Many of the disease manifestations arising from multiple myeloma, and in some cases the ultimate cause of death, relate to the production of """"""""abnormal"""""""" immunoglobulin light chains that are deposited in the kidney and other organs throughout the body. Bence Jones proteins, obtained from the urine of the patient, are the light chain component of the antibody molecule. Certain Bence Jones proteins are """"""""malignant"""""""" in that they form toxic proteinaceous deposits in the form of renal tubular casts, nonfibrilar basement membrane deposits, and fibrillar amyloid deposits. Other Bence Jones proteins are """"""""benign"""""""" in that they cause no obvious disease. An ability to determine in individual patients whether a Bence Jones protein is likely to produce disease and to understand the molecular mechanism(s) that account for this deposition will contribute to the development of therapeutic measures to prevent, arrest, and possibly to reverse light chain deposition. The investigators have applied an in vitro chromatographic system to characterize the aggregation of Bence Jones proteins under physiological conditions. They have completed a study of proteins from 40 patients and demonstrated that this system has the potential to be used diagnostically to discriminate benign from malignant Bence Jones proteins. To provide the means to systematically study light chain aggregation and pathology, they propose to bypass the limitations intrinsic to the study of randomly obtained urinary proteins by establishing systems to produce recombinant proteins of defined pathological and non-pathological quality. Site-specific mutation will be used to identify specific sites, and protein surfaces, that are responsible for pathological properties. If it is demonstrated that aggregation observed in vitro underlies in vivo pathology, then design of drugs to antagonize aggregation may be an eventual strategy for control of these currently untreatable light chain diseases.
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