People with multiple sclerosis may have significant differences in certain genes that make them more susceptible to the disease. A new study has found that MS patients have less activity in the so-called FOXP3 gene located in a small group of T-cells.1
A Possible MS Target
This abnormal, quiescent activity in the gene may reflect the suppressed ability of the body to block immune system cells' attack against myelin and the nerve fibers in the central nervous system it protects, say scientists at Oregon Health & Science University in Portland.
"This is an important marker," said lead researcher Arthur Vandenbark, PhD, a professor of Neurology and Molecular Microbiology and Immunology. "This is the first publication that links FOXP3 with reduced suppression in MS."
So far, it's not known why FOXP3 activity is reduced in people with MS, Vandenbark told Priority Healthcare. "It could be less expression per cell or fewer cells that express it," he said.
Comparing Differences in Gene Activity
To ascertain the link between reduced FOXP3 activity and MS, Vandenbark and his team of researchers from The Immune Response Corporation in Carlsbad, California took blood samples from 19 patients diagnosed with either relapsing or secondary-progressive MS, and compared them to blood samples drawn from 19 healthy volunteers. None of the MS patients was undergoing treatment when the study began.
They isolated a subgroup of regulator T-cells in the blood samples taken from the group with MS, and found that they not only contained abnormal FOXP3 genes, but also were not able to suppress a group of disease-causing T-cells that attack myelin and nerve cells, a hallmark characteristic of the disease.
T-cells are a group of white blood cells that make up the body's immune system that defend against infection. Scientists believe a smaller group of pathogenic, or disease-causing, T-cells lead the attack against the central nervous system in MS patients.2 Specifically, myelin and the nerve fibers it protects become damaged, and the nerve fibers can no longer communicate with each other, leading to the symptoms of the disease.3
T-Cell Hierarchy in MS
Studies in the last ten years have also shown that a subset of regulatory T-cells (Treg cells) provide a control mechanism that prevents the expansion of autoimmune reactive T-cells, including those that target areas in the central nervous system.4 But only recently have medical researchers begun to recognize that regulatory T-cells are directly involved in suppressing pathogenic T-cells. "There has been no specific marker for them," Vandenbark explained.
While MS patients are not deficient in Treg cells, the reduced suppression of the disease-causing T cells caused by abnormalities in the FOXP3 gene may be the culprit. "Children born with a mutation in FOXP3 who have no Treg cells develop a lethal lymphoproliferative disease and a spectrum of autoimmune diseases," Vandenbark explained. While FOXP3 has been shown in previous research to play a role in T-cell regulation,5 no studies before this one have found that the reduction in the ability of regulatory T-cells to suppress pathogenic T-cells was linked to the suppressed activity of the FOXP3 gene.
"You can't live without the FOXP3-positive cell, so we're talking about a degree of expression" in MS patients, Vandenbark pointed out. But there are still questions that remain. "How much is enough, how does that pair with the loss of regulation of pathogenic cells, and how long does it take things to happen?" he asked.
Promising Vaccine?
Meanwhile, Vandenbark was involved in a separate study to test the effectiveness of a special vaccine aimed at boosting the activity of the gene.6 The vaccine, marketed as Neuro Vax, was discovered by Vandenbark and researchers at the Immune Response Corporation. In their study, the vaccine was shown to boost FOXP3 expression levels among MS patients receiving injections for a year.
"So, not only have we identified the marker to show that there are fewer of these T-reg cells present in MS patients, but we're providing a solution for correcting the problem, at least in some patients," Vandenbark explained.
He and his colleagues believe the vaccine stimulates regulatory T-cells to suppress the activity of disease-causing T-cells that attack tissues in the central nervous system. Meanwhile, future studies will continue to evaluate the effectiveness of therapies like Neuro Vax, Vandenbark said. "In MS, the FOXP3 gene is present, but it is not expressed at a level sufficient to maintain a normal level of immune regulation. Neuro Vax appears to correct this problem," he said.
In the meantime, Vandenbark and his team want to find out if the lower expression of FOXP3 is due to fewer numbers of Treg cells, or if individual Treg cells carry reduced FOXP3 activity. Studies looking at that, as well as testing the effectiveness of Neuro Vax, are currently being planned, he said.
"If the reduced expression of FOXP3 can be related to the clinical course of MS, following the expression of this marker will allow an assessment of different types of drug activity as therapy for MS," Vandenbark explained. "Ideally, one would like to restore FOXP3 expression to normal levels and see if this leads to better control of autoimmune responses and a more stable clinical course."
1. Huan J, Culbertson N, Spencer L et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res 2005 Jun 10;81(1):45-52 [Epub ahead of print].
2. Sospedra M, Martin R. Immunology of Multiple Sclerosis. Annu Rev Immunol 2004 Sep 27;[Epub ahead of print].
3. National Multiple Sclerosis Society. What is Multiple Sclerosis? Available at: http://www.nationalmssociety.org/What%20is%20MS.asp.
4. Zylicz M, Bocian K, Korczak-Kowalska G. Regulatory cells: their development, mechanism and effects of action, and their potential use in transplantation. [Translated from Polish]. Postepy Hig Med Dosw (Online) 2005 Apr 21;59:160-71.
5. Roncador G, Brown PJ, Maestre L et al. Analysis of FOXP3 protein expression in human CD4(+)CD25(+) regulatory T cells at the single-cell level. Eur J Immunol 2005 May 18;35(6):1681-91. [Epub ahead of print].
6. Vandenbark AA. TCR peptide vaccination in multiple sclerosis: boosting a deficient natural regulatory network that may involve TCR-specific CD4+CD25+ Treg cells. Curr Drug Targets Inflamm Allergy 2005 Apr;4(2):217-29.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
