Autoimmunity, Brain & Beyond

21st Century Obesity Pandemic Still Suffering From Effects of Tuberculosis Plague of the 1800s

Modern humans are a long way from starvation or pandemic infectious diseases like tuberculosis that took the lives of a billion people. But the body’s banking system that deposits calories in the event of famine or acute infection is continuing to respond as it did in olden times. Jesse Roth, MD, a diabetes and obesity researcher at The Feinstein Institute for Medical Research, has identified a link between tuberculosis and the metabolic and inflammatory processes that is tied to obesity. In an intriguing commentary in this week’s Journal of the American Medical Association (JAMA), Dr. Roth explains how the modern body has evolved to handle this banking problem – and why it was favorable to human health more than 100 years ago but bad for human health today.

 

            “Unlike our ancestors, we are faced with an abundance of food and our bodies store excess fat that triggers a pro-inflammatory response in systems that evolution created to handle microbial threats,” said Dr. Roth. “People who are obese have more pro-inflammatory forces going on. This is a carry over from 100 years ago when tuberculosis was much more of a continuing threat and food supplies were scarce.” The result, he said, is an increase in inflammatory diseases such as diabetes, heart disease and stroke. “We’ve come to the 21^th century where starvation and tuberculosis are not a threat but we have maintained the same `body’ set as our ancestors,” he said.

 

            Dr. Roth is an expert on diabetes and obesity. Now, he’s trying to identify ways to tame the pro-inflammatory processes of the body associated with diabetes and obesity.

 

            “We now believe that many of the complications from obesity and diabetes are due to these inflammatory processes,” explained Dr. Roth. There is growing evidence that people who are obese have a pro-inflammatory program that is more active than necessary for defense. And in the absence of microbial invaders (like tuberculosis), the body is using up resources (by arming itself for defense), and this pro-inflammatory response can result in damage to cells and molecules of the body, he said.

            Dr. Roth explained that so-called “thrifty” genes evolved because the body works hard to conserve calories (as a source of energy). This energy bank account comes to good use during times of famine and infection. During starvation, the body needs energy from the stored fat cells that it can’t get from food. During infection, the body needs energy to rally up immune defenses to fend off disease.

 

            The balance between the calorie savings to prevent starvation and calorie expenditures to fight microbial invaders was upset by the tuberculosis pandemic during the 18^th and 19^th centuries. Tuberculosis was the leading killer of young adults. Once infected, people retained live bacteria even when they were seemingly recovered; bacteria could reinvade whenever the defenses of the body were down. These times included periods of starvation, illness and old age. The presence of the TB infection led to evolutionary forces that caused a shift in the body’s budgeting of calories. More calories were spent on defense at every level of calorie banking.

 

            The pro-inflammatory responses that go hand-in-hand with the large calorie stores intrinsic to modern obesity is a vestige of another era, Dr. Roth said. “What was very beneficial for our ancestors is detrimental to us today. This harmful response is magnified by the ready availability of food. This abundance of food leads to an even greater pro-inflammatory response.

             

            Fat comes in two kinds. There is subcutaneous fat stored under the skin. This is a simple bank account for fat and carries few pro-inflammatory molecules. By contrast, fat cells can also be deposited viscerally inside the abdominal cavity. What’s more, these fat cells also recruit macrophages, immune system scavenger cells that express a powerful pro-inflammatory program, and release pro-inflammatory molecules called cytokines. When people gain extra weight, most of the calories go into the visceral bank account. Weight loss also reduces fat cells in the visceral organs.         

            

            Whenever we deposit fat, the body makes a decision where it should go. Dr. Roth and his colleagues suspect that there are switches that control the travel routes that deposit fat cells. “If we could manipulate the address of the fat cells, we could reduce the level of damaging pro-inflammatory responses,” he said. The idea would be to send fat cells to the subcutaneous regions. That would reduce the pro-inflammatory response. But it could also result in even heavier bodies. Dr. Roth said that medicines would have to be designed with a one-two punch: to bypass the visceral fat stores and help reduce the burden of fat cells on subcutaneous tissue.

           

            What are the implications for today’s society? “We know that exercise, even in moderation, acts to turn down the pro-inflammatory response,” said Dr. Roth. “Very modest weight loss (five percent or less) is also an effective way to lower this damaging pro-inflammatory response.”

           

            Scientists at the Feinstein Institute are actively developing drugs that target the body’s pro-inflammatory responses and could ultimately be tested for its benefit in protecting against the damaging effects of obesity and diabetes.

           

             While these responses are disadvantageous in the U.S. and other parts of the industrialized world, they may still be of benefit for people in countries where tuberculosis is common and food is scarce.

New Risk Gene for Rheumatoid Arthritis

 Scientists at The Feinstein Institute for Medical Research and a team of collaborators from across the country have identified a new risk factor gene for rheumatoid arthritis. The paper will be published in Nature Genetics and the finding brings light to the nature of the disease. The gene, dubbed REL, is a member of the NF-kB family, important transcription factors that have many roles in the body. The NF-kB family seems to have a big hand in regulating the body’s immune response as well.

“The NF-kB is a key switching point for many cellular activities,” said Peter K. Gregersen, MD, head of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute and lead author of the study. Dr. Gregersen is part of a nationwide consortium of investigators seeking to identify risk genes for rheumatoid arthritis (RA). The hope is to figure out the genetic triggers and identify treatments that block this autoimmune process. In theory, such advances can point the way to understanding other autoimmune disorders. About one percent of the population will develop rheumatoid arthritis, which can be crippling.

        REL is a key regulator of CD40, which works through the NF-kB pathway.

“This paper represents the latest in a series of important publications chronicling an exceptionally productive collaboration between extramural and intramural scientists through the North American Rheumatoid Arthritis Consortium,” said Daniel Kastner, MD, PhD, clinical director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “In describing yet another gene in the CD40 signaling pathway that is involved in rheumatoid arthritis susceptibility, this paper reinforces the possibility of targeting this pathway in selected patients with this debilitating illness.”

The consortium has helped identify many genes involved in rheumatoid arthritis but this genetic finding is significant because of its key role in immune system regulation. It did not reveal itself in previous genetic studies because the sample size was just not large enough. In previous studies, genetic samples from about 2,000 patients were used to identify markers associated with risk for RA. In the latest study, the scientists analyzed samples from 4,000 RA patients and controls.

According to Dr. Gregersen, this particular genetic variant is rather common, found in about a third of people in North America. That means that it must confer an important survival advantage. That said, scientists need to figure out its role in increasing the risk for RA. Next on the research agenda is to see if they can measure how the gene is regulated under specific conditions that set the stage for RA. “There are a huge number of unknowns,” said Dr. Gregersen. “These findings are clear – this pathway is involved – but there is a lot of work to be done.”

Genetic differences between individuals help scientists understand many diseases. But this is just the beginning, added Dr. Gregersen. Today, most markers that are used to identify genes represent variants that occur in more than five percent of the population. The next wave in genetic screening will have to include the variants that occur in less than one percent of the population.

In addition to the Feinstein Institute, part of the North Shore-LIJ Health System, other

centers that are part of the RA consortium include: the University of Texas, MD Anderson Cancer Center; the Genetics and Genomics Branch of the National Institute of Arthritis, Musculoskeletal and Skin Diseases; the Rowe Program in Genetics, University of California at Davis; the Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco; Brigham and Women's Hospital at Harvard Medical School; University of Colorado Denver School of Medicine; University of Nebraska Medical Center; Central Hospital in Finland; University of Pittsburgh Medical Center; of Alabama at Birmingham; Mount Sinai Hospital; University Health Network in  Ontario, Canada; and Celera.

The work was supported by grants from the US National Institutes of Health NO1-AR-2-2263 (P.K.G.), RO1 AR44422 (P.K.G.) and by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the Muriel Fusfeld Foundation. The work was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by grants from the Canadian Institutes for Health Research (MOP79321) and Ontario Research Fund (RE01061) and a Canada Research Chair to K.A.S.

New Parkinson's Support Group for Newly Diagnosed Patients

The Movement Disorders Institute at North Shore-Long Island Jewish Health System has created an Early Parkinson's Disease Support Group for patients diagnosed in the last five years. The hope is to provide cutting-edge information on the science of the disease, treatments, etc with invited speakers. Patients can meet one another and caregivers will also find a place to learn about the disease. North Shore's Harvey Cushings Institutes of Neurosciences and The Feinstein Institute for Medical Research are committed to the study of Parkinson's and in the development and testing of the latest treatments based on the science underway in our health system. For more information on the new support group and other Parkinson's support groups call 516-570-4458.

 

Antidepressant Ineffective in Reducing Obsessive Behavior

A new multi-center study, conducted at The Feinstein Institute for Medical Research in collaboration with five other centers throughout the country, tested the commonly prescribed antidepressant citalopram and found that it was no more effective than placebo in altering obsessive features of the condition – the spinning, rocking and repetitive behavior.

Like everything in medicine, the use of antidepressants in children with autism spectrum disorder took off before there was strong scientific proof about its effectiveness. In the last decade, its use has grown so that today more than 40 percent of autistic children swallow a daily dose of an antidepressant.

This study, published in the June 2009 issue of Archives of General Psychiatry, should serve to reduce the number of antidepressant prescriptions written for children with autism and similar conditions on the autism spectrum.

“Parents of children with autism spectrum disorders face an enormous number of treatment options, not all of which are research based,” said NIMH Director Thomas R. Insel, MD. “Studies like this help us to better understand which treatments are likely to be beneficial and safe.” The study was funded by the National Institute of Mental Health (NIMH) and other NIH institutes.

The Feinstein Institute’s Joel D. Bregman, MD, an expert on autism and one of the study investigators, said that the initial use of antidepressants grew out of a belief that some of the repetitive behaviors are similar to those seen among people with obsessive compulsive disorder. “We can’t rely on apparent similarities to other conditions and clinical experiences to guide our treatment strategies.” Dr. Bregman said. “This was a large double-blind clinical trial that showed that this class of medicine is not effective in reducing these behaviors. These types of studies are essential.”

The study followed 149 children between the ages of five and 17. About half were given a placebo dose and the others received the antidepressant. They were tested repeatedly over the 12-week study period. A positive response was defined by improvement on a number of behavioral measurements. “There was no significant difference in the rate of positive response” on these tests, the scientists concluded. “Results of the trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorder.”

Citalopram is in a class of antidepressant medicines called selective serotonin reuptake inhibitors (SSRIs).

Initial smaller studies reported that SSRIs did make a difference. There is some biologic evidence to suggest that it would. Scientists have reported abnormalities in the brain regions that make the chemical serotonin. And people with obsessive compulsive disorder (OCD) also have serotonin abnormalities and often respond to the medication that helps the serotonin cells to function more normally. SSRIs are the most frequently prescribed medications for children with autism, Asperger disorder, or pervasive developmental disorder-not otherwise specified (PDD-NOS).spectrum disorder.

Part of the explanation for the mixed study results is that the placebo response is very high. In the latest study, one in three children in both groups—32.9 percent of those treated with citalopram and 34.2 percent those treated with placebo—were reported to have fewer or less severe symptoms.

               The authors on the paper included: Bryan H. King, M.D., Seattle Children’s Hospital; Eric Hollander, M.D., Mount Sinai School of Medicine; Linmarie Sikich, M.D., University of North Carolina, Chapel Hill; James T. McCracken, M.D., University of California Los Angeles; Lawrence Scahill, M.S.N., Ph.D., Yale University; Dr.  Bregman, M.D, of the Feinstein Institute and North Shore Long Island Jewish Health System; Craig L. Donnelly, M.D., Dartmouth Medical School; Evdokia Anagnostou, M.D., Mount Sinai School of Medicine (currently at the University of Toronto); Kimberly  Dukes, Ph.D., DM-STAT; Lisa Sullivan, Ph.D., Boston University; Deborah Hirtz, M.D., National Institute of Neurological Disorders and Stroke (NINDS); Ann Wagner, Ph.D., NIMH; Louise Ritz, M.B.A., NIMH (currently at NINDS); and the STAART Psychopharmacology Network, a novel federal initiative.

Fred Gage, PhD, of the Salk Institute talks about neurogenesis in the adult brain in Marsh Lecture

An endowed professor for research on age-related neurodegenerative diseases, Fred Gage, PhD, of the Salk Institute for Biological Sciences in La Jolla, presented his latest work on neurogenesis during this year's Marsh Lecture. "Brain cells are not just born but they are connecting," Dr. Gage said of the adult brain. His studies and others have shown that about six percent of brain cells turn over in the adult brain every month. Fifty percent of the cells born in adulthood die but there are many ways - including exercise - that can help these new brain cells survive. The hope, of course, is that research will lead to new ways to repopulate the diseased brain with healthy cells. It has long been thought that primates, including humans, are born with the complete set of neurons for a lifetime. It was dogma that throughout development and beyond, humans lose neuronal cells, but never gain new ones. Things have sure changed in the course of a decade. In 1998, Dr. Gage and his colleagues described the first evidence in humans that adult brains can grow new cells. The California scientists got hold of brain tissue from cancer patients who had received a chemical that tags the growth of new cells. The scientists were able to identify stem cells in a few regions of the brain. But did the stem cells develop into neurons? Or could they be coaxed into becoming neurons? Dr. Gage showed beautiful pictures of stem cells programmed to become neurons. They behave just like neurons, sending long projections out to other cells to communicate. By 28 days, they are mature and active. The scientists are now identifying genes that provide the signals to neuronal stem cells to turn into different cell types. Many laboratories at the Feinstein Institute are devoted to unraveling the puzzle of brain diseases, from Parkinson's disease to brain tumors. The Marsh Lecture is a coveted annual event. But throughout the year, scientists from all corners of the world are invited to the Feinstein to share their work. Feinstein scientists also present their latest findings during lectures held every few days at the institute.

Stimulating Art - and the Brain

Margaret Fleming

 

 

In the summer of 2006, Alon Mogilner, MD, a neurosurgeon at North Shore University Hospital (NSUH), took a woman in her eighties into the operating room to implant electrodes in her brain. Margaret Fleming, at 82, spent her life as a commercial artist. Her husband John was an art director and the two of them raised a daughter and filled enough canvases to cover the walls of their home in Garden City, NY. After her husband died, Mrs. Fleming kept at her art and made a good living until she was well into her seventies.  Eventually, though, her drawing hand began to tremble. Within a year, she stopped sketching and could barely scratch out her name.

          “For an artist, that’s the worst thing that can happen,” said Mrs. Fleming, who swallowed a long list of vitamins and tried acupuncture. Nothing worked. She and her daughter Diane heard about deep brain stimulation when they were in the audience for the radio program of Ronald Hoffman, MD, an alternative medicine specialist who had a large following from his books and radio show. When Mrs. Fleming and her daughter were in the audience, Dr. Hoffmann’s guest speakers were Dr. Mogilner and a colleague at NSUH, neurologist Michael Pourfar, MD.

            They called the doctors the next day. Drs. Pourfar and Mogilner were concerned about Mrs. Fleming’s age. She may have been the oldest person to sign on for the surgery and they wondered whether the risks would be worth the benefit. Most people who came through their office spent a long time on L-dopa, but Mrs. Fleming had never taken any medicine for what they believed was essential tremor. She wanted to skip the pills and have the brain surgery as soon as possible.

           

            They asked her to write a list of groceries. She could have been back in first grade, the way she took great care to scribble the letters. The pen was shaking under her grip and the letters came out slowly and sloppy; words spilling across the page. They made her take hours of cognitive tests to make sure her mind and memory were intact. She passed the tests easily.

 

Mrs. Fleming signed on for deep brain stimulation (DBS). The technique calls for drilling a hole on one or both sides of the skull and then threading a lead with four tiny electrodes deep into the brain tissue. Dr. Pourfar used computer mapping of Mrs. Fleming’s brain scans to trace a path to the final destination of the DBS electrodes. The leads were placed one side. Her tremors stopped once the stimulator was turned on and the settings adjusted.

 

During a second operation, the lead is connected to a battery pack placed in the chest wall. Then, the DBS team turns on the stimulators and adjusts the settings so that the tremor disappears.

 

“Watch my finger and tell me when you feel tingling,” Dr. Mogilner asked the artist during the surgery to implant the electrodes. Her blue eyes were clear despite the four screws in her skull that attached to an immovable metal head frame. She was quiet, even when her hand stopped trembling. A nurse handed her a pen and paper. “Write your name,” Dr. Pourfar asked. Without a thought, the artist wrote in beautiful script, straight and steady -- Margaret Fleming.

 

The next day, they implanted the battery under general anesthesia, and the following morning her daughter brought some of her mother's colored pens to the hospital. She drew a rose in bloom. 

 

To celebrate her mother’s courage to fight for her passion to paint, Diane Fleming organized a show of her mother’s decades of work on exhibit in May at the East Meadow Library. Mrs. Fleming continues to draw and paint. Her daughter is also an artist who had some of her pieces hanging alongside her mother.

 

“I am so proud of her,” said Diane. “She is an inspiration to everyone.”

 

Deep brain stimulation got its first federal approval in the summer of 1997 for the treatment of Essential Tremor. The technique grew out of surgery for movement disorders that involved cutting or freezing or burning tissue in abnormally active brain regions.

In November 1986, Alim-Louis Benabid, MD, operated on a man with essential tremor. The neurosurgeon from Grenoble, France, and his colleagues in neurosurgery used electrodes to map their destination in the brain. They would thread the electrode down into the thalamus (to treat tremors) and start stimulating, climbing to 100 hertz. Suddenly, his tremor stopped. “I was not prepared,” Dr. Benabid recalled. “Initially, I thought I obtained a contraction because I was in the wrong place, in the internal capsule. I apologized to the patient.”

“It’s no problem,” said the patient. “It was nice.”

 

Dr. Benabid repeated the stimulation at 100 hertz. The man moved his fingers, wiggling with the utmost control and surprise. The stimulation suppressed his tremor. Dr. Benabid continued with his original surgery to lesion, or destroy, an area of the thalamus called the ventral intermedius nucleus. He repeated the electrical stimulation on the next five patients. “I observed this phenomenon,” Benabid explained. “At low frequency, the tremor would worsen. At high frequency, it would completely disappear.”

 

Dr. Benabid is considered the father of deep brain stimulation. Thanks to his discovery, more than 40,000 patients worldwide have undergone deep brain stimulation. For many, like Mrs. Fleming, it worked.

 

For more information on deep brain stimulation for movement disorders (Parkinson's, dystonia and essential tremor) contact Maria Gillego at 516-570-4468.

 

Annual Fundraising Concert

Supporting research is music to the ear. That's right, every summer people who donate money for research have a fabulous opportunity. A night of fabulous food, friendship and great music. This year, Kenny Loggins is the headliner. To find out more about the concert - and about being a part of the research process -- check out the web link below... See you there

The Feinstein Summer Concert Featuring Kenny Loggins
to benefit The Feinstein Institute for Medical Research.

New Insight on Brain Tumors

     Glioblastoma multifore(GBM) is one of the most aggressive human cancers with medium survival time between one and three years. Its high tendency to infiltrate into adjacent brain tissue impedes complete surgical excision. In addition, the resistance to radiation and chemotherapy featured by invasive cells lies behind the recurrence of GBM. Dr. Maria Ruggieri and her colleagues at The Feinstein Institute for Medical Research have identified a new type of MAPkinase that mediates both invasion and treatment-resistance of glioblastomas. MRK can be activated by extracellular lipid lysophosphatidic acid (LPA), a mediator that elicits both mitogenic and motogenic signals in tumor cells. In one of their current studies they are exploring the role of MRK in the LPA induced tumor cell invasion.

        Dr. Ruggieri is presenting her study at the American Association for Cancer Research annual meeting going on this week in Denver.

        Dr. Ruggieri and Dr. Marc Symons used gene silencing technique to down regulate endogenous levels of various signaling molecules to address their relationship in the signaling pathway stimulated by LPA and mediated by MRK. They used trans-well invasion assay to study cell invasion of glioblastoma cells. Their data showed that MRK down regulation impairs LPA-stimulated invasion of glioblastoma cell lines. In the meantime, MRK depletion reduces LPA-mediated stimulation of the ERK and p38 MAP kinase signaling pathways. MRK-depleted cells also demonstrate increased levels of phosphorylated myosin light chain, which is correlated with sustained myosin activity. MRK can be activated by ionizing radiation (IR). Depletion of MRK by RNA interference leads to the failure of radiation induced cell cycle arrest, but enhances radiosensitivity of the cells. Recent in vitro studies revealed that ionizing radiation increases the invasiveness of glioblastoma. This side-effect of radiation is a potential limitation to its clinical benefit and may even contribute to tumor progression. They found that down regulation of MRK significantly reduce the glioblastoma invasion triggered by sub-lethal dose of radiation treatment. Combining all these observations they suggest that MRK is potentially a pharmaceutical target for both enhancing the response of radiation therapy and reducing its side-effect.

Learning Genetics

Joshua Smith dons a lab coat and settles in at a laboratory bench to learn how to process human cells. He will eventually understand how to extract DNA from cells and detect small variations within the genome. The 25-year-old from San Diego is part of a unique learning experience at The Feinstein Institute for Medical Research. He traveled from California to New York in October to be part of the Helen Keller National Center in Sands Point. Joshua was diagnosed in infancy with CHARGE Syndrome, an acronym that touches on many important organs of the body – the retina, heart, ears and kidney. His parents were also told that he would have development delays in his stature.

Josh was five months old when he had his first hearing aids. He was fitted for glasses at 18 months. Years later, he would undergo a cochlear implant. Still, Josh has significant hearing loss and his eyesight grows progressively worse. He has retinal colobramas, which is like a cleft in the retina that creates a blind spot and weakens the entire structure. As a toddler, his parents learned that he also failed to develop the semi-circular canals in the ears. The fluid in the canals serve as our gyroscope and allows us to know which way is upside down or right-side up and gives us directional cues as we navigate the world. This problem sometimes throws Josh off balance.

These physical limitations did not stop the curious boy from his penchant for living. As a child, he’d examine every detail of objects that he got his hands on. His mother said that as he got a little older, he proceeded to disassemble every toy possible. He was a master at building futuristic things out of Legos. He was obsessed with dinosaurs and drawing intricate creatures from his imagination.

             By junior high school, Josh’s interests in genetics (his syndrome is caused by a genetic mutation) led him to his local library where he checked out – and read – virtually every book on genetics.  “That interest has continued to this day,” said his mother.

              As a teenager, Josh spent a summer at the Helen Keller Institute. Then, they worked on developing his skills to live independently – learning how to live in an apartment and travel around without assistance. This time, they have added vocational skills, and Josh’s interest in genetics led his teacher to call the Feinstein – where genetics is a big part of the research program.

              Working once a week with Feinstein geneticist Annette Lee, PhD, and her colleagues, Josh has isolated DNA from saliva and then blood and will go on to learn how to carry out basic procedures used in genetic research.

               “He is a hard worker,” said Dr. Lee. “His enthusiasm, intelligence and love of science are felt throughout the department.”

                Josh hopes to prepare for a job in the science field. “I have always loved science,” he said during a recent work day. “I am interested in genetics in particular.

                The young man has had 8 different surgeries throughout his life and has swallowed a mix of medication for any number of problems. He has attended speech therapy since he was a year old. And along the way, doctors were always baffled over how he beats the odds of his condition. His vision and hearing was better than expected. His smarts and ambition led him to complete the first two years of college. He’s also held down several part-time jobs. “Although Josh faces many challenges on a daily basis, his curiosity, intellect and sense of humor see him through,” said his mother.

                Josh taught his parents to “expect the unexpected….   Every time the ophthalmologist does an exam he says:  “I don’t know how he sees as well as he does.  The audiologist said:  “With that audiogram I am surprised he is doing so well with his speech.”  The neurologist said: “With no semi-circular canals, I’m surprised he can walk without falling down.”

                And Josh has learned that he can expect to follow his passion for science and see where it will lead.

What's Past is Prologue -- in B cells

B cells of the immune system meet every unwanted visitor to an individual's body by making antibodies against them. It's part of our complex immune system that fights off pathogens that we become exposed to throughout our lives. But the B cell can also get mixed messages and start doing battle on its own turf, which is the story behind many autoimmune diseases. Thomas L. Rothstein, MD, PhD, directs the Immunobiology Laboratory at the Feinstein Institute and focuses his research on the role and function of B lymphocyes in normal immune responses, autoimmune diseases and malignant lymphomas.

Dr. Rothstein is hoping that unraveling how B cells normally do their job will help in understanding how the immune system misfires to trigger a battle against the self. His latest discovery caught him off guard. While carefully tracing the flow of information, known as the signaling pathway, produced when an antigen meets up with a B cell, Dr. Rothstein and his colleagues found that B cell signaling changes whenever that meeting occurs after the B cell has been exposed first to the immune system hormone-like molecule, interleukin-4.  Essentially, IL-4 constructs in B cells a new road for antigen-triggered signals to travel. "Scientists have long known that the activity and the fate of B cells are determined by antigen binding to the B cell receptor," said Dr. Rothstein. "But it was not suspected that B cell receptor processes would turn out to be influenced so dramatically by the action of another receptor, specifically, IL-4.  We term this concept reprogramming by receptor crosstalk”

These insights took form as Dr. Rothstein, Benchang Guo, PhD, and their colleagues worked to identify the molecular mediators responsible for common outcomes of B cell activation produced by antigen receptor engagement, such as ERK phosphorylation.  In one aspect of this investigation they questioned the nature of signaling events in B cells exposed to IL-4, as compared to naïve, that is, untreated, B cells.  For naïve B cells the classical pathway to ERK phosphorylation is well-known. It involves a specific group of mediators.  In contrast to the situation in naïve B cells, Rothstein and colleagues found that events changed dramatically after B cell exposure to IL-4.  Following B cell exposure to IL-4, even after the IL-4 was removed, B cell signaling traveled a completely new and distinct route that relies on mediators different from those required for the classical pathway.  Rothstein termed this new route the “alternate pathway.”  In further studies Rothstein and colleagues found that the alternate pathway produced by B cell exposure to IL-4 does not replace the classical pathway, but rather operates in parallel with it.  Because the two pathways operate in parallel, complete blockade of the cellular consequences of antigen binding in IL-4-exposed B cells requires interference with both the classical and the alternate pathways.  

It is a basic principle that cells don’t expend energy unless there is some advantage, so Rothstein questioned the purpose and function of the alternate pathway; that is, why is there an alternate pathway and of what use is it to the B cell. "It is possible that the alternate pathway strengthens B cell signaling," explained Dr. Rothstein. Still, he was surprised that exposure to IL-4 could tell the B cell to do something totally different upon antigen encounter than it was ordinarily expected to do. So he performed a molecular screen to detect expressed genes and through this approach found, surprisingly, that IL-4-exposed B cells in which the alternate pathway is operative produce a previously described cytokine molecule, osteopontin. Osteopontin has been known to be secreted by T cells and other cells of the immune system but not by B cells. And the fascinating thing about osteopontin is that it has a good side and a bad side---it stimulates B cells in general to assist in the B cell immune response, but it also triggers autoantibody production and is strongly associated with autoimmunity.  IL-4 is elevated during serious infectious conditions known as sepsis.

Dr. Rothstein thinks that the alternate pathway may act as a fail-safe or last chance mechanism, by stimulating osteopontin expression that calls into play all available B cells to assist in fighting the invading microorganism.  At the same time, this general call for B cells has the side effect of activating autoantibody producing B cells and so risks autoimmunity.  In fact, this could be why, as we get older, levels of autoreactive antibodies in the blood increase—because occasional episodes of severe illness lead to alternate pathway triggering, osteopontin production, and autoantibody secretion. Dr. Rothstein and his colleagues are now trying to figure out whether people exposed to high levels of IL-4 are at greater risk for autoimmune diseases. 

Beyond this consideration, Dr. Rothstein says, the concept of signal reprogramming by receptor crosstalk seems to be a general one, and likely applies to receptors and cell types beyond B cells.  This concept holds that context is determinative for receptor signaling—in other words, that which has gone before influences future actions and events that are yet to come.  Rothstein stresses that this is nothing new—it is something we all intuitively accept in our own lives and voiced most eloquently many years ago by Shakespeare as "what's past is prologue”.  So in addition to their many other properties, B cells turn out to be literate as well!

Are you at risk for Type I diabetes?

Doctors at the North Shore-LIJ Health System are participating in a federal study on the natural history of Type I diabetes.

It is now known that Type I diabetes is an autoimmune disease probably caused by a mix of risk genes and environmental triggers. Scientists are studying children with siblings who developed Type I diabetes because they are at higher than normal risk of the same disease. In Type I diabetes, the body's immune system destroys the pancreatic islet cells that make insulin. Insulin is critical in the regulation of blood glucose - the body's main source of fuel. When insulin is not around, blood glucose rises and can lead to serious complications. People with Type I diabetes rely on insulin injections to manage their body's glucose levels.

            Once scientists understood that diabetes is an autoimmune disease, the next step was to identify autoantibodies that are specifically produced by the immune system to target insulin-producing pancreatic islet cells. Scientists in the federal study, called TrialNet, take blood from people at risk of diabetes and look for the presence of autoantibodies. Those with autoantibodies are at high risk of developing Type I diabetes during the next five years, said Phyllis Speiser, MD, an endocrinologist at Schneider Children's Hospital and a scientist at The Feinstein Institute for Medical Research who is working with colleagues at Columbia University to enroll patients on Long Island. 

               Researchers are recruiting children and young adults with a family history of diabetes. IF they are found to be at high risk, they may be enrolled in a study to reduce their risk of developing diabetes. People in the study will be followed throughout childhood to identify risk factors.  Relatives of patients with type 1 diabetes have a 10 to 15 times higher risk for developing the disease than people with no family history. About 3 to 4 percent of family members of people with type 1 diabetes will have autoantibodies in their blood, according to the TrialNet investigators.

In the study, antibody tests are repeated in those who initially test positive. A glucose tolerance test is then given to measure their body's response to high glucose.

            There are many other prevention studies underway and Dr. Speiser and her colleagues also help link children with a high risk for developing diabetes to other studies designed to test experimental treatments designed to delay or prevent Type I diabetes. For more information call Margaret Pellizzari at 718-470-3290.