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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019658-05
Application #
3129019
Study Section
(SSS)
Project Start
1984-04-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1990-03-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
School of Medicine & Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Perl, A; Gorevic, P D; Condemi, J J et al. (1991) Antibodies to retroviral proteins and reverse transcriptase activity in patients with essential cryoglobulinemia. Arthritis Rheum 34:1313-8
Perl, A; Abraham, G N (1990) [Clonal immunoglobulin rearrangement in patients with essential cryoglobulinemia] Orv Hetil 131:1019-22
Perl, A; DiVincenzo, J P; Ryan, D H et al. (1990) Rearrangement of the T-cell receptor alpha, beta and gamma chain genes in chronic lymphocytic leukemia. Leuk Res 14:131-7
Perl, A; Rosenblatt, J D; Chen, I S et al. (1989) Detection and cloning of new HTLV-related endogenous sequences in man. Nucleic Acids Res 17:6841-54
Perl, A; Gorevic, P D; Ryan, D H et al. (1989) Clonal B cell expansions in patients with essential mixed cryoglobulinaemia. Clin Exp Immunol 76:54-60
Perl, A; Divincenzo, J P; Gergely, P et al. (1989) Detection and mapping of polymorphic KpnI alleles in the human T-cell receptor constant beta-2 locus. Immunology 67:135-8
Williams, J M; Gorevic, P D; Looney, R J et al. (1987) Isoelectric focusing characterization of IgM-VKiiib immunoglobulin light chains and their association with anti-IgG autoantibodies in essential mixed cryoglobulinaemia, Sjogren's syndrome and rheumatoid arthritis. Immunology 62:529-36
Perl, A; Wang, N; Williams, J M et al. (1987) Aberrant immunoglobulin and c-myc gene rearrangements in patients with nonmalignant monoclonal cryoglobulinemia. J Immunol 139:3512-20
Podell, D N; Packman, C H; Maniloff, J et al. (1987) Characterization of monoclonal IgG cryoglobulins: fine-structural and morphological analysis. Blood 69:677-81
Perl, A; Looney, R J; Ryan, D H et al. (1986) The low affinity 40,000 Fc gamma receptor and the transferrin receptor can be alternative or simultaneous target structures on cells sensitive for natural killing. J Immunol 136:4714-20

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