DEFECTIVE REPAIR OF O-6-METHYLGUANINE-DNA IN PRIMARY SJOGRENS-SYNDROME PATIENTS PREDISPOSED TO LYMPHOMA

Objective--To investigate a role for mutation in the aetiogenesis of autoimmune disease by examining levels of repairing enzyme for the promutagenic DNA base lesion, O-6-methylguanine, in lymphocyte extracts from patients with autoimmune diseases. We included primary Sjogrens syndrome (PSS) patients because of the additional relevance of their being at increased risk (>40-fold) of developing lymphoma. Methods-Lymphocytes were prepared from patients with PSS (n = 22) (12 with parotid gland enlargement, an indicator of extensive lymphoproliferation), rheumatoid arthritis (n = 12), primary biliary cirrhosis (n = 11), osteoarthritis (n = 12), and healthy individuals (n = 11). MGMT amounts were determined in lymphocyte extracts by direct enzyme assay and expressed in relation to total extract DNA, protein, or cell number. Results-We found no defect in the repairing methyltransferase enzyme between any of the groups, except in PSS patients at increased risk of developing lymphoma (those with enlarged parotid glands): p < 0.0001 and p = 0.0056, compared with healthy controls and PSS patients without parotid gland swelling, respectively. Conclusions-Our findings implicate persistence of O-6-methylguanine-DNA in the aetiology of lymphoma associated with PSS, and raise the possibility that an alternative repair process for O-6-methylguanine-DNA, nucleotide excision repair, might be defective in autoimmune disease.