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Posts Tagged ‘antibodies’

Caltech biologists spy on the secret inner life of a cell

Josh: This isn’t a field I’m that familiar with, but is it known how the baby’s immune system uses the antibodies provided by the mother’s milk? How does it stimulate the baby’s cells to produce the same anti-bodies? The mention of the clathrin coat not being completely shed is particularly interesting. Either their observations were flawed, other researchers never noticed that the coat was not completely shed, or this is a special case where the coat is just not completely shed.

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.

Source: California Institute of Technology

FcRn-mediated antibody transport across epithelial cells revealed by electron tomography. Wanzhong He, Mark S. Ladinsky, Kathryn E. Huey-Tubman, Grant J. Jensen, J. Richard McIntosh,  &  Pamela J. Björkman. Nature 455, 542-546 (25 September 2008) | doi:10.1038/nature07255

Ancient antibody molecule offers clues to how humans evolved allergies

Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have discovered how evolution may have lumbered humans with allergy problems. The team from the Randall Division of Cell & Molecular Biophysics, King’s College London are working on a molecule vital to a chicken’s immune system which represents the evolutionary ancestor of the human antibodies that cause allergic reactions. Crucially, they have discovered that the chicken molecule behaves quite differently from its human counterpart, which throws light on the origin and cause of allergic reactions in humans and gives hope for new strategies for treatment. The work is published today (13 June) in The Journal of Biological Chemistry.

Researcher, Dr Alex Taylor said: “This molecule is like a living fossil – finding out that it has an ancient past is like turning up a coelacanth in your garden pond. By studying this molecule, we can track the evolution of allergic reactions back to at least 160 million years ago and by looking at the differences between the ancient and the modern antibodies we can begin to understand how to design better drugs to stop allergic reactions in their tracks.”

The chicken molecule, an antibody called IgY, looks remarkably similar to the human antibody IgE. IgE is known to be involved in allergic reactions and humans also have a counterpart antibody called IgG that helps to destroy invading viruses and bacteria. Scientists know that both IgE and IgG were present in mammals around 160 million years ago because the corresponding genes are found in the recently published platypus genome. However, in chickens there is no equivalent to IgG and so IgY performs both functions.

Lead researcher, Dr. Rosy Calvert said: “Although these antibodies all started from a common ancestor, for some reason humans have ended up with two rather specialised antibodies, whereas chickens only have one that has a much more general function.

“We know that part of the problem with IgE in humans is that it binds extremely tightly to white blood cells causing an over-reaction of the immune system and so we wanted to find out whether IgY does the same thing.”

By examining how tightly IgY binds to white blood cells the researchers have found that it behaves in a much more similar way to the human IgG, which is not involved in allergic reactions and binds much less tightly.

Professor Brian Sutton, head of the laboratory where the work was done said: “It might be that there was a nasty bug or parasite around at the time that meant that humans needed a really dramatic immune response and so there was pressure to evolve a tight binding antibody like IgE. The problem is that now we’ve ended up with an antibody that can tend to be a little over enthusiastic and causes us problems with apparently innocuous substances like pollen and peanuts, which can cause life-threatening allergic conditions.”

The next stage of the work is to examine in very fine detail the interaction between the antibodies and the surface of the white blood cell. This is with a view to designing drugs that could alter this interaction and therefore ‘loosen’ the binding of IgE, making it more like its chicken counterpart.

Source: Biotechnology and Biological Sciences Research Council

Alexander I. Taylor, Hannah J. Gould, Brian J. Sutton, and Rosaleen A. Calvert. Avian IgY Binds to a Monocyte Receptor with IgG-like Kinetics Despite an IgE-like Structure. J. Biol. Chem. 2008 283: 16384-16390. First Published on April 9, 2008; doi:10.1074/jbc.M801321200

Josh says:

I’ve always found the immune system fascinating. IgG, IgE, IgM, and IgA are all extremely similar, so it makes sense that they started as one gene that was later duplicated, in this case producing IgG and IgE.

The most natural drug

In the fight against infection, the human immune system isn’t ready for a war.

Vaccines push the immune system to create defenses against illness, but they take time to work. A new process developed by scientists at the Oklahoma Medical Research Foundation (OMRF) and Emory University stands to revolutionize the process.

In an advance online publication in Nature, the researchers describe a method that can identify and clone human antibodies specifically tailored to fight infections. The new technology holds the potential to quickly and effectively create new treatments for influenza and a variety of other communicable diseases.

When an infection invades, the immune system goes to work manufacturing antibodies to fight it. Most of the antibodies created will have no effect, but a very few will bond to the invader and replicate to neutralize the enemy.

The new process develops a “smart bomb” for the immune system, using fully human monoclonal antibodies specifically designed to fight the infection without doing any harm to the body. The work was led by OMRF’s Patrick Wilson, Ph.D., and J. Donald Capra, M.D., and Emory’s Rafi Ahmed, Ph.D., and Jens Wrammert, Ph.D. … Continue Reading »