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PTSD Invokes Sex-Different Immune Responses Print E-mail
SciMed - Healthcare
TS-Si News Service   
Saturday, 30 April 2011 15:00
San Francisco, CA, USA. Men and women had starkly different immune system responses to chronic post-traumatic stress disorder (PTSD), with men showing no response and women showing a strong response, in two studies by researchers at the San Francisco VA Medical Center (SFVAMC) and the University of California, San Francisco (UCSF).

While a robust immune response protects the body from foreign invaders, such as bacteria and viruses, an over-activated response causes inflammation, which can lead to such conditions as cardiovascular disease and arthritis.


In a study published in the journal Brain, Behavior, and Immunity, the authors took blood samples from 49 men (24 with PTSD and 25 controls) and 18 women (10 with PTSD and 8 controls). [C1] They then used gene microarray technology to determine which genes were activated in the subjects’ monocytes, which are immune cells that regularly cross the barrier between the bloodstream and the brain, and thus give a broad picture of immune reaction in both the body and brain.


Bioinformatics applies information technology (IT) to molecular biology. Paulien Hogeweg coined the term in 1978.

The rapid development of genomic and other molecular research technologies have combined with IT to produce very large quantities of complex data and information.

Bioinformatics exploits this situation by the development and application of computationally intensive techniques (e.g., data mining, and machine learning algorithms).

The field entails theory development, the creation and advancement of algorithms, computational and statistical techniques, and databases to solve formal and practical problems that arise when managing and analyzing biological data.

Bioinformatics was applied in the creation and maintenance of a biological information database at the beginning of genomic investigations (e.g., nucleotide and amino acid sequences). Database development involved technical design issues and development of complex new interfaces, enabling data submissions and access.

Common activities include mapping and analyzing DNA and protein sequences, gene finding and genome assembly, protein structure alignment and prediction, aligning different DNA and protein sequences for comparison, creating and viewing 3-D models of protein structures, and modeling evolutionary interrelationships.

Software tools range from simple command-line access to more complex graphical programs and standalone web-services available from various bioinformatics companies or public institutions.

The tool best-known among biologists may be BLAST, one of a number of generally available programs for doing sequence alignment. An algorithm determines the similarity of arbitrary sequences against other sequences (from curated databases of protein or DNA sequences).

The US National Center for Biotechnology Information (NCBI) provides a popular web-based implementation that searches their databases.

Current initiatives, such as SATé from the University of Texas at Austin have further extended the speed, accuracy, and detail obtained from such searches.
“We were looking for evidence of inflammation caused by immune activation,” explained lead author Thomas Neylan, MD, director of the PTSD program at SFVAMC and a professor in residence of psychiatry at UCSF.

“We know that people with PTSD have higher rates of cardiovascular disease and arthritis, which are diseases associated chronic inflammation. We also hoped that seeing which genes were expressed in PTSD might show us potential therapeutic approaches that we hadn’t thought of.”

The researchers found no evidence of increased immune activation among the men with PTSD compared to those without PTSD. In contrast, the women with PTSD showed significant evidence of immune activation compared to women without PTSD.

“Previous gene microarray studies on PTSD grouped men and women together, which gave inconclusive results,” said senior investigator Lynn Pulliam, MS, PhD, chief of microbiology at SFVAMC and professor of laboratory medicine and medicine at UCSF.

“This is the first time that it’s been shown that men and women respond differently to PTSD on a very basic biological level.”

Neylan characterized the finding as “unexpected.” The researchers do not know why there seems to be such a marked difference between men and women, said Neylan.

However, in a study published in the journal Disease Markers, they analyzed data collected from the same subjects to explore one possible explanation: gender differences in cell signaling pathways. [2]

“We know that gene expression patterns are determined by hormones and proteins that are circulating in the body, and we know that some of those hormones and proteins are produced in response to signals from the brain or central nervous system,” explained lead author Aoife O’Donovan, PhD, a researcher in psychiatry at SFVAMC and UCSF.

“These signaling pathways are used by the brain and central nervous system to communicate with the immune system and tell immune cells what to do.” The researchers used sophisticated bioinformatics software to look at three different signaling pathways associated with inflammation: NF-kappa B, glucocorticoid receptor (GR), and CREB/ATF.

In the NF-kappa B and GR pathways in both men and women with PTSD, they found evidence of signaling that could promote inflammation.

In the CREB/ATF pathway, however, they found what O’Donovan called “totally contrasting” effects: men with PTSD had increased signaling, which in turn could possibly lead to less inflammation, while women with PTSD had decreased signaling, which could lead to more inflammation.

“This particular pathway might be a clue to the gender difference in monocyte gene expression in PTSD,” said Pulliam.

“It’s still very early,” cautioned O’Donovan, “but these bioinformatics results are telling us something about how PTSD could increase the risk for autoimmune disorders like arthritis as well as cardiovascular disease, cancer, and other diseases of aging. They also point us in the direction of some potential treatment targets, telling us where future investigative energy might be well spent.”

Neylan emphasized that because of the small sample size, particularly among the women, the results of the two studies are suggestive rather than conclusive. “The next step is to look at larger groups of men and women, and we are working on that,” he said.

FundingBoth studies were supported by grants from the Department of Defense and the Department of Veterans Affairs Sierra Pacific Mental Illness Research & Education Clinical Center. Some of the funds were administered by the Northern California Institute for Research and Education.
Participation[P1] Co-authors of the Brain, Behavior, and Immunity study are Bing Sun, MD, PhD, and Hans Rempel, PhD, of SFVAMC; Jessica Ross, MD, MS, of SFVAMC and UCSF; and Maryann Lenoci, MA, of SFVAMC. [cf. C1]

[P2] Co-authors of the Disease Markers study are Bing Sun, MD, PhD; Steve Cole, PhD, of UCLA; Hans Rempel, PhD; and Maryann Lenoci, MA. [cf. C1]
Citation[C1] Suppressed monocyte gene expression profile in men versus women with PTSD. Thomas C. Neylan, Bing Sun, Hans Rempel, Jessica Ross, Maryann Lenoci, Aoife O’Donovan, Lynn Pulliam. Brain, Behavior, and Immunity 2011; 25(3): 524-531. doi:10.1016/j.bbi.2010.12.001

Highlights

•  Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes).

•  There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects.

•  In contrast, preliminary data from our pilot sample of female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation.

•  The results indicate differential patterns of monocyte gene expression in PTSD, and are suggestive of gender dimorphism in biologic pathways activated in PTSD.

Abstract

There have been several attempts to use gene microarrays from peripheral blood mononuclear cells to identify new biological pathways or targets for therapy in Posttraumatic Stress Disorder (PTSD). The few studies conducted to date have yielded an unclear pattern of findings, perhaps reflecting the use of heterogeneous samples of circulating immune cells for analysis. We used gene microarrays on a homogeneous sample of circulating monocytes to test the hypothesis that chronic PTSD would be associated with elevated inflammatory activity and to identify new pathways dysregulated in the disorder. Forty-nine men (24 PTSD+ and 25 age-matched trauma-exposed PTSD- controls) and 18 women (10 PTSD+ and 8 age-matched PTSD- controls) were recruited. Gene expression microarray analysis was performed on CD14+ monocytes, immune cells that initiate and respond to inflammatory signaling. Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). A rigorous correction for multiple comparisons and verification with qPCR showed that of only 3 genes that were differentially expressed, all were under-expressed. There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. In contrast, preliminary data from our pilot female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. The results indicate differential patterns of monocyte gene expression in PTSD, and the preliminary data from our female pilot subjects are suggestive of gender dimorphism in biologic pathways activated in PTSD. Changes in immune cell gene expression may contribute to medical morbidity in PTSD.

Keywords: posttraumatic stress disorder, cdna microarray, cytokines, monocyte.



[C2] Transcriptional control of monocyte gene expression in post-traumatic stress disorder. Aoife O'Donovan, Bing Sun, Steve Cole, Hans Rempel, Maryann Lenoci, Lynn Pulliam, Thomas Neylan. Disease Markers 2011; 30(2-3): 123-132. doi:10.3233/DMA-2011-0768

Abstract

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associated alterations in inflammatory activity may contribute to this increased risk. However, little is known about convergent SNS, HPA and inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined the prevalence of specific transcription factor binding motifs in the promoter regions of differentially expressed genes in monocytes from individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls) and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-?B/Rel family of transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors, which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveys glucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-?B and non-significant down-regulation of target genes for GR, but significant down-regulation of target genes for CREB/ATF. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

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Last Updated on Sunday, 01 May 2011 14:02
 
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