Caltech biologists spy on the secret inner life of a cell

October 10, 2008

PASADENA, Calif.-- The transportation of antibodies from a mother to her newborn child is vital for the development of that child's nascent immune system. Those antibodies, donated by transfer across the placenta before birth or via breast milk after birth, help shape a baby's response to foreign pathogens and may influence the later occurrence of autoimmune diseases. Images from biologists at the California Institute of Technology (Caltech) have revealed for the first time the complicated process by which these antibodies are shuttled from mother's milk, through her baby's gut, and into the bloodstream, and offer new insight into the mammalian immune system.

Newborns pick up the antibodies with the aid of a protein called the neonatal Fc receptor (FcRn), located in the plasma membrane of intestinal cells. FcRn snatches a maternal antibody molecule as it passes through a newborn's gut; the receptor and antibody are enclosed within a sac, called a vesicle, which pinches off from the membrane. The vesicle is then transported to the other side of the cell, and its contents--the helpful antibody--are deposited into the baby's bloodstream.

Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute, and her colleagues were able to watch this process in action using gold-labeled antibodies (which made FcRn visible when it picked up an antibody) and a technique called electron tomography. Electron tomography is an offshoot of electron microscopy, a now-common laboratory technique in which a beam of electrons is used to create images of microscopic objects. In electron tomography, multiple images are snapped while a sample is tilted at various angles relative to the electron beam. Those images can then be combined to produce a three-dimensional picture, just as cross-sectional X-ray images are collated in a computerized tomography (CT) scan.

"You can get an idea of movement in a series of static images by taking them at different time points," says Bjorkman, whose laboratory studies how the immune system recognizes its targets, work that is offering insight into the processes by which viruses like HIV and human cytomegalovirus invade cells and cause disease.

The electron tomography images revealed that the FcRn/antibody complexes were collected within cells inside large vesicles, called "multivesicular bodies," that contain other small vesicles. The vesicles previously were believed to be responsible only for the disposal of cellular refuse and were not thought to be involved in the transport of vital proteins.

The images offered more surprises. Many vesicles, including multivesicular bodies and other more tubular vesicles, looped around each other into an unexpected "tangled mess," often forming long tubes that then broke off into the small vesicles that carry antibodies through the cell. When those vesicles arrived at the blood-vessel side of the cell, they fused with the cell membrane and delivered the antibody cargo. The vesicles also appeared to include a coat made from a molecule called clathrin, which helps form the outer shell of the vesicles. Researchers previously believed that a vesicle's clathrin cage was completely shed before the vesicle fused with the cell membrane. The new results suggest that only a small section of that coating is sloughed off, which may allow the vesicle to more quickly drop its load and move on for another.

"We are now studying the same receptor in different types of cells in order to see if our findings can be generalized, and are complementing these studies with fluorescent imaging in live cells," Bjorkman says. "The process of receptor-mediated transport is fundamental to many biological processes, including detection of developmental decisions made in response to the binding of hormones and other proteins, uptake of drugs, signaling in the immune and nervous systems, and more. So understanding how molecules are taken up by and transported within cells is critical for many areas of basic and applied biomedical research," she adds.
-end-
The paper, "FcRn-mediated antibody transport across epithelial cells revealed by electron tomography," was published in the September 25 issue of Nature. The work was supported by the National Institutes of Health, a Max Planck Research Award, the Gordon and Betty Moore Foundation, the Agouron Institute, and National University of Singapore AcRF start-up funds.Visit the Caltech Media Relations website at: http://pr.caltech.edu/media.

California Institute of Technology

Related Autoimmune Diseases Articles from Brightsurf:

Study identifies key enzyme for development of autoimmune diseases
An enzyme associated with energy production in cells also participates in the differentiation of immune cells involved in exacerbated inflammation.

Targeting the treatment of autoimmune diseases
A team of researchers from Charité - Universitätsmedizin Berlin and the Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, a Leibniz Institute, have successfully treated two patients with the autoimmune disease systemic lupus erythematosus.

Mouse study shows 'chaperone protein' protects against autoimmune diseases
Like a parent of teenagers at a party, Mother Nature depends on chaperones to keep one of her charges, the immune system, in line so that it doesn't mistakenly attack normal cells, tissues and organs in our bodies.

Study finds molecule in lymphatic system implicated in autoimmune diseases
A study by investigators at Hospital for Special Surgery (HSS) has discovered a molecule in the lymphatic system that has the potential to play a role in autoimmune disease.

Research adds new twist to fight against autoimmune diseases
Scientists describe in Nature Immunology an entirely new molecular process in mice that triggers T cell-driven inflammation and causes different auto-immune diseases.

Repurposing existing drugs or combining therapies could help in the treatment of autoimmune diseases
Research has found that re-purposing already existing drugs or combining therapies could be used to treat patients who have difficult to treat autoimmune diseases.

Discovery may help explain why women get autoimmune diseases far more often than men
New evidence points to a key role for a molecular switch called VGLL3 in autoimmune diseases, and the major gap in incidence between women and men.

Autoimmune diseases of the liver may be triggered by exposure to an environmental factor
Investigators from a large population-based study conducted in northern England have suggested that exposure to a persistent, low-level environmental trigger may have played a role in the development of autoimmune diseases of the liver within that population.

Autoimmune diseases are related to each other, some more than others
Researchers using the world's largest twin registry to study seven autoimmune diseases found the risk of developing the seven diseases is largely inherited, but that some diseases are more closely related than others.

Researchers identify possible role of Foxp1 protein in control of autoimmune diseases
Scientists at the Higher School of Economics, the Institute of Bioorganic Chemistry of the Russian Academy of Sciences (IBCh RAS), and the Memorial Sloan Kettering Cancer Center created a genetic model that helps to understand how the body restrains autoimmune and oncological diseases.

Read More: Autoimmune Diseases News and Autoimmune Diseases Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.