Quinn Eastman

Dissecting a pediatric autoimmune disease

When a child is just learning to play sports, swim or even simply get dressed on her own, it can be heartbreaking to see that she is already being affected by symptoms of arthritis: swelling, limping, and/or restricted range of motion.

At the recent research retreat held by the Emory–Children’s Pediatric Research Center, rheumatologist Sampath Prahalad described his efforts to define the genetics and contributing factors for juvenile idiopathic arthritis (JIA).

Sampath Prahalad, MD

A challenge in this area is determining what makes juvenile idiopathic arthritis both different from other autoimmune diseases such as lupus or type I diabetes and what makes the disease appear early in life, decades before adult-onset rheumatoid arthritis usually appears.

Determining genetic and other risk factors for the disease can help increase understanding of the mechanisms of disease, leading to better treatments, and knowing how the cheap oakley disease develops can improve diagnosis. On this second point, we asked Prahalad two questions about his work:

What proportion of patients come to you because there is a suspected genetic connection?

Most come because of symptoms of rheumatic disease. I would estimate about 20 percent of our referrals come because of a mild symptom or abnormal lab test plus a family cheap oakley sunglasses history of autoimmunity, which prompts the PCP to seek a rheumatology evaluation. Less than 2 percent come purely for a family history of autoimmunity where they are concerned the child also has it.

Under what circumstances would a doctor seek to determine a genetic risk score for a child?

We know that twins, siblings and children of individuals with an autoimmune disease have a higher risk of the condition. So a genetic risk score could help identify those at risk for closer follow up or further evaluation. Conceivably in a child with symptoms suspicious for an autoimmune disease but not definitive, a genetic risk score could help increase the probability of being able to diagnose a specific condition.

Prahalad and colleagues published a paper in the June issue of Arthritis & Rheumatism investigating the applicability of a genetic risk score for JIA involving variations in four genes. In their study looking at 155 children with JIA and 684 controls, individuals with a risk score in the top fifth have odds of childhood-onset disease 12 times of those in the bottom fifth.

A key passage from the discussion of the Arthritis & Rheumatism paper indicates that genetic factors specific for childhood onset remain to be found.

Studying children has the advantage of focusing more on the influence of genetic factors compared to the influence of environmental factors, such as smoking. Notably, the magnitude and direction of the association between childhood-onset RA [rheumatoid arthritis] and TNFAIP3, STAT4, and PTPN22 variants were similar to those observed in RA. The observation that the selected variants did not have an elevated OR in childhood-onset RA as compared to RA suggests that there are other variants still to be investigated that may influence the risk of childhood-onset RA.

Prahalad says he wants to find out whether genetic http://www.gooakley.com/ factors contributing to childhood onset are simply cumulatively more intense, and thus drive the appearance of the disease earlier, or whether they are active in a childhood-specific context.

Notably, many of the genetic risk factors identified so far are shared with other autoimmune diseases. A recent Nature Genetics paper, which Prahalad contributed to, used a customized “Immunochip” to find several new risk factors for JIA.

Non-genetic risk factors: At the retreat, Mina Rohani Pichavant, a researcher working with Prahalad, had a poster discussing her preliminary data on the types of microorganisms found in the intestines of JIA patients. Previous studies in adults with rheumatoid arthritis have shown a link between intestinal bugs and disease risk, but this area of research is new for JIA. There are also connections between gum disease and JIA.

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A model for fetal hemolytic disease

Part of standard prenatal care for a pregnant woman is to test her blood for antibodies against the red blood cells of her baby, such as anti-Rhesus D antibodies. An incompatibility can result in hemolytic disease, where the mother’s antibodies attack fetal red blood cells. The development of a therapy for Rhesus D incompatibility was one of the major success stories of medical research in the 1960s.

Jeanne Hendrickson, MD

Although Rhesus D is the most common troublemaker, other anti-red blood cell antibodies such as those against the Kell protein can also cause hemolytic disease of the fetus. The origin is often from sensitization related to previous blood transfusions. At a recent seminar, pediatric hematologist Jeanne Hendrickson described a recent case that illustrates how serious this condition can be. Hendrickson is associate medical director of Children’s Healthcare of Atlanta’s Blood and Tissue Bank, and an assistant professor in pediatrics and pathology at Emory.

Early in her second pregnancy, a woman had developed anti-Kell antibodies, causing the baby to develop anemia and the early stages of fetal heart failure. Several intrauterine transfusions, which carry a risk of miscarriage, were required. At one point, Hendrickson says, the mother was in the http://www.raybani.com/ hospital for a week while doctors looked for compatible blood. When the baby was born, he was very pale and continues to need medical care, because anti-Kell antibodies interfere with red blood cell development.

Unfortunately, there is nothing analogous to RhoGam (the standard therapy for Rhesus D) for this situation. Today, 6 out of 1000 pregnancies are affected by red blood cell immunization. And despite its success, Hendrickson says some mystery remains about exactly how RhoGam works.

First author Sean Stowell, MD, PhD

First author Sean Stowell, MD, PhD

She and her colleagues have a new paper in the journal Blood describing an animal model for hemolytic disease of the fetus and newborn involving anti-Kell antibodies. Postdoc Sean Stowell is the first author Ray Ban outlet of the paper. This is the first animal model of anti-red blood cell antibodies generated through pregnancy – previous rabbit experiments dating back to the 1950s involved transfusions and/or immunizations.

The model uses mice that have been engineered to produce a human form of Kell protein on their red blood cells. When male mice positive for this extra gene mate with females who don’t have it, the litters are smaller and some of the pups are anemic or stillborn. The authors say that the model could provide a platform for studying how anti-red blood cell antibodies develop, as well as potential therapies.

Another recent paper from Stowell and Hendrickson describes a similar mouse model involving anti-red blood cell antibodies that develop because of transfusions rather than pregnancy. Between 3 and 5 percent of patients who get a blood transfusion will develop antibodies against Ray Ban online something on the red blood cells they received, making future transfusions possibly more problematic.

At the seminar, we learned that Hendrickson will be moving to Yale University later this summer. We wish her good luck at her new job.

 

 

 

 

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A Human Vaccine Project?

Emory Vaccine Center director Rafi Ahmed, is a co-author on a recent Science paper advocating a “Human Vaccines Project”. Wayne Koff, chief scientific officer of IAVI (International Aids Vaccine Initiative) is lead author and several other vaccine experts are co-authors.

The idea behind a “Human Vaccine Project” is to combine efforts at developing vaccines for major (but very different) diseases such as influenza, dengue, HIV, hepatitis C, tuberculosis and malaria, with the rationale that what scientists working on those diseases have in common is the Ray Ban outlet challenge of working with the human immune system.

Technology has advanced to the point where whole genome-type approaches can be brought to bear on vaccine problems. The authors cite work by Bali Pulendran’s laboratory on “systems vaccinology” and their analysis of the yellow fever vaccine as an example.

One major puzzle confronting vaccine designers is to coax the immune system into producing broadly neutralizing antibodies against a rapidly mutating virus, whether it is Gafas Ray Ban outlet influenza or HIV. Our own Cynthia Derdeyn has been analyzing this problem through painstaking work following how the immune system pursues a twisting and turning HIV.

An interesting related tidbit:

There are hints that the reverse engineering of vaccines has taken a leap forward in the case of RSV (respiratory syncytial virus): Scientists at Scripps Research Institute have designed vaccine components by computer and have used them to provoke neutralizing antibodies in monkeys.

Also check out Mike King’s feature in Emory Health on HIV vaccine research.

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From the genetic code to new antibiotics

Biochemist Christine Dunham and her colleagues have a new paper in PNAS illuminating a long-standing puzzle concerning ribosomes, the factories inside cells that produce proteins.

Ribosomes are where the genetic code “happens,” because they are the workshops where messenger RNA is read out and proteins are assembled piece by piece. As a postdoc, Dunham contributed to Nobel Prize-winning work determining the molecular structure of the ribosome with mentor Venki Ramakrishnan.

Ribosomes are the workshops for protein synthesis and the targets of several antibiotics

The puzzle is this: how messenger RNA can be faithfully and precisely translated, when the interactions that hold RNA base pairs (A-U and G-C) together are not strong enough. There is enough “wobble” in RNA base pairing such that transfer RNAs that don’t match all three letters on the messenger RNA can still fit.

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Supreme decision on DNA patents

In these days of political polarization, how often does the United States Supreme Court make a unanimous decision? When the case has to do with human genes and their patentability!

The case concerned patents held by Utah firm Myriad Genetics on the BRCA1 and 2 genes. Mutations in those genes confer an increased risk of breast and ovarian cancer. The patents in dispute claimed the genes themselves rather than just the technology for reading them.

Cecelia Bellcross, director of Emory’s genetics counseling program and an expert on breast cancer genetics counseling, reports that “in general, the clinical genetics community is jumping up and down, as are a lot of genetics lab directors and definitely patient advocacy groups.”

Myriad’s BRCA tests cost more than $3,000. Several competing firms announced that they would offer tests for the BRCA1 and 2 mutations at significantly lower prices.

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Fragile X clinical trials: this is not the end

A clinical trial testing a therapy for children with fragile X syndrome is closing down, after the sponsoring company announced that the drug, called arbaclofen, was not meeting its goals.

Readers of Emory Health magazine may remember Samuel McKinnon, an arbaclofen study participant who was featured in a 2012 article and video (below).

“We were surprised,” Samuel’s mother Wendy told us Monday. “But we knew going in that there were no guarantees.”

She reports that Samuel has made significant progress in the last couple of years. He likes playing and talking with the family’s new puppy, Biscuit. Samuel’s language skills have Ray Ban outlet blossomed and he will be headed to second grade this fall. But it’s hard to say whether that’s mainly because of the experimental drug or because Samuel has been continuing to grow and work hard in school and in therapy, she says.

A sizable fraction of patients in the study appeared to benefit from the drug, just not the majority of them, says Emory genetics chair Steve Warren.

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An indicator of aberrant stem cell reprogramming

The 2012 Nobel Prize in Medicine was awarded to Shinya Yamanaka and John Gurdon for the discovery that differentiated cells in the body can be reprogrammed. This finding led to the development of “induced pluripotent stem cells.”

These cells were once skin or blood cells. Through a process of artificial reprogramming in the lab, scientists wipe these cells’ slates clean and return them to a state very similar to that of embryonic stem cells. But not exactly the same.

It has become clear that iPS cells can retain some memories of their previous state. This can make it easier to change an iPS cell that used to be a blood cell (for example) back into a blood cell, compared to turning it into another type of cell. The finding raised questions about iPS cells’ stability and whether http://www.troakley.com/ iPS cell generation – still a relatively new technique – would need some revamping for eventual clinical use.

Hotspots where iPS cells differ from ES cells

Chromosomal hotspots where iPS cells differ from ES cells

It turns out that iPS cells and embryonic stem cells have differing patterns of methylation, a modification of DNA that can alter how genes behave even if the underlying DNA sequence remains the same. Some of these differences are the same in all iPS cells and some are unique for each batch of reprogrammed cells.

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ScienceSeeker honors Anna’s story

The story of Anna Sumner’s extraordinary experience — disabling chronic sleepiness, leading to scientific discovery and treatment at Emory — has been told in several places, among them the Wall Street Journal and the Today Show.

One of the most extensive and elegant approaches, in our opinion, was science journalist Virginia Hughes‘ post “Re-Awakenings,” originally written for the group blog Last Word on Nothing. (Hughes is now part of National Geographic’s Phenomena quartet of bloggers.) Yesterday “Re-Awakenings” won some recognition, receiving the “Post of the Year” award from ScienceSeeker, a community square for science blogging.

Note: We here at Emory Health Now are still learning about the thriving world of science blogging, but Scientific American’s blog impresario cheap oakley sunglasses Bora Zivkovic calls ScienceSeeker “the main portal for collecting, connecting and filtering science writing online.” The judges for the awards were Fraser Cain, Maggie Koerth-Baker, and Maryn McKenna.

In addition, the most recent issue of Emory Medicine has a feature on Anna’s story, and neurologist David Rye, who leads the Emory team who treated Anna, has his own take in the June issue of Discover magazine.

 

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Alphabet of modified DNA keeps expanding

Move over, A, G, C and T. The alphabet of epigenetic DNA modifications keeps getting longer.

A year ago, we described research on previously unseen information in the genetic code using this metaphor:

Imagine reading an entire book, but then realizing that your glasses did not allow you to distinguish “g” from “q.” What details did you miss?

Geneticists faced a similar problem with the recent discovery of a “sixth nucleotide” in the DNA alphabet. Two modifications of cytosine, one of the four bases http://www.raybani.com/ that make up DNA, look almost the same but mean different things. But scientists lacked a way of reading DNA, letter by letter, and detecting precisely where these modifications are found in particular tissues or cell types.

Now, a team… has developed and tested a technique to accomplish this task.

Well, Emory geneticist Peng Jin and his collaborator Chuan He at the University of Chicago are at it again.

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Detecting clandestine chlamydia

In recent years public health authorities have raised concern that many strains of Chlamydia trachomatis, a bacterium that is the most common cause of sexually transmitted infections around the world, can be missed by conventional genetic tests. A mutation in part of its genomc can make Chlamydia undetectable by the most commonly used tests.

Microfluidic

The Chlamydia tests are performed in a microfluidic cassette platform and data is returned about an hour after sample collection. In comparison, standard tests take a day or longer.

Most infections are asymptomatic but left untreated, Chlamydia infection can lead to pelvic inflammatory disease, infertility and ectopic pregnancy. It is also a Ray Ban online leading cause of blindness in developing countries.

Microbial geneticist Tim Read at Emory has been collaborating with Deborah Dean at Children’s Hospital Oakland and the Massachusetts firm NetBio to develop a fast, accurate and sensitive genetic test for Chlamydia.

“We used tools that were developed initially to answer basic scientific questions,” Read says. “We compared multiple genomes of C. trachomatis to find targets that would work across a broad selection of bacterial strains.”

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