found very similar results. Using PGR they found expression of HTLV-I tax gene without pol, gag or env in four of 14 patients with SS. In this case confirmation of identity was provided by sequence data which showed 100% homology between the nucleotide sequences from the four SS patients and that of the HTLV-I pXIV gene derived from the MT-2 cell line. These studies have not been confirmed in a series of 49 British patients from our unit. Using a highly sensitive PCR-based assay for proviral DNA

in salivary gland biopsies, tax was not detected in any of the samples, except one from a patient who was known to be seropositive for HTLV-I.

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