The neonatal Fc receptor, known as FcRn, is a protein that plays a role in the body’s immune system. While initially discovered for its involvement in transferring maternal antibodies to offspring, its functions extend throughout an individual’s life, influencing how the body manages certain protective proteins. FcRn is found on various cell types, including those lining blood vessels, hematopoietic cells, and cells in the intestines.
The FcRn Receptor’s Primary Role
FcRn’s most recognized function involves the recycling of immunoglobulin G (IgG) antibodies and albumin, both abundant proteins in the bloodstream. This recycling mechanism helps extend their lifespan in circulation by preventing their degradation. Without FcRn, IgG and albumin would be broken down much more quickly, leading to lower levels in the body.
The process begins when IgG and albumin are taken into cells through a process called pinocytosis, which forms small sacs called endosomes. Inside these endosomes, the environment becomes acidic. This acidic pH causes IgG and albumin to bind to FcRn.
Once bound, the FcRn-IgG and FcRn-albumin complexes are protected from being sent to lysosomes. Instead, these complexes are transported back to the cell surface. As they reach the cell surface, the pH becomes neutral, causing IgG and albumin to detach from FcRn and be released back into the bloodstream. This constant cycle ensures that these proteins remain at stable levels in the body.
Diverse Functions of FcRn
Beyond its role in recycling, FcRn also facilitates the transfer of maternal antibodies to offspring, providing passive immunity. This transfer occurs during pregnancy across the placenta. This mechanism is important because newborns have an underdeveloped immune system and rely on these maternal antibodies for protection against infections.
FcRn also transfers antibodies through milk to infants, contributing to early-life protection. In addition to maternal-fetal transfer, FcRn is involved in mucosal immunity, which refers to immune responses occurring at surfaces like the lining of the gut or lungs. At these sites, FcRn can transport IgG across epithelial cells, acting as a defense mechanism against pathogens encountered through these barriers.
FcRn can retrieve IgG that has bound to antigens, delivering these to immune cells in the underlying tissue. This process allows for the presentation of antigens to T cells, contributing to immune responses at mucosal surfaces. FcRn’s ability to transport IgG across these barriers contributes to protection against infections.
FcRn and Human Health
Understanding FcRn’s functions has opened avenues for addressing various health conditions, particularly autoimmune diseases. Many autoimmune disorders are driven by pathogenic IgG antibodies that mistakenly target and damage the body’s own tissues. In these conditions, the FcRn receptor’s normal function of recycling IgG can inadvertently maintain high levels of these harmful autoantibodies, prolonging the disease.
Targeting FcRn has emerged as a therapeutic strategy to reduce the levels of these pathogenic IgG autoantibodies. FcRn inhibitors work by binding to the FcRn receptor, blocking its ability to recycle IgG. This blockade leads to increased degradation of IgG antibodies, reducing their concentration in the bloodstream.
Clinical trials have shown promise for FcRn inhibitors in treating various IgG-mediated autoimmune disorders, such as generalized myasthenia gravis, rheumatoid arthritis, and systemic lupus erythematosus. These new therapies offer a more targeted approach compared to traditional treatments that broadly suppress the immune system. By selectively reducing pathogenic IgG levels, FcRn inhibitors aim to alleviate symptoms and reduce disease activity, potentially improving the quality of life for individuals with these conditions.