The Role of the Neonatal FC Receptor (FCRN) in the Transfer of Passive Immunity and Maintenance of Active Autoimmunity
Date of Award
Level of Access Assigned by Author
Doctor of Philosophy (PhD)
Biochemistry and Molecular Biology
Second Committee Member
Charles E. Moody
Third Committee Member
THE ROLE OF THE NEONATAL FC RECEPTOR (FCRN) IN THE TRANSFER OF PASSIVE IMMUNITY AND MAINTENANCE OF ACTIVE AUTOIMMUNITY By Hana J. Al-Khabbaz Thesis Advisor: Dr. Deny C. Roopenian An Abstract of the Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (in Biochemistry and Molecular Biology) May, 2008 The Neonatal Fc Receptor (FcRn) is a unique receptor that belongs to the Major Histocompatibility Complex (MHC) protein family and was first isolated from the neonatal rodent's gut and identified as the receptor responsible for transferring maternal IgG from milk across the neonatal intestine. Because FcRn is expressed on human placental tissues, it is believed to perform the same function of transferring IgG across the placental barrier. This is supported by the fact that most of the antibodies in the human fetal circulation at birth are of maternal origin and all are of IgG isotype. Determining whether FcRn is actually involved in this transplacental transfer is of great importance for the development of prenatal therapeutic intervention that might be utilized both to deliver therapeutic antibodies prenatally and to develop methods to block the transfer of passively acquired autoimmune diseases from mother to her fetus. In this study, we show that FcRn is required for the prenatal transfer of IgG across the placental barrier both in mice and in an FcRn humanized mouse model. However, another molecule, albumin that interacts with and is protected by FcRn is not transported across the placenta. We further show that by increasing the affinity of humanized IgG binding to FcRn we can increase the efficiency of these antibodies transferred to the fetal mice, and at the same time we can interfere with the amount transferred by therapeutically blocking the ability of FcRn to bind and protect IgG from degradation. In adult tissues, FcRn has the ability to protect IgG from catabolic degradation. This protection mechanism carried out by FcRn is responsible for extending the half life of IgG and maintaining homeostatic serum level of this antibody compared to other proteins in the serum. Herein we show that if the formation of FcRn-IgG complexes is directly blocked in these adult mice by using anti-FcRn monoclonal antibody, the ability of the passively transferred arthritic IgG to cause inflammation in the treated mice is inhibited.
Al-Khabbaz, Hana J., "The Role of the Neonatal FC Receptor (FCRN) in the Transfer of Passive Immunity and Maintenance of Active Autoimmunity" (2008). Electronic Theses and Dissertations. 764.
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