Date Approved

8-2019

Document Type

Dissertation

Degree Name

PhD in Cell & Molecular Biology

Department

Cell and Molecular Biology, Graduate School of Biomedical Sciences

College

School of Osteopathic Medicine

First Advisor

Robert Nagele, PhD

Committee Member 1

Kingsley Yin, PhD

Committee Member 2

Bernd Spur, PhD

Committee Member 3

Venkataswar Venkataraman, PhD

Subject(s)

Autoantibodies, Diagnosis, Biomarkers, Molecular Pathology, Immune System Diseases

Disciplines

Biological Phenomena, Cell Phenomena, and Immunity | Cell Biology | Immune System Diseases | Immunopathology | Medical Cell Biology | Medical Immunology | Medical Molecular Biology | Medicine and Health Sciences | Molecular Biology

Abstract

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and breast cancer.

In case of neurodegenerative diseases, we were able to demonstrate the connection of neuron-specific autoantibodies with neuropathology and their ubiquitous presence in the blood. Further investigations also elaborated on the complex diversity of human autoantibody profiles amongst individuals under healthy and disease conditions, and how these differences could be used to establish disease specific biomarkers.

To correlate disease associated debris production and its autoimmune response, we used a solid tumor model to demonstrate a probable sequence of morphological changes that take place within a solid tumor during tumorigenesis in vivo, and how it leads to an immunological response that was evident from the gradually changing autoantibody profile in mouse sera. We were able to establish a model that would explain how the morphological changes within a solid tumor leads to vascular breakdown and eventual exposure of tumor debris to the immune system leading to a humoral response. Next, we used human protein microarrays to identify autoantibodies in human breast cancer sera that can be utilized as biomarkers to successfully distinguish between early stage breast cancer and sera from age-matched control (healthy) subjects. We also identified autoantibodies against cytokines in human sera, that suggested a possible role of autoantibodies in maintenance and regulation of cytokine activity and half-life.

Overall, in this study we were able to demonstrate a direct relationship between the progression of pathology with the changing autoantibody profile, thus, establishing the importance of employing disease associated autoantibodies as biomarkers for nonautoimmune diseases.

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