The long term aim of our studies is the definition of the etiology, pathogenesis and treatment of various forms of amyloidosis. To accomplish these aims, we plan to approach the pathogenesis of secondary amyloidosis through studies of inflammation, in relation to serum amyloid A component (SAA), to identify various types of amyloid by biochemical and immunocytochemical methods leading to the isolation and more precise delineation of these components. Aspects of cellular immune function of amyloid will be analyzed and efforts will continue to define and alter the natural history of human amyloid by pharmacologic intervention. In AA (secondary) amyloidosis, we hypothesize that SAA is produced to fulfill an essential role in nonspecific host defense, and in the process of host restitution, is normally cleared from the circulation. However, during chronic inflammation, insoluble AA fibrils accumulate from carboxyl terminal proteolysis of SAA(L). Studies are proposed to elucidate further those cells and cell products involved in the synthesis and degradation of SAA. In AL (primary) amyloidosis, we shall examine the hypothesis that this is an immunocyte dyscrasia and extend sequence data to examine further the light chains involved, and develop better typing antisera. The role of prealbumin in familial amyloidosis and in various types of senile amyloid will be further examined. Methodologies will include tissue culture, amino acid sequencing, immunocytochemical analyses with peroxidase labels, electron microscopy and use experimental models. Patients with various forms of amyloid, especially those with a variety of familial amyloid syndromes will be followed in the Thorndike Memorial Laboratory. Continuing studies of the natural history of amyloid and intervention with agents such as colchicine will continue, as well as studies of the cardiovascular lesions of amyloidosis. Since amyloid is ubiquitous in its distribution in man, and is increasingly recognized as an accompaniment of aging as well as a complication of many inflammatory and malignant diseases, it has become increasingly important to define its multiple etiologies and devise realistic methods of therapy.
