Malondialdehyde (MDA), a product of lipid peroxidation and arachidonic acid metabolism, can react with free amino groups to form crosslinks which may form neoantigens and result in autoantibody production. Under hyperlipidemic conditions, excess MDA produced endogenously could conjugate with proteins to generate new antigenic sites, new antigenic sites could stimulate autoantibody production resulting in immune complex formation leading to complement activation and tissue damage. This study was designed to develop an immunological assays to determine whether the presence of plasma MDA-modified proteins existed and to study a time-course relationship for plasma anti-MDA IgG, MDA-modified protein conjugates and circulating immune complexes containing MDA in both normal and hyperlipidemic rabbits. This study also attempts to determine whether these factors relate to the extent of atheromatous lesion development and whether immune complexes alone can accelerate the progression of atherosclerosis. An MDA-modified plasma protein (> 200 KDa) was demonstrated for the first time in rabbits by the Western blot techniques. This MDA-modified plasma protein was present in both control and cholesterol-fed rabbit plasma and its amount increased during 8 weeks of cholesterol feeding. Anti-MDA IgG antibody activity decreased over time in the control group but there was no significant decline in cholesterol-fed rabbits. Circulating immune complexes containing IgG and MDA increased in control and cholesterol-fed groups. Following injections of MDA-modified proteins, circulating immune complexes containing IgG and MDA increased significantly in rabbits fed with a normal diet but not in all cholesterol-fed rabbits. Immune complexes did not accelerate the progression of atherosclerosis. These results suggest that anti-MDA IgG may provide an immune mechanism for the normal clearance of lipid peroxidation products via circulating immune complexes and that this mechanism may be altered by a high cholesterol intake. Immunohistochemical evidence demonstrates that MDA-modified epitopes, complement C3 component and IgG are present in the atherosclerotic lesions. These results provide evidence that circulating immune reactants which involve MDA, specific autoantibodies, antigen and immune complexes may play a role in the development or progression of atherosclerosis.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1962. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 240-248).

Biochemical and computer-assisted digital image analysis techniques were used to study the proliferation and granulocytic differentiation of HL-60 leukemia cells which were induced to differentiate by retinoic acid (RA). HL-60 cells were synchronized by density arrest (DA), double thymidine block (TB), or flow cytometric sort (FCM). Following release from the 3 modes of synchrony, proliferation was evaluated by immunoperoxidase staining for incorporated bromodeoxyuridine (BrdUrd, % S phase cells), mitotic index, cell counts, and digital image analysis of Feulgen stained cells. Data revealed increased synchronization of cells by TB. Digital image analysis of changes in total optical density (TOD) of Feulgen stained cells following release from TB verified the greater synchrony achieved by TB. Fisher linear discriminant analysis using chromatin textural features was used to distinguish G₁ from S and G₂ phase cells. Evaluation of biological descriptors over a 7 day period demonstrated less proliferation and increased differentiation for RA-induced TB cells than for RA-induced DA cells. These descriptors included differential counts of Wright-Giemsa stained cells, nitroblue tetrazolium (NBT) reduction (superoxide production), staining for myeloperoxidase (MPO) and immunofluorescence staining for C3bi receptors using OKM1 monoclonal antibody. Digital image analysis revealed suppression of DNA synthesis by lower Feulgen TOD or RA-treated cells when compared with uninduced controls. The suppression of DNA synthesis was noted as early as one day after induction. The decreasing trend in Feulgen TOD of RA-treated cells correlated with decreased percentages of these cells incorporating BrdUrd. Similarly, differentiation related changes in many image feature values (e.g., decreasing Feulgen TOD, decreasing nuclear area and increasing nuclear convolution) of RA-treated cells, corresponded with decreased c-myc expression, decreased MPO production, increased C3bi receptor expression and increased superoxide production beginning on day 1 after RA-induction. Changes in differentiation-related image feature values preceded decreases in the intensity of bands on silver stained polyacrylamide gels. Additionally, several textural image features demonstrated statistically significant differences from time-matched controls as early as day 1 after RA induction. A combination of 4 image features was used in Bayesian analysis to achieve an approximately 90% correct classification of RA-treated and untreated cells by the 7th day of RA exposure.

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