Lorene M. Nelson

Epidemiology of Environmental Exposures and Human Autoimmune Diseases: Findings from a National Institute of Environmental Health Sciences Expert Panel Workshop

Autoimmune diseases (AID) are a collection of many complex disorders of unknown etiology resulting in immune responses to self-antigens and are thought to result from interactions between genetic and environmental factors. Here we review the epidemiologic evidence for the role of environmental factors in the development of human AID, the conclusions that can be drawn from the existing data, critical knowledge gaps, and research needed to fill these gaps and to resolve uncertainties. We specifically summarize the state of knowledge and our levels of confidence in the role of specific agents in the development of autoimmune diseases, and we define the areas of greatest impact for future investigations. Among our consensus findings we are confident that: 1) crystalline silica exposure can contribute to the development of several AID; 2) solvent exposure can contribute to the development of systemic sclerosis; 3) smoking can contribute to the development of seropositive rheumatoid arthritis; and 4) an inverse association exists between ultraviolet radiation exposure and the risk of development of multiple sclerosis. We suggest that more studies of phenotypes, genotypes, and multiple exposures are needed. Additional knowledge gaps needing investigation include: defining important windows in the timing of exposures and latencies relating to age, developmental state, and hormonal changes; understanding dose-response relationships; and elucidating mechanisms for disease development. Addressing these essential issues will require more resources to support research, particularly of rare AID, but knowledge of the risks conferred by environmental factors in specific genetic contexts could pave the way for prevention of AID in the future.

Is head trauma a risk factor for amyotrophic lateral sclerosis? An evidence based review

Our objective was to evaluate the epidemiological literature regarding the association between trauma to the head and ALS, in order to determine if trauma to the head is a risk factor for ALS. A Medline literature search was conducted for the period between 1980 and October 2010 using the search terms: (‘head trauma’ OR ‘head injury’) AND (ALS OR ‘amyotrophic lateral sclerosis’ OR MND OR ‘motor neuron disease’). The references of primary articles and reviews were checked to assure completeness of the search. Articles with primary data and reference groups were reviewed. The American Academy of Neurology evidence based method for classification of evidence for inferring causality and assigning level of conclusion was used. Twelve of 14 articles published since 1980 met the inclusion criteria. One class II article and three class III articles showed an association between a single instance of head trauma and ALS that did not exceed what might be seen due to chance alone. Eight class IV evidence articles could not inform conclusions. We concluded that evidence based analysis of the epidemiologic literature does not permit concluding that a single instance of head trauma is a risk factor for, or causes, ALS (Level U conclusion).

Interferon-γ–Producing T Cells, Pregnancy, and Postpartum Relapses of Multiple Sclerosis

OBJECTIVEnTo determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period.nnnDESIGNnCase-control study.nnnSETTINGnKaiser Permanente Northern California and Stanford University.nnnPARTICIPANTSnTwenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum.nnnMAIN OUTCOME MEASURESnSixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors.nnnRESULTSnFifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses.nnnCONCLUSIONSnOur findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.

Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis: The GENEVA Study: Rationale, Study Design and Demographic Characteristics

Recent reports of a potentially increased risk of amyotrophic lateral sclerosis (ALS) for veterans deployed to the 1990–1991 Persian Gulf War prompted the Department of Veterans Affairs to establish a National Registry of Veterans with ALS, charged with the goal of enrolling all US veterans with a neurologist-confirmed diagnosis of ALS. The Genes and Environmental Exposures in Veterans with ALS study (GENEVA) is a case-control study presently enrolling cases from the Department of Veterans Affairs registry and a representative sample of veteran controls to evaluate the joint contributions of genetic susceptibility and environmental exposures to the risk of sporadic ALS. The GENEVA study design, recruitment strategies, methods of collecting DNA samples and environmental risk factor information are described here, along with a summary of demographic characteristics of the participants (537 cases, 292 controls) enrolled to date.

Response to Hill-Burns et al. letter: An attempt to replicate interaction between coffee and CYP1A2 gene in connection to Parkinson’s disease

R. A. Popat, S. K. Van Den Eeden, C. M. Tanner, F. Kamel, D. M. Umbach, K. Marder, B. Ritz, G. Webster Ross, H. Petrovitch, B. Topol, V. McGuire and L. M. Nelson Department of Health Research and Policy, Division of Epidemiology, Stanford University, School of Medicine, Stanford, CA; Division of Research, Kaiser Foundation Research Institute, Oakland, CA; The Parkinson s Institute, Sunnyvale, CA; Epidemiology Branch, National Institute of Environmental Health Sciences, NIH Research Triangle Park, NC; Biostatistics Branch, National Institute of Environmental Health Sciences, NIH Research Triangle Park, NC; Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY; The Gertrude H Sergievsky Center and the Taub Institute, Columbia University, College of Physicians and Surgeons, New York, NY; Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, CA; Veterans Affairs Pacific Islands Health Care System, Honolulu, HI and The Pacific Health Research Institute, Honolulu, HI, USA