Autoimmunity, Brain & Beyond

Identification of Pathway that Brain and Immune System Speak

In a major step in understanding how the nervous system and the immune system interact, scientists at The Feinstein Institute for Medical Research have identified a new anatomical path through which the brain and the spleen communicate. The spleen, once thought to be an unnecessary bit of tissue, is now regarded as an organ where important information from the nervous reaches the immune system. Understanding this process could ultimately lead to treatments that target the spleen to send the right message when fighting human disease.

Mauricio Rosas-Ballina, MD, working with colleagues in the laboratory of Kevin J. Tracey, MD, figured out that macrophages in the spleen were making tumor necrosis factor, a powerful inflammation-producing molecule. When they stimulated the vagus nerve, a long nerve that goes from the base of the brain into thoracic and abdominal organs, tumor necrosis factor (TNF) production in the spleen decreased. This study complements previous research performed in Dr. Tracey’s laboratory, which showed that stimulation of the vagus nerve increases survival in laboratory models of sepsis.

The findings were published today in the Proceedings of the National Academy of Sciences. Many laboratories at The Feinstein Institute study the immune system in health and in disease. Every year, about 500,000 people develop severe sepsis, a syndrome triggered when the body’s immune system wages an attack on the body that is well beyond its normal response to an invader. Sepsis kills about 225,000 deaths in the United States each year.

A hundred years ago, the spleen (located in the upper quadrant of the abdomen) was thought to be only reservoir for blood. It has only been in recent years that scientists discovered that the spleen is a manufacturing plant for immune cells, and a site where immune cells and nerves interact. The spleen defends the body against infection, particularly encapsulated bacteria that circulate through the blood.

The hope is to modulate other immune functions like antibody production through the spleen (via vagus nerve stimulation) as a way to modify the course of infections and possibly some autoimmune disorders.

Dr. Rosas-Ballina began following the winding path of the vagus nerve to establish the route it follows to reach the spleen. He was trying, without much luck, to find fibers of the vagus nerve in this organ. And then he went a little further south to the splenic nerve, the nerve that innervates the spleen. Their results indicate that the vagus nerve inherently communicates with the splenic nerve to suppress TNF production by macrophages in the spleen.

            According to the prevailing paradigm, the autonomic nervous system is anatomically and functionally divided in sympathetic and parasympathetic branches, which act in opposition to regulate organ function. “The division between the parasympathetic and sympathetic nervous systems is not clear cut,” said Dr. Rosas-Ballina, explaining that the vagus nerve (the major parasympathetic nerve) acts through the splenic nerve to modulate immune function. He said that results of this study suggest that there may be two separate ways the brain communicates with the spleen to regulate immune function. This points the way to a possible solution for treating sepsis. It may be more effective to take advantage of the central nervous system to control cells of the spleen. This way, “you know where the treatment is going,” said Dr. Rosas-Ballina

BENEFIT CONCERT FEATURES DIANA ROSS & AWARDS FEINSTEIN INVESTIGATOR

Feinstein Institute's Joseph R. Tumang, PhD, was awarded this year’s National Grid Award for  his work in unraveling B-lymphocyte development and B cell lymphoma. Dr. Tumang is an expert in immunology. He      has identified changes in the programming of genes that trigger lymphoma. Understanding this process can ultimately help in the development of targeted medicines to treat this common cancer of the lymphatic system.

            In a laboratory model of lymphoma, Dr. Tumang and colleagues have investigated how a molecule called BRD2 literally opens up the chromatin structure of the genome and allows for lots of genes to get activated, which then triggers cells to enter abnormal cell cycle division. He has identified processes that could help in determining why some patients are resistant to a particular lymphoma treatment and others are not. In addition to his work in lymphoma, Dr. Tumang also studies B1 lymphocytes which are implicated in many autoimmune diseases.

            The National Grid fellowship will provide funding to further Dr. Tumang’s research. 

            Dr. Tumang works in the Feinstein’s Center for Oncology and Cell Biology,  which is headed by Thomas L. Rothstein, MD, PhD. They are among hundreds of scientists at the institute commited to translational research – carrying out studies that will translate quickly into diagnostics or therapeutics that will alter the practice of medicine. The Feinstein Institute is part of the North Shore-LIJ Health System. Dr. Tumang will receive his award tonight, July 16^th, during the Feinstein’s annual benefit concert featuring singer Diana Ross. The concert will be held at Planting Fields Aboretum.

            National Grid is an international electricity and gas company that recently acquired KeySpan. The company is now the second largest U.S. electricity and natural gas provider that supplies electricity and contract services to the Long Island Power Authority.

IMMUNOLOGY CONFERENCE HIGHLIGHTS

May 29^th – The Feinstein Institute for Medical Research hosted a fabulous immunology conference today, The Elmezzi Symposium in Molecular Medicine. It was a morning filled with new findings from the field of immunology – and it touched on basic and clinical science of inflammatory diseases, rheumatoid arthritis, lupus, cytokine biology, immune cells and intriguing evidence of how gut flora (the bacteria present in the gut) may pave the way to good health or disease.

• Ulf Andersson, MD, of the Karolinska Institutet in Sweden, talked about a nuclear structural protein that many in our institute are familiar with: HMGBI. This protein is in every cell but generally it stays put. When it does get outside of the cell, it can set up a dangerous inflammatory process. The protein is expressed in arthritis, sepsis and other inflammatory conditions and substances that block this protein are now in many phases of clinical testing. Dr. Andersson told the story of the Golden Frog living in Columbia who could kill 20 humans with its natural toxin. Only when this frog is bred in captivity does it secrete its poison. The lesson: Context is everything. Let’s figure out why some proteins in the body can be so beneficial under certain conditions and dangerous in others.

• Anthony Cerami, PhD, of Warren Pharmaceuticals, also talked about two cytokines of the body’s immune system – tumor necrosis factor (TNF) and erythropoietin (EPO) that, according to Dr. Cerami, are the Lucifer and Gabriel of the Cytokines. Decades ago, Dr. Cerami, who was at Rockefeller University, identified a molecule involved in a wasting disease and once they cloned it they found that it was identical to a molecule the body makes called tumor necrosis factor. He went on to co-develop a monoclonal antibody that blocks TNF, which is now federally approved for the treatment of rheumatoid arthritis and Crohn’s disease. His work now centers on the other cytokine, EPO, which is if you haven’t guessed the Gabriel of the Cytokines. EPO has been studied as a treatment for many conditions – from brain trauma to heart disease – but because it has so many effects on the body he is working to design a compound with all the good effects of EPO and not some of the dangerous side effects. Dr. Cerami talked about his discovery of a peptide that just might do what he wants. It is now in clinical testing.

• Betty Diamond, MD, is a scientist at the Feinstein Institute, and presented her stunning discoveries on anti-DNA antibodies that trigger lupus and how these antibodies target any number of body systems. More recently, as patients with lupus live longer, a new set of symptoms have emerged: Problems with cognition and mood that are caused by anti-DNA antibodies that get into the central nervous system and alter key networks. She did a brilliant job of explaining how infection or stress can compromise the blood brain barrier and allow the antibody entrance into the brain to cause a number of neuropsychiatric symptoms.

• Charles A. Dinarello, MD, a professor at the University of Colorado School of Medicine, did a great job of explaining the differences between an auto-inflammatory disease versus an auto-immune disease. Autoimmune diseases like lupus arise when the immune system turns against itself to attack a part of the body. His work has shown that a cytokine called interleukin-1 sets in motion an auto-inflammatory disease that can also cause a number of human illnesses. Molecules that block IL-1 shuts down this auto-inflammatory circuit and can be used to treat a number of these conditions, including rheumatoid arthritis, Crohn’s and psoriasis.

• Tak W. Mak, PhD, director of The Campbell Family Institute for Breast Cancer Research in Ontario, talked about the body’s innate system of balancing lymphocyte survival and death as a way of keeping harmony in the body. Maintaining lymphocyte homeostasis is critical for appropriate responses to pathogens and maintaining an immunological memory.

• William E. Paul, MD, chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases, spoke about his favorite avenue of research: CD4 T-cells and how the body’s adaptive immune system works to protect against disease or makes it vulnerable. He talked about four very different functions of the CD4 cells and how scientists are unraveling each piece of this immune system puzzle.

• Sven Pettersson, MD, also of the Karolinska Institutet presented a compelling view of the microflora of the gut and how it may play a role in keeping us healthy or not. He said that the bacteria that live in the gut may play a fundamental role in maintaining absence of disease. And he presented his evidence, laying out the way bacteria respond to the host and the genes that are turned on during this process that may ultimately help explain what makes some people susceptible to certain conditions. He showed in laboratory models how raising animals from birth in germ-free environments has effects on the size of the liver and has profound changes in the amount of time animals slept. He also presented intriguing evidence that gut flora can regulate body weight. The animals bred in germ-free environments were armed with a system to handle high-fat diets without gaining weight compared to animals exposed to bacteria that eventually take up space in the gut.

In the afternoon, we celebrated the annual commencement of the Elmezzi Graduate School of Molecular Medicine and the honorary degrees conferred to Joseph Loscalzo, MD, PhD, of Harvard Medical School and Hans Wigzell, MD, PhD, of the Karolinska Institutet. And Howard Kerpen, MD, was presented with the Bette and Jerome Lorber professorship. Congrats to all.

Jamie

FIRST WORLD'S SCIENCE FESTIVAL IN NEW YORK CITY

Today is the opening day of the World Science Festival, which was organized by a team of scientists at Columbia University in addition to a long list of contributors.  On May 28 several of my favorite brain scientists -- Dr. Pasko Rakic of Yale University  and Dr. Thomas Jessell of Columbia -- in addition to five other world leaders in scientific research were roused from sleep with word that they are the first recipients of the Kavli Prize. They will each share $1 million that will be used to forward their research. The Kavli prizes were created through a partnership between the Kavli Foundation, the Norwegian Academy of Sciences and Letters and the Norwegian Ministry of Education and Research.  Fred Kavli is an entreprenur who understands the importance of scientific discovery and the five-day festival will inspire people of every age. Click on the link to the festival web site and enjoy the inspiring events that will be at various venues throughout the city.

World Science Festival

Dr. Michael S. Brown Talks about WHY HEARTS ATTACK

Michael S. Brown, MD, and Joseph L. Goldstein, MD, were awarded the Nobel Prize in Physiology or Medicine in 1985 for their research on cholesterol and its effects on the heart. Since that time, they have tried to stay clear of the controversies over good and bad forms of cholesterol, and continue in their collaborative effort to figure out how high levels of low-density lipoproteins or LDL lead to heart attacks.

          Dr. Brown presented his latest research at a special symposium sponsored by The Feinstein Institute for Medical Research. Dr. Brown, a Regental chair of biomedical sciences at the University of Texas Southwestern Medical Center in Dallas, will talk about the importance of lowering low-density lipoproteins to prevent heart attacks and lower the incidence of the number one killer in the nation. Cardiovascular disease is the most frequent cause of death in men over age 35 and women over age 65 in the United States. Dr. Brown is this year’s Match Distinguished Scientist, a lecture series sponsored by the Feinstein.

          “Heart attacks might well disappear if people could get LDLs low enough,” said Dr. Brown. He believes that scientists already have enough knowledge about the role of LDL to dramatically reduce the rates of cardiovascular disease. In fishing villages in Japan, the rates are 25 times lower than in the U.S. The key, Brown said, is controlling LDL through diet and a better understanding of the genes that regulate LDL.

          Cholesterol is a fatty substance that is critical for every cell in the body. The liver makes cholesterol and it is also found in many of the foods we eat. Cholesterol is transported in the blood carried in lipoproteins. LDLs are lipoproteins of low density that circulate in the blood. Normally, receptors on liver cells destroy the extra burden of LDL, but if there are too many LDL particles in the system it can deposit on artery walls. There is strong evidence that high LDL levels can dramatically increase the risk of heart disease, Dr. Brown said. Animals with low levels of LDL have no atherosclerosis, and raising LDL levels trigger disease. As the LDL levels rise in certain human populations, so does heart disease. Genetic mutations that impair the body’s ability to remove LDL from the plasma cause severe atherosclerosis. And finally, there have been a number of large clinical studies that show heart disease is lowered in people taking medicines to clear LDL from the body.

          Diets rich in saturated fats produce high levels of LDL. If the receptors in liver cells aren’t destroying LDL efficiently, it builds up in the system. Once LDL particles deposit in the wall of the artery, the body’s immune system wages an attack to get rid of it. But the cells that come in to destroy the LDL particles end up damaging the wall. The wall thickens and the result could be a heart attack.

          After two decades, the vexing question remains: Why do people who consume a high-fat, high-cholesterol diet have high LDL levels? 

          Dr. Brown explained that the genes for the search-and-destroy receptors in liver cells are under a tight feedback regulation system. When people eat diets rich in cholesterol, it builds up in the liver and the gene for the LDL receptor becomes less active. The result: LDL levels increase. The Texas scientists have been trying to figure out how the cells in the liver know there is too much cholesterol around. What’s more, how does it turn down the receptor?

          In 1993, Dr. Brown and Dr. Goldstein discovered sterol regulatory elementary binding protein (SREBP) that works like a thermostat for cholesterol inside of the cell. If there is too much cholesterol, the gene that makes the LDL receptor is turned off. “The SREBP senses that there is too much cholesterol and lowers the thermostat,” they say. Since their initial findings, Dr. Brown and Dr. Goldstein have found that the class of cholesterol-lowering drugs called statins turns up the thermostat. With the proverbial heat on, the liver makes more receptors and LDL levels fall.

LDL receptor deficiency can also be acquired through a diet high in cholesterol. More than half of all people in the United States have levels of circulating LDL cholesterol that are above the threshold at which atherosclerosis is accelerated. What’s more, one in 500 Americans suffer an inherited defect that leads to high blood cholesterol. One in a million people are born with no LDL receptors at all. People with this inherited gene defect called familial hypercholesterolemia often have heart attacks before they even reach adulthood.

          The bottom life-saving line is this: “We should all eat low cholesterol diets or take a drug that turns on this thermostat,” said Dr. Brown.

Molecular Medicine Journal

Molecular medicine has come of age. With great advances in the biomedical sciences -- molecular and structural biology, biochemistry and immunology -- scientists have made amazing discoveries that bridge the gap from the laboratory to the bedside. The field of molecular medicine is concerned with understanding the pathogenesis of disease at the molecular level, and, based on that knowledge, designing specific molecular tools for diagnosis, treatment and prevention.  Our journal, Molecular Medicine, was introduced in 1994 to serve as a forum through which scientists and researchers could communicate recent discoveries to a multi-disciplinary, international audience interested in understanding and curing disease. It's published biomonthly. www.molmed.org     And listen to Molecular Medicine's new podcast --  Mollie Medcast. http://www.molmed.org/podcast.html