To scrutinize the specificity of the observed interaction, we asked if the preference of Trx1 for CD30 might be caused by an unusual density of disulfide bonds within CD30 and/or exceptional cell surface expression levels. Although the CD30 ectodomain harbors a significant number of predicted disulfide bridges within CRDs, it does not appear to be unusual in terms of disulfide bond composition/density when compared to other members of the superfamily. When tested experimentally, Trx1 failed to interact with other CRD-containing proteins, including the EGFR featuring a total of 25 ectodomain disulfide bonds. The preference for CD30 could not be explained by exceptional surface expression levels either. While Hodgkin's disease cell lines typically express high levels of CD30, other cell lines including LCL-721.220 or CCRF-CEM show at least 20-to 100-fold lower expression as determined by flow cytometry, yet the same selective targeting was observed. Conversely, ectopic overexpression of several related TNFR superfamily members in HeLa cells did not lead to their interaction with Trx1, yet CD30 strongly interacted on the same cells under the same conditions. Consistent with these findings, recent experiments demonstrate that Trx1 targets a particular site within the CD30 ectodomain (Y Balmer and TP Dick, unpublished data) .