Date Approved

5-2020

Document Type

Dissertation

Degree Name

PhD in Cell and Molecular Biology

Department

Cell Biology and Neuroscience

College

Graduate School of Biomedical Sciences

First Advisor

Robert Nagele, PhD

Committee Member 1

Kingsley Yin, PhD

Committee Member 2

Gary Goldberg, PhD

Committee Member 3

Bernd Spur, PhD

Committee Member 4

Martin Forsberg, MD

Subject(s)

Autoantibodies, Cerebrospinal Fluid Proteins, Immunoglobulin G, Stress, Physiological, Pregnancy, Immunomodulation, Immune Tolerance, Glycosylation

Disciplines

Biological Phenomena, Cell Phenomena, and Immunity | Cell Biology | Immunity | Laboratory and Basic Science Research | Life Sciences | Medical Molecular Biology | Medicine and Health Sciences | Molecular Biology | Other Physiology | Physiological Processes

Abstract

The presence of thousands of autoantibodies (aABs) in the human sera is typical, and therefore it is possible to identify an aAB profile for each individual. In the first part of this thesis, we will show the cerebrospinal fluid also exhibits an extraordinarily complex immunoglobulin G aAB profile that is composed of thousands of aABs. We show that the pattern of expression of individual aABs in CSF closely mimics that in the blood, indicative of a blood-based origin for CSF aABs. In addition, using longitudinal serum samples obtained over a span of nine years, we show remarkable stability in aAB profiles over time, establishing that in the absence of stressors, individual aAB profiles show fidelity over time. We next explore the effect of one specific physiological stressor, pregnancy, on an aAB profile, using longitudinal samples taken before, during and after pregnancy. We are able to show a global reduction in aAB titers, followed by almost a full recovery, indicating that aAB profiles have a set-point that they try to re-establish. Lastly, though the presence of glycosylated antibodies in serum has already been established, there are no studies that have looked at the prevalence and distribution of glycosylated aABs. Glycosylation of antibodies infers different consequences based on the location of the glycosylation on the antibody molecule. During pregnancy, there is shift in the distribution of aAB glycosylation, from the majority of aAB initially glycosylated at 10-39% in early pregnancy to 30-69% in late pregnancy. This number then shifts dramatically post-pregnancy with the majority of aABs glycosylated at 10-19%. The increase in glycosylation during pregnancy is speculated to play an immunomodulatory role to foster immune tolerance of the fetus.

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