The studies described in this proposal are designed to broaden our understanding of the genetic and structural basis of antibody specificity and idiotypes, the definition of immunoglobulin variants and the elucidation of the mechanism of amyloid fibril formation. The primary structure of the variable region of light and heavy chains of human monoclonal immunoglobulin M with antibody activity against self antigens and bacterial antigens will be determined in search of insights into the structural-idiotype-antigen specificity relationships and the genetic restrictions that appear to be present in autoantibody synthesis. The occurrence of variable region subgroups and complementarity-determining region antigens in monoclonal autoantibodies with defined specificity and normal immunoglobulins using antisera raised to synthetic framework residues fragments and complementarity determining region peptides will be studied. Our theory is that certain complementarity determining antigens and variable region subgroups are selectively associated with autoantibodies and that in spite of the heterogeneity of some autoantibody responses, the specificities of the binding sites and the idiotypes of autoantibodies are germline- gene encoded. The first clues to the discontinuous nature of gene coding for immunoglobulin chains, heavy chains in particular, emerged from serological and structural studies of Heavy Chain Disease proteins or immunoglobulin variants, which clearly indicated the existence of separate gene segments coding for different domains, a prediction confirmed by analysis of murine and human heavy chain gene structure. Studies of patients with these disorders and the proteins they produce are important in order to describe additional clinical syndromes associated with abnormal Ig synthesis and define their molecular defects. Studies of human AA amyloidosis and murine secondary amyloidosis due to chronic inflammation will be continued in order to confirm our hypothesis that amyloid fibrils are derived by degradation of a soluble precursor; that processing of the amyloid precursor is tissue specific, and that other factors, like amyloid enhancing factor, are involved in amyloidogenesis. This may in turn provide leads as to possible therapeutic approaches for the prevention of amyloid fibril formation and deposition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR002594-32
Application #
3481350
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1978-09-01
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
32
Fiscal Year
1990
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Sigurdsson, Einar M (2006) Immunotherapy for conformational diseases. Curr Pharm Des 12:2569-85
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Sigurdsson, Einar M; Knudsen, Elin; Asuni, Ayodeji et al. (2004) An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives. J Neurosci 24:6277-82
Berasain, Patricia; Carmona, Carlos; Frangione, Blas et al. (2003) Specific cleavage sites on human IgG subclasses by cruzipain, the major cysteine proteinase from Trypanosoma cruzi. Mol Biochem Parasitol 130:23-9
Sigurdsson, Einar M; Brown, David R; Alim, Muhammad A et al. (2003) Copper chelation delays the onset of prion disease. J Biol Chem 278:46199-202
Sigurdsson, Einar M; Brown, David R; Daniels, Maki et al. (2002) Immunization delays the onset of prion disease in mice. Am J Pathol 161:13-7
Sigurdsson, E M; Scholtzova, H; Mehta, P D et al. (2001) Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol 159:439-47
Aucouturier, P; Geissmann, F; Damotte, D et al. (2001) Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest 108:703-8
Vidal, R; Calero, M; Revesz, T et al. (2001) Sequence, genomic structure and tissue expression of Human BRI3, a member of the BRI gene family. Gene 266:95-102

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