WHAT: A trio of large-scale genome-wide association studies, or GWAS, have identified more than 15 gene variants responsible for the diversity of white blood cell counts among whites, African-Americans, and Japanese. Supported in part by the National Institutes of Health, each study examined the genomes of tens of thousands of people. Combined, the studies offer the first comprehensive analysis into why some people, and some populations, have more or fewer white blood cells than others.
All three articles will be published online June 30 in PLoS Genetics.
White blood cells are part of the immune system, which fights infections and diseases. Measuring white blood cell levels is a common diagnostic test that can reveal underlying infections, cancers, or immune system disorders. Some scientific studies have also linked higher levels of white blood cells to increased risk of disease, including heart disease.
Different genetic variants influence immune function in different ways. One of the benefits of studying genetic variants is that it leads to the identification of which genes play a role in which metabolic subsystems and organs.
Some of the identified gene variants were responsible for altering total numbers of white blood cells, while other variants affected only one specific cell subtype, such as neutrophils, basophils, eosinophils, lymphocytes, and monocytes.
The findings could lead to important clinical advances. For example, these gene variants could be tested to pinpoint disease risks earlier in life. In addition, understanding the genetic basis behind altered white blood cell counts might also lead to gene therapies, such as boosting white blood cells in immune compromised people or reducing them in leukemia patients.
What is so important about genetic variants that influence immune function? Researchers at Wake Forest U found that mice differ greatly in how well their immune systems attack cancer cells and so do humans. So one reason to care about immune system genetic variants is that some variants could probably substantially reduce our risk of cancer if we could get our immune systems upgraded with some gene therapy.We need immune system upgrades anyway just to reverse the effects of immune system aging. That immune system aging doesn't just put us at greater risk of death from infection. As the immune system ages it becomes less able to kill cancer cells. It probably also becomes less able to remove intercellular debris. So immune system rejuvenation would cut our death risk from multiple causes.
You can read the 3 papers on genetic variants in immune systems: Multiple Loci Are Associated with White Blood Cell Phenotypes, Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT), and Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population.
CHICAGO --- Researchers from Northwestern University's Feinberg School of Medicine appear to have reversed the neurological dysfunction of early-stage multiple sclerosis patients by transplanting their own immune stem cells into their bodies and thereby "resetting" their immune systems.
"This is the first time we have turned the tide on this disease," said principal investigator Richard Burt, M.D. chief of immunotherapy for autoimmune diseases at the Feinberg School. The clinical trial was performed at Northwestern Memorial Hospital where Burt holds the same title.
The patients in the small phase I/II trial continued to improve for up to 24 months after the transplantation procedure and then stabilized. They experienced improvements in areas in which they had been affected by multiple sclerosis including walking, ataxia, limb strength, vision and incontinence. The study will be published online January 30 and in the March issue of The Lancet Neurology.
Why does this work? Maybe because the stem cells do not differentiate into immune cells that have the exact set of antibodies the original immune system held before the therapy.
In the procedure, Burt and colleagues treated patients with chemotherapy to destroy their immune system. They then injected the patients with their own immune stem cells, obtained from the patients' blood before the chemotherapy, to create a new immune system. The procedure is called autologous non-myeloablative haematopoietic stem-cell transplantion.
"We focus on destroying only the immune component of the bone marrow and then regenerate the immune component, which makes the procedure much safer and less toxic than traditional chemotherapy for cancer," Burt said. After the transplantation, the patient's new lymphocytes or immune cells are self-tolerant and do not attack the immune system.
I'm not keen to get treated with chemotherapy to wipe out my immune system. However, the ability to wipe out an existing old immune system and replace it with a more youthful set of stem cells would work as an immune rejuvenation therapy. A rejuvenated immune system would probably reduce one's risk of cancer and very likely reduce risk of death from influenza and other infections.
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.
These press releases do not go into much detail about exactly what these researchers did. But they must have a way to rapidly identify and separate out immune cells that are especially reactive to an infectious agent.
"This method could find broad application towards almost any infectious disease," says Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.
As a first example, doctors could quickly generate human antibodies against a pandemic flu strain as a stop-gap therapy or to protect people from infection. In this study, the antibodies were not tested on influenza virus strains with pandemic potential, such as the H5N1 strain although such studies are underway.
Ahmed and postdoctoral fellow Jens Wrammert, PhD, from the Emory Vaccine Center and Emory University School of Medicine, collaborated with Don Capra, PhD, and Patrick Wilson, PhD, immunology researchers at the Oklahoma Medical Research Foundation.
"With just a few tablespoons of blood, we can now rapidly generate human antibodies that can be used for immunization, diagnosis and treatment of newly emerging strains of influenza," Wilson says. "In the face of a disease outbreak, the ability to quickly produce infection-fighting human monoclonal antibodies would be invaluable."
They clone the genes involved in making the desired antibodies.
The methods previously used to make human monoclonal antibodies can be relatively laborious, Ahmed says. They involve sifting through human B cells and looking for those that make the right antibodies, or vaccinating mice and "humanizing" the mouse antibody genes by altering them so that they resemble human antibodies.
To make human antibodies against influenza, the Emory and University of Oklahoma researchers isolated antibody-secreting cells (plasma cells) from volunteers' blood a week after vaccination and cloned the antibody genes from these antibody-secreting cells.
With an otherwise well functioning immune system the monoclonal antibodies would be useful for treating life threatening diseases. But for an aged immune system how much benefit would the antibodies provide?
Many proteins in the body need sugars attached to them (the process is called glycosylation) in very specific patterns to make them work optimally. A biotech company and some university researchers have developed a way to make human monoclonal antibodies in yeast which have sugars attached to them.
Researchers at GlycoFi and Dartmouth College have reported the first production of monoclonal antibodies with human sugar structures in yeast. This research, published online January 22 and in the February issue of the journal Nature Biotechnology, demonstrates that antibodies with human sugar structures (glycosylation) can be produced in glyco-engineered yeast cell lines, and that by controlling the sugar structures of antibodies, their therapeutic potency can be significantly improved. Moreover, this same approach offers the potential to improve other glycosylation-dependent drug properties (such as solubility, half-life, or tissue distribution). Given the mature and well-established nature of yeast-based protein production technology, the reported work also promises to improve the production and scale-up economics of antibody manufacturing.
"Mammalian cell cultures currently used for most therapeutic protein production produce a mixture of glycoforms and typically do not allow for the control of glycosylation," said Tillman Gerngross, chief scientific officer of GlycoFi, and professor of Bioengineering at Dartmouth College. "We have spent the last five years engineering yeast cell lines that perform human glycosylation, which now allows us to glycosylate proteins with unprecedented control and uniformity."
Since yeast can grow so fast and is easier to grow than mammalian cells I'd also expect this approach to eventually lower the production cost for antibodies and other protein products.
The ability to glycosylate antibodies is very important because monoclonal antibodies are used against cancer. The glycosylation makes the monoclonal antibodies more effective.
"By controlling the sugar structures on antibodies we have shown that the antibodies ability to kill cancer cells can be significantly improved and that therapeutic proteins can be optimized by controlling their sugar structures," says Dr. Huijuan Li, associate director of Analytical Development at GlycoFi, and the lead author of the study. She noted that while the current report focuses on antibodies, the approach taken by the GlycoFi team can be applied to any therapeutic glycoprotein. Moreover, in addition to cell killing, this approach can be applied to optimize other protein characteristics such as solubility, therapeutic half-life, tissue distribution and interaction with complement proteins. Currently glycoproteins comprise about 70% of all approved therapeutic proteins and the therapeutic protein market is expected to grow at over 20% annually over the next decade.
Just as the yeast were genetically engineered to use human genes to make useful products for the human body the same is going to be done with other organisms and for even grander purposes. What I'd most like to see is extensive genetic engineering of pigs to create pigs that make organs that are transplantable into humans. That's a more distant prospect. But it is an achievable goal.
Some Harvard University researchers have found a key piece of the puzzle about how the body prevents the immune system from attacking the self. One can easily imagine how a deficiency of one kind of protein in the thymus could cause an auto-immune disorder when T cells encounter the same protein in some organ of the body:
Building on work of other groups, first author Mark Anderson, a research fellow in medicine at Joslin; Emily Venanzi, a Harvard Medical School graduate student in immunology; Christophe Benoist, a professor of medicine at Joslin; Mathis, and colleagues, reported that a small network of thymic cells -- the medullary epithelial cells -- expresses hundreds of genes usually associated with organs such as the pancreas, brain, and liver.
"No one would think you would encounter your big toe protein in the thymus, but in fact proteins from the eye, the liver, from all over the place are specifically expressed in a small population of stromal cells in the thymus," said Benoist.
A majority of these expressed proteins are used by the peripheral organs to tell T cells to stay away. Indeed, the researchers believe the proteins are used in the thymus to foreshadow the very self-antigens that the T cells will encounter once they travel out into the body.
"There is a foretelling of these proteins in the thymus, which is why we call it an immunological self-shadow," said Mathis.
In a critical step, the Joslin team discovered that the transcription factor aire plays a critical role in producing these self-shadow proteins in the thymus (hence its name, which is formed from two letters in each word of autoimmune regulator). Mutant mice lacking aire exhibited in their thymus only a fraction of the peripheral self-proteins found in the thymus of normal mice. And the mutants exhibited widespread autoimmunity. In fact, their condition was reminiscent of a condition found in humans carrying a defective AIRE gene, autoimmune polyglandular syndrome.
It is not yet clear how the shadow proteins educate developing T cells inside the thymus, though Benoist suspects the processes are similar to those used to eliminate T cells that react to ubiquitous or circulating proteins. Nor is it clear how aire controls the expression of so many shadow proteins. One possibility is that it works by binding to other transcription factors.
"It is going to be interesting to figure out what the mechanism really is," Mathis said. While novel, the mechanism is probably only one of many that the immune system uses to educate peripheral T cells about the self-vs.-foreign distinction.
"It is very dangerous for the immune system to have self-reactive T cells," Anderson said. "It takes advantage of any mechanism to get rid of these cells. So there is a whole net of mechanisms."
A better understanding of the role of the thymus in prevention of auto-immune response will open up avenues for the development of therapies to treat auto-immune disorders. Also, it may become possible to add cells or do gene therapy to the thymus in order to teach immune cells not to attack transplanted organs. Plus, this information may even turn out to be useful for inducing immune responses against cancers and infectious diseases.