The overall objectives of this research are to acquire further knowledge of antibody structure and diversity through correlative immunochemical, biochemical, physicochemical, genetic, and functional properties of the homogeneous immunoglobulins (Igs) found in patients with multiple myeloma and related B-cell malignancies. For the past year our studies of the monoclonal Ig components in these and other patients with neoplastic and inflammatory diseases have revealed: (1) Light chains of the serologically-defined kappaIIIb subgroup are preferentially associated with monoclonal IgMkappa autoantibodies (rheumatoid factors, cold agglutinins, anti-low density lipoprotein antibodies) and that the amino acid sequence of the nu gene-encoded segment of these proteins is virtually identical--these structures provide further evidence that the V?kappaIIIb? germline gene is selected preferentially in the human IgM autoimmune response. (2) Further evidence has been obtained to support our earlier findings that lambda light chains of the V?lambdaVI? subgroup are exclusively found in patients with primary or myeloma-associated amyloidosis. (3) Sequence analyses of two lambdaVI-amyloid associated proteins have demonstrated a unique 2-residue insertion in the third framework region that appears characteristic for lambdaVI proteins and may have important functional implications regarding the amyloidogenecity of these proteins. (4) Sequence analyses of the C region of the lambdaVI protein Mor (a protein we have found to have unusual serological properties) revealed two heretofore undescribed substitutions--this finding extends to 14 the number of different C?lambda? sequences reported and provide further evidence for extensive polymorphism of the human C?lambda? gene. (5) Biosynthetic studies with plasma cells of a patient with light chain deposition disease have shown the formation of an 18,000 dalton kappa chain component, the structure of which is currently under study. (6) Using an experimental in vivo assay in which mice are injected intraperitoneally with purified Bence-Jones proteins, we have demonstrated that the formation of typical homogeneous proteinaceous casts identical in appearance to that found in patients with """"""""myeloma"""""""" kidney and that only clinically """"""""nephrotoxic"""""""" Bence-Jones proteins induce such lesions in the experimental mouse model. (AB)
| Murphy, C; Wang, S; Kestler, D et al. (2011) Leukocyte chemotactic factor 2 (LECT2)-associated renal amyloidosis. Amyloid 18 Suppl 1:223-5 |
| Murphy, C; Wang, S; Kestler, D et al. (2011) Vesicular senile systemic amyloidosis. Amyloid 18 Suppl 1:178-9 |
| Murphy, C; Eulitz, D; Weiss, D et al. (2011) Light chain deamidation in AL? amyloid-associated protein. Amyloid 18 Suppl 1:27-8 |
| Davern, S; Murphy, C L; O'Neill, H et al. (2011) Effect of lysine modification on the stability and cellular binding of human amyloidogenic light chains. Biochim Biophys Acta 1812:32-40 |
| Murphy, C; Wang, S; Macy, S et al. (2011) Nature of os labrum-associated amyloid deposits. Amyloid 18 Suppl 1:206-7 |
| Murphy, C; Kestler, D; Weiss, D et al. (2011) Non-hereditary apolipoprotein AI-associated pulmonary amyloid. Amyloid 18 Suppl 1:219-20 |
| Larsen, Christopher P; Walker, Patrick D; Weiss, Deborah T et al. (2010) Prevalence and morphology of leukocyte chemotactic factor 2-associated amyloid in renal biopsies. Kidney Int 77:816-9 |
| Murphy, Charles L; Wang, Shuching; Kestler, Daniel et al. (2010) Leukocyte chemotactic factor 2 (LECT2)-associated renal amyloidosis: a case series. Am J Kidney Dis 56:1100-7 |
| Wall, Jonathan S; Kennel, Stephen J; Stuckey, Alan C et al. (2010) Radioimmunodetection of amyloid deposits in patients with AL amyloidosis. Blood 116:2241-4 |
| Phipps, Jonathan E; Kestler, Daniel P; Foster, James S et al. (2010) Inhibition of pathologic immunoglobulin-free light chain production by small interfering RNA molecules. Exp Hematol 38:1006-13 |
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