Abstract
The malignant Reed-Sternberg cell of Hodgkin disease is an aberrant B cell that persists in an immunolgically mediated inflammatory infiltrate. Despite its nonproductive immunoglobulin genes, the Reed-Sternberg cell avoids the usual apoptotic fate of defective immune cells through an unknown mechanism. A likely candidate is the surface receptor, CD40, consistently expressed by Reed-Sternberg cells, and the first link in the pathway to NF-κB activation, the central regulator of cytokine production and apoptosis. CD40 signaling in B lymphocytes coordinates the immune response, including immunoglobulin isotype switch and Fas-mediated apoptosis. CD40-induced NF-κB activation is mediated by adapter proteins, the TNF receptor (TNFR)-associated factors (TRAFs), especially TRAFs 2, 3, and 5. Using a Hodgkin cell line, this study demonstrates that CD40 activation of NF-κB is mediated by proteolysis of TRAF3. Results further demonstrate that the pathway can be blocked by treatment with pharmacologic doses of a specific protease inhibitor, pepstatin-A, even in the presence of a mutated NF-κB inhibitor, I-κBα. The stability of TRAF3 regulates CD40/NF-κB–mediated control of the immune response, which is central to the biologic activity of the Reed-Sternberg cell. Prevention of TRAF3 proteolysis may be an entry point for design of novel pharmaceuticals to treat Hodgkin disease and immune system disorders.
CD30 antigen and cellular biology of Reed-Sternberg cells [letter; comment]