Subgroups of Graves' patients identified on the basis of the biochemical activities of their immunoglobulins.

Graves' patient immunoglobulins (IgG) are known to activate adenylyl cyclase. Recently, we have shown that they also stimulate phospholipase A2 (PLA2). Here we analyze the relationship of these biochemical activities of Graves' IgG to thyroid growth in vitro ([3H]thymidine incorporation) and in vivo (patient goiter size) as well as to clinical indicators of severity of the disease, such as ophthalmopathy, T3 levels, T3/T4 molar ratio, and TSH binding-inhibiting IgG activity. A cluster analysis of the biochemical parameters referring to the whole population (158 subjects) led to the identification of 4 subgroups of Graves' patients based on the different capabilities of IgG to stimulate adenylyl cyclase, PLA2, and [3H]thymidine incorporation. Importantly, a trend of increasing severity of the disease from group 1 to group 4 could be identified. In particular, patients in group 4 (characterized by elevated stimulation of adenylyl cyclase, PLA2, and [3H]thymidine incorporation) had the largest goiter, highest serum concentration of T3, highest T3/T4 molar ratio, and highest prevalence of ophthalmopathy. These results indicate that Graves' IgG induce thyroid growth by stimulating both adenylyl cyclase and PLA2, and suggest a method for the subclassification of Graves' patients that identifies four groups with different degrees of severity of the disease. Moreover, this classification might lead to the targeted use of a novel therapeutic approach based on the inhibition of PLA2 and arachidonic acid metabolism.