Neonatal Fc receptor

Neonatal Fc receptor (FcRn) is a protein that plays a crucial role in the immunoglobulin G (IgG) and albumin homeostasis in mammals, including humans. It is responsible for the transfer of maternal IgG to the fetus, providing the newborn with passive immunity before its own immune system becomes fully functional. Additionally, FcRn is involved in the protection of IgG and albumin from lysosomal degradation, thereby extending their half-lives in the circulation.

Structure and Function

The neonatal Fc receptor is a heterodimeric protein composed of a major histocompatibility complex (MHC) class I-like alpha chain and a beta-2-microglobulin (β2m) light chain. It binds IgG at a pH-dependent manner, with high affinity in acidic environments (pH 6.0) such as those found in lysosomes, and low affinity at physiological pH (7.4), which facilitates the release of IgG into the bloodstream.

FcRn's primary function is to protect IgG and albumin from degradation. It recycles these proteins by binding to them within endosomes, then transporting them back to the cell surface where they are released. This recycling process significantly extends the half-lives of IgG and albumin, which are critical for immune defense and maintaining osmotic pressure, respectively.

Role in Immune System

In addition to its role in protein recycling, FcRn is also involved in the passive transfer of immunity from mother to fetus. During the late stages of pregnancy, IgG is transported across the placenta by FcRn, providing the newborn with a repertoire of maternal antibodies that offer protection against infections during the early months of life.

Clinical Significance

The unique properties of FcRn have been exploited in the development of therapeutic antibodies. Engineering antibodies to have increased affinity for FcRn at neutral pH can enhance their half-lives, potentially reducing the frequency of dosing required in treatments. Conversely, reducing an antibody's affinity for FcRn can decrease its half-life, which may be beneficial in reducing the duration of action for certain therapies.

FcRn is also implicated in several autoimmune diseases. Abnormalities in the function or expression of FcRn can lead to altered IgG and albumin levels, contributing to the pathogenesis of diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Research Directions

Current research on FcRn is focused on further understanding its role in the immune system and exploiting its properties for therapeutic purposes. This includes the development of FcRn antagonists to treat autoimmune diseases and the engineering of therapeutic proteins with altered FcRn binding properties to improve their pharmacokinetic profiles.

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