Biomarkers Found Harmful For Human Lupus

A team of Wake Forest University School of Medicine has found biomarkers for lupus that may play a role in causing the disease. The biomarkers are micro-ribonucleic acids (micro-RNAs), said Nilamadhab Mishra, M.D.

Mr. Mishra and his colleagues reported at the American College of Rheumatology meeting in Washington that they had found profound differences in the expression of micro-RNAs between five lupus patients and six healthy control patients who did not have lupus.

'We are the first to show that these micro-RNAs are a problem in human lupus,' said Mishra, an assistant professor of rheumatology.

Mishra said microRNAs are a class of small chains of ribonucleic acid that have important regulatory functions in the body, particularly in suppressing genes (RNA serves as the template for translation of genes into proteins).

The research is part of Mishra's broader focus on histones, the tiny spools in the nuclei of cells around which DNA winds and compacts when it is not in the process of copying in cell division. Changes in these histones, called epigentic changes, can alter gene expression and the proteins these genes produce without altering the underlying DNA.

In the new study, the researchers found 40 microRNAs in which the difference in expression between the lupus patients and the controls was more than 1.5 times, and focused on five micro-RNAs where the lupus patients had more than three times the amount of the microRNAs as healthy controls, and one, called miR 95 where the lupus patients had just one third of the gene expression of the micro-RNA of the controls.

The team reported the lesser amount of miR 95 'results in aberrant gene expression in lupus patients.'

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Furthermore, Mishra said, the microRNAs are associated with enzymes called histone deacetylases, which provide 'further rationale for the use of histone deacetylase inhibitors (HDIs) for the treatment of lupus.' Mishra has shown that HDIs reset the histone modifications. He and his colleagues are investigating two HDIs–TSA (Trichostatin A) and SAHA (suberoylanilide hydroxamic acid )–in lupus patients and have reported positive results against a number of lupus symptoms and conditions.

Coauthors with Mishra on this study are Kerri Keiger, Ph.D., and Emmanuel Labourier, Ph.D., of Ambion Inc. in Austin, Texas, which makes RNA-based research products for the life sciences markets.

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In a second presentation, Mishra discussed his hypothesis that environmental factors trigger histone modifications that activate a type of white blood cell called the B cell and turn these cells into self-destructive attackers, a key element in lupus, an autoimmune disorder.

Mishra said removing these activated B cells is one current treatment for lupus. 'The lupus patients have activated B cells that cause antibody production and kidney disease, but we don't know why,' he said.

But he is continuing to pursue resetting part of the epigenetic code as a way to improve lupus treatment.

'We demonstrated that the response to bacterial and viral byproducts induce B-cell activation through the epigenetic mechanism,' he said. These changes lead to activation of the histone deacetylase enzymes. The HDIs stop this activation.

Working with Mishra on this project is Isaac Snowhite, Ph.D., of Wake Forest.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.

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SRM