Primary idiopathic IgG cryoglobulinemia is a disease whose clinical signs are directly related to the presence of a circulating monoclonal IgG cryoglobulin. These proteins have the ability to self-associate in vivo and in vitro and can thus aggregate or polymerize in a concentration-dependent manner at temperatures of 37 C or less. When the cryoglobulin spontaneously appears and disappears, it possibly represents a """"""""normal"""""""" antibody, but with an unusual physical property. Other cryoglobulins may be formed as a paraprotein during a lymphoproliferative or plasma cell dyscrasia. Any cryoglobulin is presumed to contain diverse primary structural mutations related to its ability to precipitate in the cold. These investigations will study the biophysical process of the intermolecular self-associations and the primary structural properties of the IgG cryoglobulins. The intermolecular association process and possible temperature-induced intramolecular conformational changes which cause cryoprecipitation will be studied by three techniques: circular dichroism spectroscopy, laser Raman spectroscopy and the analytical ultracentrifuge. Example of the three morphologic types of IgG cryos so far defined, i.e., amorphous, gelatinous and crystalline, will be studied. The primary structure of these proteins will be studied by primary amino acid sequence analysis of representative cryoproteins: specifically, those whose conformational properties have been determined, and that subset which has cross-reactive idiotype like determinants. While the hypothesis is that mutations of primary structure such as insertions or deletions will be noted at genomic splice points, the entire V- region and junctional region structure will nevertheless be determined. It is felt that primary structural mutations may be present in numerous regions of the molecules. Finally, in order to demonstrate that mutations found are specific, a non-cryoprecipitable IgG or matched heavy chain subclass or light chain variable and constant region type will be isolated from the same patient's serum and their primary structure defined.
Showing the most recent 10 out of 13 publications
