Corporate Banner
Satellite Banner
Immunology
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Estrogen Fuels Autoimmune Liver Damage

Published: Wednesday, May 01, 2013
Last Updated: Wednesday, May 01, 2013
Bookmark and Share
Johns Hopkins research in mice unravels mystery behind sex disparities in drug-induced hepatitis.

A Johns Hopkins Children’s Center study in mice may help explain why women are more prone than men to a form of liver damage by implicating the female sex hormone estrogen in the development of autoimmune hepatitis.

A life-threatening condition that often requires transplantation and accounts for half of all acute liver failures, autoimmune hepatitis is often precipitated by certain anesthetics and antibiotics. Researchers say these drugs contain tiny molecules called haptens that ever so slightly change normal liver proteins, causing the body to mistake its own liver cells for foreign invaders and to attack them. The phenomenon disproportionately occurs in women, even when they take the same drugs at the same doses as men.

Results of the new study, described in the April issue of the journal PLoS One, reveal that estrogen and a signaling molecule called interleukin-6 collude to form a powerful duo that leads to immune cell misconduct and fuels autoimmune liver damage.

The findings, the research team says, also suggest therapeutic strategies to curb damage in people who develop drug-induced liver inflammation.

“Our study shows that estrogen is not alone in its mischief but working with an accomplice to set off a cascade of events that leads to immune cell dysregulation and culminates in liver damage,” says Dolores Njoku, M.D., a pediatric anesthesiologist and critical care expert at Johns Hopkins Children’s Center.   

In the study, led by Njoku, researchers induced liver inflammation in mice by injecting them with drug-derived haptens. Female mice developed worse liver damage than male mice, and castrated male mice fared worse than their intact brethren, likely due to loss of testosterone and altered estrogen-to-testosterone ratio, the researchers say. Female mice with missing ovaries — the chief estrogen-secreting organs — suffered milder forms of hepatitis than mice with intact ovaries.

Female mice produced more liver-damaging antibodies and more inflammation-triggering chemicals, specifically the inflammatory molecule interleukin-6, known to fuel autoimmunity. Liver damage was notably milder in female mice whose interleukin-6 receptors were blocked or missing compared with normal female mice. On the other hand, male mice and female mice with missing ovaries had nearly undetectable levels of interleukin-6, while castrated male mice showed simultaneous upticks in both estrogen and interleukin-6.

The research team further zeroed in on a class of cells known as regulatory T cells, whose main function is keeping tabs on other immune cells to ensure they don’t turn against the body’s own tissues. When researchers compared the number of regulatory T cells present in the spleens of male and female mice, they noticed far fewer regulatory T cells in the spleens of female mice. The spleen, the researchers explain, is the primary residence of mature immune cells.

“Deficiency of regulatory T cells effectively takes the reins off other immune cells, leading to overactive immunity,” Njoku says.

In a final, dot-connecting move, the researchers immersed spleen-derived immune cells in estrogen. What they observed proved beyond doubt that estrogen, interleukin and regulatory T cells form a powerful triangle. Estrogen induced the immune cells of female mice to express more interleukin-6, which in turn diminished the expression of inflammation-taming regulatory T cells.

When the researchers injected sick female mice with a booster dose of regulatory T cells, their liver inflammation subsided to levels seen in male mice.

This powerful response, the researchers say, suggests that therapy with regulatory T cells may reduce estrogen-related liver damage in patients with autoimmune hepatitis. Such treatment, however, remains years away from human application.

One reason, the researchers say, is that regulatory T cells maintain the fine equilibrium between overactive and underactive immunity. Because an overactive immune system can lead to autoimmune diseases and an underactive one can promote tumor growth, any therapy with regulatory T cells must be precisely calibrated to avoid tipping this precarious balance.

“We first must figure out where the golden mean lies,” Njoku says.
            
Co-investigators on the study included Joonhee Cho, Lina Kim, Zhaoxia Li, Noel Rose and Monica Vladut Talor, all from Johns Hopkins.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,900+ scientific posters on ePosters
  • More than 4,200+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Enzyme's Alter Ego Helps Activate the Immune System
Findings could shed light on related Alzheimer's protein.
Tuesday, January 06, 2015
Researchers Tease Out Glitches in Immune System's Self-Recognition
A new study revises understanding of how the process works and sheds light on autoimmune disease.
Saturday, November 22, 2014
Enzyme-Activating Antibodies Revealed As Marker for Severe Rheumatoid Arthritis
Finding could lead to earlier diagnosis and new, more aggressive treatment for worst cases.
Thursday, May 30, 2013
Osteoarthritis Progression Halted in Mice
If successful in humans, joint replacement surgery might be avoidable.
Tuesday, May 21, 2013
Scientific News
Tricked-Out Immune Cells Could Attack Cancer
New cell-engineering technique may lead to precision immunotherapies.
Neural Networks Adapt to the Presence of a Toxic HIV Protein
HIV-associated neurocognitive disorders (HAND) afflict approximately half of HIV infected patients.
HIV Protein Manipulates Hundreds of Human Genes
Findings search for new or improved treatments for patients with AIDS.
Breaking the Brain’s Garbage Disposal
The children’s ataxia gene problem turned out to be not such a big deal genetically — it was such a slight mutation that it barely changed the way the cells made the protein.
Flesh-Eating Bacteria Work Together
Scientists recently discovered different strains of deadly flesh-eating bacteria working together to spread infection and they now have a better understanding of the role of the toxins they produce. The discovery could change how the illness and other diseases are treated.
Utilizing Antibodies from Ebola Survivors
A collaborative team from The University of Texas Medical Branch at Galveston, Vanderbilt University, The Scripps Research Institute and Integral Molecular Inc. have learned that antibodies in the blood of people who have survived a strain of the Ebola virus can kill various types of Ebola.
Antibiotic Use in Early Life Disrupts Gut Microbiota
The use of antibiotics in early childhood interferes with normal development of the intestinal microbiota, shows research conducted at the University of Helsinki.
Easier Diagnosis for Fungal Infection of the Lungs
A new clinical imaging method developed in collaboration with a University of Exeter academic may enable doctors to tackle one of the main killers of patients with weakened immune systems sooner and more effectively.
Mitochondrial Troublemakers Unmasked in Lupus
Drivers of autoimmune disease inflammation discovered in the traps of pathogen-capturing white blood cells.
Important Regulator of Immune System Decoded
Plasma cells play a key role in our immune system. Now scientists at the Research Institute of Molecular Pathology (IMP) in Vienna, Austria, and at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, succeeded in characterizing a central regulator of plasma cell function.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,200+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!