The VH4-34 represents an unusual Ig heavy chain variable region gene given that it is conserved and overexpressed despite its autoreactivity. Besides RBC 'I/i' recognition, a subset of VH4-34 encoded Igs bind and kill human B-lymphocytes via interaction with a cytoskeletally-associated ligand similar in structure to the cord RBC 'i' antigen. In vivo, secretion of VH4-34 gene encoded antibodies is minimal in healthy individuals. The turn on signal occurs in few clinical conditions such as, systemic lupus erythematosus, AIDS and infectious mononucleosis. Here we show that secretion of VH4-34 Abs is also switched on in hepatitis C and nasopharyngeal carcinoma; but not in diseases such as HPV-associated cervical carcinoma, multiple sclerosis and sarcoidosis. All syndromes with increased VH4-34 Igs appear to be associated with B cell hyperproliferation and B cell lymphotropic viruses, particularly EBV. The significance of the tightly controlled secretion of an autoreactive, conserved Ig gene is discussed.