Featured Research

from universities, journals, and other organizations

Pore formation in cell membranes linked to triggers of rheumatoid arthritis

Date:
October 30, 2013
Source:
Johns Hopkins Medicine
Summary:
Experiments by scientists have unraveled two biological mechanisms as the major cause of protein citrullination in rheumatoid arthritis. Protein citrullination is suspected of sparking the immune system and driving the cascade of events leading to the disease.

Experiments by scientists at Johns Hopkins and in Boston have unraveled two biological mechanisms as the major cause of protein citrullination in rheumatoid arthritis. Protein citrullination is suspected of sparking the immune system and driving the cascade of events leading to the disease.

In a report to be published online in the journal Science Translational Medicine on Oct. 30, the research team describes how it found pore-forming pathways in cell membranes that are associated with the abnormal citrullination occurring in rheumatoid joints. The pathways, called perforin and complement (also known as membrane attack complex, or MAC), are normally used by the immune system to fight pathogens.

Researchers say such disruptions in cell membrane integrity produce enzyme-activating imbalances of calcium ions. The activated enzymes, called PADs, are known to citrullinate specific, protein-forming amino acids in hand, knee, foot, and elbow joints, setting off the inflammatory immune response that is rheumatoid arthritis' hallmark.

According to researchers, the latest study findings open up a whole new field of study into rheumatoid arthritis' origin and into the mechanisms that might start the disease process.

"For a long time, it has been suspected that immune pathways activated in response to pathogens play a role in initiating immune responses in rheumatoid arthritis," says senior study investigator and rheumatologist Felipe Andrade, M.D., Ph.D.

"This study offers a renewed framework to support and to study this hypothesis, and provides novel targets that may be amenable for monitoring and treatment," says Andrade, an assistant professor at the Johns Hopkins University School of Medicine.

In the study, researchers initially identified that cells obtained from the joints of patients with rheumatoid arthritis contain a unique pattern of citrullination, which they termed cellular hypercitrullination. Lab experiments showed that this pattern was not reproduced by cell death and cell activating pathways previously thought to be responsible for the process. Some stimuli induced citrullination, but none induced the hypercitrullination seen in the disease.

"This was a surprising finding and suggests that the pathological citrullination occurring in the rheumatoid joint differs qualitatively and quantitatively from the citrullination occurring under physiological conditions," says Andrade.

Of 20 stimuli studied, all known to promote inflammatory pathways active in the rheumatoid joint, only two, perforin and MAC, reproduced the hypercitrullination detected in rheumatoid arthritis patients.

Andrade says the series of experiments, which took three years to complete, represents the first evidence that perforin and MAC are active contributors in generating the targets to the immune response, or auto-antigens, thought to initiate and maintain inflammation in rheumatoid arthritis. Perforin and MAC were previously believed to play secondary roles in rheumatoid joint destruction.

"Our results suggest that inhibiting these pathways may have real benefit in patients and represent an important field of study for investigating new and alternative treatments," says Andrade.

Andrade and his team next plan to determine the mechanisms responsible for abnormal activation of the perforin and MAC pathways in rheumatoid joints. He says this may lead to the identification of the earliest components that initiate the disease process.

The team also plans to define novel biomarkers to monitor the citrullination activity induced by these pathways in people with rheumatoid arthritis, with the goal of matching levels to disease progression and response to treatment.


Story Source:

The above story is based on materials provided by Johns Hopkins Medicine. Note: Materials may be edited for content and length.


Journal References:

  1. V. Romero, J. Fert-Bober, P. A. Nigrovic, E. Darrah, U. J. Haque, D. M. Lee, J. van Eyk, A. Rosen, F. Andrade. Immune-Mediated Pore-Forming Pathways Induce Cellular Hypercitrullination and Generate Citrullinated Autoantigens in Rheumatoid Arthritis. Science Translational Medicine, 2013; 5 (209): 209ra150 DOI: 10.1126/scitranslmed.3006869
  2. K. B. Elkon. Poking Holes in Rheumatoid Joints. Science Translational Medicine, 2013; 5 (209): 209fs39 DOI: 10.1126/scitranslmed.3007515

Cite This Page:

Johns Hopkins Medicine. "Pore formation in cell membranes linked to triggers of rheumatoid arthritis." ScienceDaily. ScienceDaily, 30 October 2013. <www.sciencedaily.com/releases/2013/10/131030142416.htm>.
Johns Hopkins Medicine. (2013, October 30). Pore formation in cell membranes linked to triggers of rheumatoid arthritis. ScienceDaily. Retrieved April 18, 2014 from www.sciencedaily.com/releases/2013/10/131030142416.htm
Johns Hopkins Medicine. "Pore formation in cell membranes linked to triggers of rheumatoid arthritis." ScienceDaily. www.sciencedaily.com/releases/2013/10/131030142416.htm (accessed April 18, 2014).

Share This



More Health & Medicine News

Friday, April 18, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
Powered by NewsLook.com
Obama: 8 Million Healthcare Signups

Obama: 8 Million Healthcare Signups

AP (Apr. 17, 2014) President Barack Obama gave a briefing Thursday announcing 8 million people have signed up under the Affordable Care Act. He blasted continued Republican efforts to repeal the law. (April 17) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins