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Team Taps Immune T-Cell Regulators to Find Early Markers of Disease in Blood

NEW YORK (GenomeWeb) – The regulatory network controlling differentiation of the immune system's T cells may contain markers of disease that differ in individuals' blood samples even before symptoms appear, according to a new study in Science Translational Medicine.

An international team led by investigators in Sweden team used a series of array-based expression and methylomic profiling experiments to put together a so-called gene regulatory network for T cells differentiating into four T helper cell groups.

By cross-referencing transcription factors from this analysis with information from past genome-wide association studies on common human diseases, the group narrowed in on three transcription factors showing disease-related differences in their expression, SNP profiles, and splice variant patterns.

To test their hypothesis that the transcription factors might offer a window on symptom development, the researchers then tracked their expression in the blood of individuals with two relapsing diseases: multiple sclerosis and seasonal allergic rhinitis. Indeed, their results pointed to distinct expression profiles in those with or without symptoms, suggesting similar T-cell regulators could help in finding, treating, or perhaps preventing other common diseases down the road.

"[We think] that different functional variants of these three transcription factors or their expression levels … can be used to predict many T cell-associated diseases with high accuracy," senior author Mikael Benson, a physician researcher with Linköping University's Centre for Individualized Medicine in Sweden, told GenomeWeb.

"But," he cautioned, "to really make it clinically relevant, I think you have to perform more studies of at-risk populations for certain diseases and study many different types of molecules, like methylation and proteins, and pick the most discriminating molecules for discriminating purposes."

For the most part, diseases aren't successfully diagnosed until symptoms are obvious, creating problems for those tasked with trying to treat conditions that may already have caused irreparable damage, Benson noted. Along with suffering for patients, this treatment failure leads to health care costs associated with both ineffective drugs and new drug development.

"Ideally, you should actually start treatment for preventing disease before symptoms occur, early in the disease process," he explained.

In their search for early blood markers of disease, Benson and his colleagues drew from their ongoing work on T cells — a group of white blood cells tasked with patrolling the body to find and stave off forms of disease ranging from metabolic conditions and heart disease to inflammatory conditions and cancer.

"If you can tap into that information — what's happening in those T cells — ideally you could diagnose disease processes early before symptoms occur," Benson said.

With that in mind, the researchers did array-based gene expression and methylation profiling on T cells over time as they differentiated into four subsets of T helper cells, hoping to find regulators relevant to early-stage disease.

After assessing such in vitro T-cell differentiation events at six time points in four replicate experiments, the researchers plugged their data into a mathematical model designed by first author Mika Gustafsson, also at Linköping University, to tease apart factors involved in T-cell differentiation regulation.

And from the set of transcription factors pinned to T cell differentiation, the team narrowed in further by folding in information on the genes and variants implicated in common human diseases through past GWAS.

The search led to three transcription factors — GATA3, MYB, and MAF — that were confirmed as T-cell regulators through the researchers' subsequent chromatin immunoprecipitation sequencing, gene expression profiling, and gene knockdown experiments in differentiated T helper 1 and T helper 3 cells.

From publicly available gene expression data, the researchers found that these three transcription factors and/or their target genes were differentially expressed in T cell-associated diseases such as rheumatoid arthritis, acute myeloid leukemia, or systemic lupus erythematosus.

Meanwhile, their own experiments in T cell samples from individuals with seasonal allergic rhinitis, individuals with MS, and unaffected control individuals suggested splicing patterns and gene expression of the three transcription factor markers shifted as symptoms appear in each of the relapsing diseases.

While there may not be a clear clinical need to test for allergic seasonal rhinitis, Benson explained, he and his colleagues believe a similar approach could be used for finding informative markers in individuals at risk of certain diseases such as hereditary breast cancer, for example, to diagnose, treat, or attempt to prevent disease.

"A likely continuation would be to study various forms of common cancer in at-risk populations to show clinical feasibility," he said. "We believe that it's probably easier to find drugs that can stop earlier disease processes than established ones."

More generally, Benson said, it would be ideal to start testing markers identified through these sorts of studies over decades in prospective studies of thousands or hundreds of thousands of individuals who start out healthy, using longitudinal blood samples such as those planned for President Obama's Precision Medicine Initiative.

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