Muscle & Nerve

kazamel MNMuscle biopsy. Hematoxylin and eosin (A) and trichrome (B) stained sections show rimmed vacuoles (arrows), muscle fiber size variability, internal nuclei, and groups of atrophic fibers. (C) Vacuoles overreact for acid phosphatase, suggesting lysosomal dysfunction (arrow). (D) Congo red stained section viewed under rhodamine optics shows rare congophilic inclusions (arrow). (E) ATPase pH 4.3 reacted section shows type 1 fiber grouping. (F) Nicotinamide adenine dinucleotide reacted section demonstrates lobulated fibers in patient 5 (arrow points to a lobulated fiber). Original magnification: 40 × (A–D and F) and 20 × (E).

 

ubogu photoEroboghene Ubogu, M.D., professor in the Department of Neurology

Investigators at the University of Alabama at Birmingham have identified an intriguing potential treatment target for the most common form of Guillain-Barré syndrome. In a study published online in July in Acta Neuropathologica, the authors offer evidence of a crucial pathogenic role for a molecule that is associated with acute inflammatory demyelinating polyradiculoneuropathy — or AIDP, the most common variant of Guillain-Barré syndrome.

Guillain-Barré syndrome is the most common cause of sudden peripheral nerve disease in the world. It is an autoimmune disease affecting about one to three per 100,000 people a year. This year marks the 100th anniversary of the first recognized description of Guillain-Barré syndrome, a disorder that can lead to long-term disability, paralysis and death. There have been no new therapies for more than 20 years.

Autoimmune diseases are characterized by an inappropriate response by the body’s immune system. Normally, the immune system protects the body by attacking foreign invaders such as viruses, bacteria and other pathogens. But for those who develop an autoimmune disease, the immune system fails to work properly and attacks the body’s own healthy tissue with often devastating results.

White blood cells, also known as leukocytes, are the immune system’s front-line soldiers. When the body recognizes the presence of a foreign substance, leukocytes are activated and migrate to the appropriate area to do battle with the invaders. Leukocytes travel from blood vessels into tissues by means of a process called leukocyte trafficking. This is a coordinated process by which leukocytes are attracted to blood vessels, then attach and migrate across them into the tissues to do their work.

“We have had a very poor understanding of the leukocyte trafficking process in Guillain-Barré syndrome,” said Eroboghene E. Ubogu, M.D., professor and director of the neuromuscular division in the Department of Neurology, UAB School of Medicine and lead author of the study. “We knew that leukocytes crossed into nerves through the blood-nerve barrier with deleterious effects, but we did not understand the mechanism. We undertook this study to examine whether a molecule called alpha M integrin, or CD11b, was involved. This molecule was known to make certain leukocytes attach to blood vessels, and our previous published work using AIDP patient leukocytes in the laboratory provided a clue that it may be crucially important.”

news cells 3 375Leukocyte cells travel over the endothelial cells of the blood/nerve barrier. Those that stop and attach have the capacity to enter the nerve and cause demyelination.

In the AIDP variant of Guillain-Barré syndrome, the focus of the autoimmune attack is the myelin sheath, a layer of insulation that surrounds nerve axons, similar to the insulation around the wires of an electric cable. The myelin sheath’s role is to rapidly move electrical impulses along nerves, and if it is damaged — or demyelinated — then nerve function is compromised.

The first step taken by Ubogu and his team was to examine nerve samples from an archive of patients with AIDP located in the Shin J. Oh Muscle and Nerve Histopathology Laboratory at UAB. Oh, a professor emeritus in the UAB Department of Neurology, is a pioneer in the study of neuromuscular diseases.

“From these archived nerve samples, we studied three adult patients with AIDP compared to three matched controls,” Ubogu said. “We hypothesized that we would find CD11b on the leukocytes in those AIDP patient nerve samples, and we did. It was especially present in areas with significant demyelination.”

Next, Ubogu and his team looked at an animal model of AIDP where they were able to block CD11b early in the disease process. With CD11b inhibited, the affected mice exhibited less overall weakness and reduced inflammation, as well as less demyelination and axon loss.

“These two results strongly indicated that CD11b is essential for these autoimmune leukocytes to migrate into the nerves and cause demyelination in AIDP,” he said. “What we still didn’t know was how the cells physically managed to cross the blood-nerve barrier. Was the barrier leaky with gaps between cells? Did the leukocytes push through or between the blood-nerve barrier endothelial cells?”

Using a technique called phase contrast video microscopy, Ubogu’s team produced videos that show AIDP patient leukocytes as they migrated across the layer of endothelial cells that form the blood-nerve barrier in the laboratory. Normally, the leukocytes keep on moving, but Ubogu’s video evidence indicates that some leukocytes are able to stop and squeeze in between endothelial cells. CD11b played a crucial role in this process.

The team verified the laboratory results in actual patients by looking at the inflammation in the nerves of AIDP patients at very high magnification. This showed leukocytes crossing between the blood-nerve barrier endothelial cells without gaps in the barrier or change in how the barrier is structured.

“In a healthy immune system, one of CD11b’s normal jobs is to make specific leukocytes adhere to the surface of blood vessel cells,” Ubogu said. “Unfortunately, they do the same in the AIDP form of Guillain-Barré syndrome. This allows the autoimmune leukocytes to adhere to the blood vessel walls within the inner parts of the nerve, ultimately migrating with direct access to the axons where demyelination can occur.”

Ubogu says the results of these proof-of-concept studies strongly point to CD11b as a treatment target for peripheral nerve inflammation.

“If we can find ways to block or inhibit CD11b early on, we should be able reduce or limit the amount of abnormal leukocyte trafficking, inflammation, and the resulting demyelination and loss of axons in AIDP,” he said. “This should result in better patient outcomes. Another approach might be to selectively remove CD11b leukocytes from the blood circulation so that they are not available to adhere to the blood-nerve barrier endothelial cells in patient’s nerves. Either way, our findings suggest that CD11b is a key candidate for specific drug development strategies in Guillain-Barré syndrome.”

 Ubogu says the findings are very exciting, as they provide knowledge of leukocyte trafficking in human nerves, but more work needs to be done in affected patients to develop an effective drug. The findings may also be applicable to other peripheral nerve inflammatory diseases. The research was funded by the National Institutes of Health and UAB.

Collaborators on the study are Chaoling Dong, Steven P. Palladino and Eric Scott Helton, Ph.D., of theNeuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology at UAB.

By Bob Shepherd
UAB Media Relations

UAB Hospital remains at top in Birmingham and Alabama, and rises in several specialty rankings in 2016-2017 U.S. News & World Report Best Hospitals report.

vickers usnewsThe UAB Health System is dedicated to providing every patient with the best experience and highest quality care available.

U.S. News & World Report’s 2016-2017 Best Hospitals report ranks UAB Hospital No. 1 in Birmingham and Alabama, and nine UAB specialties are listed among the nation’s top 50, up from six specialties the previous year.

“We are proud to be one of the best hospitals in America, and located in Alabama,” said Health System CEO Will Ferniany. “UAB Medicine is something all people in Alabama should be proud of. We even have a bumper sticker that says ‘Our Nationally Ranked Team Wears Scrubs.’ While we are nationally ranked and internationally known, our faculty and staff never forget they are here to serve the people of Alabama with the best medical care possible.” 

Rheumatology (11), Gynecology (16) and Nephrology (20) appeared in the nation’s top 20; Neurology and Neurosurgery (25), Pulmonology (29), Ear, Nose and Throat (29), and Diabetes and Endocrinology (30) appeared in the top 30; and Cardiology and Heart Surgery (37) and Urology (47) rounded out UAB’s highest-ranked programs.

The biggest jumps in rankings came from Ear, Nose and Throat and Diabetes and Endocrinology, which were ranked as high-performing last year and both leapt to top-30 national rankings this year. Cardiology and Heart Surgery went unranked last year and appeared at 37 this year. Rehabilitation, Orthopedics, Cancer and Geriatrics all earned the high-performing designation.

Rankings like U.S. News & World Report’s are just one tool available to patients as they make informed decisions about their health care, Ferniany says. UAB Medicine recently launched another when it became the first care provider in Alabama to empower patients to publicly rate and review its physicians — a reliable source of verified and up-to-date information from actual patients in UAB’s Find a Provider directory. The rating and reviews feature gives patients an alternative to third-party rating sites that often exist with little if any oversight and feature outdated, inaccurate and in some cases libelous information. At its launch, more than 81 percent of eligible UAB physicians had a posted rating of at least four stars on the five-star scale.

By Jim Bakken
UAB Media Relations

 


standaart 2016David Standaert, M.D., Ph.D., the John N. Whitaker Professor and chair of the UAB Department of NeurologThough the drug levodopa can dramatically improve Parkinson’s disease symptoms, within five years one-half of the patients using L-DOPA develop an irreversible condition — involuntary repetitive, rapid and jerky movements. This abnormal motor behavior appears only while taking L-DOPA, and it stops if the drug is stopped. However, if L-DOPA is taken again, even many months later, it quickly re-emerges.

In research to prevent this side effect and extend the usefulness of L-DOPA — which is the most effective drug treatment for Parkinson’s disease — University of Alabama at Birmingham researchers have uncovered an essential mechanism of this long-term memory for L-DOPA-induced-dyskinesia, or LID.

They report a widespread reorganization of DNA methylation — a process in which the function of DNA is modified — in brain cells caused by L-DOPA. They also found that treatments that increase or decrease DNA methylation can alter dyskinesia symptoms in an animal model.

Thus, modification of DNA methylation may be a novel therapeutic target to prevent or reverse LID behavior.

“L-DOPA is a very valuable treatment for Parkinson’s, but in many patients its use is limited by dyskinesia,” said David Standaert, M.D., Ph.D., the John N. Whitaker Professor and chair of the Department of Neurology at UAB. “Better means of preventing or reversing LID could greatly extend the use of L-DOPA without inducing intolerable side effects. The treatments we have used here, methionine supplementation or RG-108, are not practical for human use; but they point to the opportunity to develop methylation-based epigenetic therapeutics in Parkinson’s disease.”

The research by David Figge, Karen Eskow Jaunarajs, Ph.D., and corresponding author David Standaert, Center for Neurodegeneration and Experimental TherapeuticsUAB Department of Neurology, was recently published in The Journal of Neuroscience.

Research details

Although studies of LID in animal models have shown changes in gene expression and cell signaling, a key unanswered question still remained: Why is the neural sensitization seen in LID persistent when delivery of L-DOPA is transient?

The UAB researchers suspected DNA methylation changes — the attachment of a methyl group onto nucleotides in DNA — because methylation is known to stably alter gene expression in cells as they grow and differentiate. Furthermore, methylation changes in neurons have been shown to be involved during the formation of place memory and the development of addictive behavior after cocaine use.

In general, increased DNA methylation has a silencing effect on nearby gene expression, while removal of the methyl groups enhances gene expression.

Figge and colleagues found that:

  • L-DOPA treatment of parkinsonian rodents enhanced the expression of two DNA demethylases.
  • Cells in the dorsal striatum in the LID model showed extensive, location-specific changes in DNA methylation, mostly seen as demethylation.
  • The changes in DNA methylation were near many genes with established functional importance in LID.
  • Modulating global DNA methylation — either by injecting methionine to increase methylation or applying RG-108, an inhibitor of methylation, to the striatum — modified the dyskinetic behavior of LID, down or up, respectively.
“Together,” the researchers wrote, “these findings demonstrate that L-DOPA induces widespread changes to striatal DNA methylation and that these modifications are required for the development and maintenance of LID.”

Funding for this work came from the Alacare Mary Sue Beard Predoctoral Fellowship, the Jurenko family, the American Parkinson Disease Association, and National Institute of Neurological Disorders and Stroke grant F31NS090641.