Tuesday, November 18, 2014

Immunogenomics advances point to new biomarkers, therapies

Next-generation gene-sequencing technology and new data-analysis tools are pointing the way to fresh diagnostic and treatment approaches for autoimmune diseases, cancer and many other conditions. That was the message at Immunogenomics 2014, a recent conference hosted by Huntsville’s HudsonAlpha Institute for Biotechnology and Science magazine for researchers studying the interaction between genes and the immune system. The event was sponsored in partnership with UAB and its Comprehensive Arthritis, Musculoskeletal and Autoimmunity Center (CAMAC).

Investigators from major national and international research institutions described how detailed profiles of immune cells could improve response to influenza vaccines and accelerate new treatments for emerging infectious diseases. They explained new immune-mediated links between microbial populations and cancer risk, and highlighted progress in understanding the pathogenesis of complex diseases such as multiple sclerosis.

“We now have the tools to examine these gene-disease associations in finer detail,” said S. Louis Bridges Jr., M.D., Ph.D., director of UAB’s Division of Clinical Immunology and Rheumatology and the CAMAC. Bridges is using genomic techniques to study the autoimmune condition rheumatoid arthritis. Bridges presented his research at Immunogenomics 2014, and served as chair of a session on the genetics of complex disease. “We’ve started to refine our analysis to home in on cells with an increasing degree of specificity,” Bridges said. “Technology is now allowing us to analyze in more detail specific subsets of cells, including ultimately at the single-cell level.”

From Associations to Biomarkers

Genomewide association studies have identified a host of genetic changes linked with disease. “Now investigators are looking at the functional effects of these polymorphisms,” Bridges said. “It could be that a polymorphism affects expression of a certain gene, or it may only affect expression of that gene in a certain cell type.” Bridges’ project, being performed in collaboration with UAB epidemiology chair Donna Arnett, Ph.D., and HudsonAlpha investigator Devin Absher, Ph.D., is examining genetic risk factors in African-Americans with RA.

"We now have the tools to examine these gene-disease associations in finer detail," Bridges said. "We've started to refine our analysis to home in on cells with an increasing degree of specificity."

In his talk at Immunogenomics 2014, Bridges demonstrated that overexpression of the interferon gamma 2 receptor gene is strongly linked with severity of disease in African-American patients with RA. “Our next step is to see in which cells that particular expression occurs,” Bridges said. This work could ultimately point the way to biomarkers that tell clinicians which of several known signaling pathways is active in a patient with RA, guiding treatment decisions.

Epigenetics and Therapeutics

Researchers are also focusing increasing attention on the ways gene expression is regulated dynamically in cells through epigenetic changes, says Robert P. Kimberly, M.D., director of the UAB Center for Clinical and Translational Science. Epigenetics refers to mechanisms that alter gene expression without changes in the actual DNA sequence. One of the most common epigenetic changes is methylation. When a methyl group attaches to the DNA base cytosine, it blocks the ability of the neighboring gene to be expressed.

Tracking and analyzing epigenetic markers implicated in a particular disease — such as systemic lupus erythematosus, one of Kimberly’s own research interests — could give clinicians crucial information on “if to treat, when to treat and also how to treat” that condition, he said.

For example, if a key risk gene is hypo-methylated in a patient — increasing the likelihood of the gene’s being expressed — “that could mean the patient is poised for a flare-up of disease,” Kimberly said. Another patient, who would look exactly the same to a clinician, would be much less likely to have a flare-up if that gene is hyper-methylated, he adds. “Understanding this epigenetic regulation, and eventually manipulating it to therapeutic advantage, is very exciting.” This research is a focus of several investigative teams at UAB, Kimberly says.

A “tree map” depicting the immune diversity in a patient diagnosed with Parkinson’s disease. Each rectangle represents a unique antigen receptor detected in the sample, and the size of each rectangle represents the relative frequency of that receptor within the sample. (Color is arbitrary.) Image courtesy iRepertoire.

Profiling Immune Signatures

One advance highlighted by several presenters at Immunogenomics 2014 was immune repertoire sequencing. Researchers now understand that an individual’s immune response is based greatly on the specific cell populations, or “repertoire,” present in that individual. For both T and B cells, for example, millions of distinct variants are possible. The exact mix is determined by a person’s encounters with microbes, disease and other environmental exposures over a lifetime, explains HudsonAlpha investigator Jian Han, M.D., Ph.D., a 1991 graduate of UAB’s medical genetics doctoral program.

Everyone produces T cells, for example, Han says. “But which one of those naive T cells gets used is determined by if it met, and was activated by, its antigen.” By analyzing the variety of T and B cells present in a particular patient, or mapping the repertoire commonly found in a particular disease, researchers can identify biomarkers to aid in diagnosis and treatment, Han notes.

Han’s HudsonAlpha lab has pioneered the multiplex PCR technology needed to gather the massive amounts of data required for repertoire sequencing, and the analytical tools required to resolve that data into meaningful reports. His presentation at Immunogenomics 2014 focused on Repertoire10K, a HudsonAlpha-funded project to sequence the immune repertoires of 10,000 patients: 100 with each of 100 critical diseases. The goal is to identify a signature in the immune repertoire for each disease. UAB researchers have been key contributors of the genetic samples that are critical to the project, Han says. In return, the investigators have access to state-of-the-art sequencing data that can advance their own studies.

Team-based Science

Collaborations between investigators at HudsonAlpha and UAB have taken place since the institute first opened in 2008, Kimberly says. But the new UAB–HudsonAlpha Center for Genomic Medicine, launched this summer, will increase these research partnerships and speed new discoveries in immunology, cancer, cardiovascular disease and many other fields, he notes.

Leveraging the strengths of each institution is critical as the scale of the research challenges becomes ever greater, Kimberly adds. “To understand what’s really happening in disease states, we’re going to have to be able to take all the data on genomics, epigenetics and more and figure out how to pull it all together,” he said.

That’s why UAB is also creating a new Informatics Institute. It will work in tandem with the UAB–HudsonAlpha Center for Genomic Medicine and a third initiative, the UAB Personalized Medicine Institute, to build the infrastructure and recruit the data scientists needed to succeed in this new era of research.

“It’s a major frontier right now,” Kimberly said. “The algorithms to combine all this data for the most part haven’t even been formulated yet. But it’s clear that the institutions that succeed in the future will be the innovators in this area.”

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