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Expert panel examines autoimmunity research

By Eddy Ball
October 2010

Patrick Leung, Ph.D., holds a microphone and addresses an audience.
Mechanisms Group chair Patrick Leung, Ph.D., is an associate adjunct professor in the Division of Rheumatology, Allergy, and Clinical Immunology at the University of California, Davis. (Photo courtesy of Steve McCaw)

Michael Pollard, Ph.D., addresses an audience as he leans on a podium. He is holding a microphone.
Discussing animal models, Scripps Research Institute investigator Michael Pollard, Ph.D., admonished his colleagues, "Future studies should be shaped by what happens in humans, not by what is possible in mice." (Photo courtesy of Steve McCaw)

Fred Miller, M.D., Ph.D., addresses an audience from a podium. He is holding a microphone.
Referring to years of flat budgets ahead, Miller said, "Focusing the work to these most promising areas is more important than looking at everything." He suggested that humanizing mice could make animal studies more relevant to understanding human disease. (Photo courtesy of Steve McCaw)

Christine Parks, Ph.D., stands in front of a group of people.
NIEHS Epidemiology Branch Research Fellow Christine Parks, Ph.D., gave the Exposure Assessment Group report and stressed that complex exposures mean fine-tuning questionnaires for epidemiological studies. "One size doesn't fit all," she told the group. (Photo courtesy of Steve McCaw)

Closeup photo of Pat Mastin, Ph.D., looking at someone out of frame
Pat Mastin, Ph.D., acting deputy director of the NIEHS extramural program, was one of five NIEHS scientists who served on the planning committee for the meeting. He worked with Humble, Miller, Parks, and NTP Immunology Discipline Leader Dori Germolec, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/tob/germolec/index.cfm), to make the meeting a productive learning experience for everyone involved. (Photo courtesy of Steve Mccaw)

Photo of two women and a man listening to a speaker. Focus is on the woman in center, Marilyn Diaz, Ph.D.
NIEHS Somatic Hypermutation Group Principal Investigator Marilyn Diaz, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/lmg/sh/index.cfm), center, contributed to the discussion of B cell activation in AD. (Photo courtesy of Steve McCaw)

An NIEHS meeting in Durham, N.C. Sept. 7-8 brought together an interdisciplinary group of experts to evaluate the state of the science regarding the role of the environment in the development of autoimmunity and related diseases. Organized and moderated by NIEHS Program Administrator Mike Humble, Ph.D., the meeting of approximately 40 NIEHS grantees and other experts also enjoyed generous support from the American Autoimmune Related Diseases Association, Inc. (AARDA) Exit NIEHS (http://www.aarda.org/), the leading national advocate for the more than 24 million Americans who suffer from autoimmune diseases.

For more than a decade, NIEHS has been a part of the trans-NIH Autoimmune Diseases Coordinating Committee, co-sponsored workshops, and funded research on the role of the environment in the development of autoimmune diseases (AD).

Identifying knowledge gaps in AD research

As Gwen Collman, Ph.D., interim director of the NIEHS Division of Extramural Research and Training (DERT), explained in her introductory comments, studies of twins and victims of environmental emergencies, such as the World Trade Center attack, offer compelling presumptive evidence for a role of the environment in dysregulation of the immune response and the development of a wide range of diseases (see text box).

Although there is increasing support for gene-environment interactions as a cause of AD, Humble said, "There are still numerous gaps in knowledge in this field." The expert panel meeting, he added, offers participants an opportunity "to explain to the world what we need to be doing."

A comprehensive cross-disciplinary meta-analysis and needs assessment

NIEHS convened the expert panel to evaluate levels of confidence about existing research on the role of the environment in the development of autoimmune diseases and the directions future investigations should take, as well as foster productive relationships among the several disciplines involved in research. In addition to members of DERT, NIEHS representatives at the meeting included scientists involved in basic, clinical, and epidemiological research in the Division of Intramural Research and the National Toxicology Program.

Following months spent preparing white papers prior to the meeting, the writing and review panels worked in two breakout sessions to complete draft consensus statements on the strength of current data and study design. During the first breakout session, participants were assigned to one of four research-area groups - mechanisms, animal models, epidemiology and human data, and exposure assessment - to create 25-minute presentations of their key points based on the model made famous by the 2005 Vallombrosa Consensus Statement on Environmental Contaminants and Human Fertility Compromise Exit NIEHS (http://www.healthandenvironment.org/infertility/vallombrosa_documents).

The next day, participants met in four integrated groups containing members from each of the research-area groups to tackle some of the overarching questions related to the role of the environment in the development of AD. They considered such topics as the adequacy of animal models in recapitulating AD in humans; the relative contributions of genetics, environment, and timing in the disease; the utility of in vitro and in vivo mechanistic studies; and the promise of new or existing approaches, such as biomarker development, epigenomic mapping, genome-wide association studies, biostatistical modeling, and disease registries.

Tangible outcomes of the expert panel deliberations

Following the meeting, writing groups will work on consensus statements that Humble said he expects to submit collectively for publication. Not surprisingly, the panelists agreed far more often than they differed, and they uniformly called for more research and funding, as well as more effective integration of disciplinary approaches and methodologies.

In his remarks on day two, NIEHS Environmental Autoimmunity Group Principal Investigator Fred Miller, M.D., Ph.D. (http://www.niehs.nih.gov/research/clinical/ea/index.cfm), seemed to speak for many in the audience, as he praised meeting organizers for "forcing us to talk to people with different backgrounds." He also seemed to express the group's shared commitment to answering the important questions about AD. "We can't let research momentum in understanding how autoimmune diseases develop stop at this point," he urged. "Our goal is to identify better ways to predict and eventually prevent the development of some autoimmune diseases, because by the time we see obvious clinical disease, less can be done."

Autoimmune disease - striking "like a thief in the night"

Autoimmunity is a result of a misdirected immune response that causes one's own immune system to attack itself. Some of the more than 100 autoimmune diseases Exit NIEHS (http://www.aarda.org/research_display.php?ID=47) listed by AARDA are lupus, type 1 diabetes, scleroderma, celiac disease, multiple sclerosis, Crohn's disease, autoimmune hepatitis, rheumatoid arthritis, Graves' disease, myasthenia gravis, myositis, antiphospholipid syndrome (APS), Sjogren's syndrome, uveitis, polymyositis, Raynaud's phenomenon, and demyelinating neuropathies.

As every presenter at the expert panel observed, the triggers, mechanisms, and timing of disease development remain largely unknown for the majority of ADs, despite numerous lines of experimental and epidemiological investigation. As Miller explained in his comments at the meeting, many ADs apparently develop long after whatever triggers them has laid the foundation for development of autoimmunity and ultimately the progressive development of the clinical criteria for diagnosing disease.

One possibly useful approach in future research, suggested NIEHS grantee (http://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=R15ES018986) and immuntoxicologist Jean Pfau, Ph.D. Exit NIEHS (http://www.isu.edu/bios/Professors_Staff/pfau_j.shtml), could be to determine the cluster of phenotypes that together make up patterns of AD, both for early signs of disease and to better utilize animal and in vitro models. Along with Pfau, several panelists also called for looking at shared patterns of mechanisms and outcomes of the many ADs, which have typically been recognized singularly as relatively rare disorders rather than within the overall category of autoimmunity.



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