August 2016

 

CORNEA

 

Research identifies powerful indicator of Sjögren’s syndrome


by Liz Hillman EyeWorld Staff Writer

 
   

New biomarker and possible treatment target for difficult to diagnose autoimmune disease

Multiple scientific studies estimate that between 1 million and 4 million people in the U.S. have Sjögren’s syndrome. Part of the reason for this large range in prevalence of the autoimmune disease, which is characterized by inflammation and dysfunction of the lacrimal and salivary glands, among other things, could be because the condition is so difficult to diagnose. Sarah Hamm-Alvarez, PhD, vice chair of basic research, and professor of ophthalmology, University of Southern California Roski Eye Institute, Los Angeles, said when she first started Sjögren’s research, it took between five and seven years to diagnose a patient. Now, it takes an average of 3.5 years, according to the Sjögren’s Syndrome Foundation.

But even that time frame can lead to debilitating disease progression that clinicians think could be prevented if diagnosed and addressed earlier. There is no single test to confirm a Sjögren’s diagnosis; it is usually driven by a rheumatologist who considers salivary and gland function along with other physically observed symptoms and blood and ocular tests. Recent research has identified a possible new biomarker that could potentially serve as an early diagnostic tool. Researchers also drilled down further into the mechanism behind this biomarker to understand a potential treatment pathway that could target dry eye symptoms unique to Sjögren’s patients.

Searching for early diagnostic biomarkers

A couple of years ago, Dr. Hamm-Alvarez and her colleagues published a paper on research announcing they had found the activity of the protein cathepsin S is “significantly enhanced” in the tears of Sjögren’s patients compared to non-Sjögren’s, dry eye patients or those with other autoimmune diseases.1

This group has identified other tear biomarkers of disease as well, but none, Dr. Hamm-Alvarez said, are substitutes for cathepsin S. “Cathepsin S is the single most powerful indicator of disease status,” she said, explaining that she and her colleagues are speaking with numerous companies about the potential to develop a tear test for the protein. “What we know from our studies in disease model mice is that tear cathepsin S is elevated early and continues to rise as disease advances, so we do think it could be an early indicator of the inflammation of the lacrimal gland,” Dr. Hamm-Alvarez said. Several blood biomarkers have been identified as having early diagnostic potential for Sjögren’s as well, said Penny Asbell, MD, director of cornea and refractive services, Icahn School of Medicine at Mount Sinai, New York. One test, the Sjö Diagnostic Test (Bausch + Lomb, Bridgewater, New Jersey), includes four traditional biomarkers as well as three novel, proprietary biomarkers to help detect early Sjögren’s syndrome. “There is definitely a hunt in looking for the right biomarker that would be diagnostic, not just for Sjögren’s syndrome but for other types of dry eye as well, and one that might respond to treatment that we could use as an indicator to show that [the disease is] getting better,” Dr. Asbell said.

“Starting a fire in the lacrimal gland”

Dr. Hamm-Alvarez and her colleagues more recently published research that further looked into the proteins involved in cathepsin S release in a mouse model to better understand how it is getting into tears and what it might be doing on the ocular surface. “Cathepsin S has some active roles in the body in inflammation,” Dr. Hamm-Alvarez said. “It’s actually one of the proteins that’s activated early on in the inflammatory response by proinflammatory cytokines, such as interferon gamma, so if there is an early challenge in response to infection or insult … one of the proteins that is often upregulated as part of the immune response is cathepsin S. We think that its presence in the tissue is increased partly because there is local inflammation in the tissue. “What’s rather unusual is that [cathepsin S] is secreted into the tears, rather than just present in the tissue,” Dr. Hamm-Alvarez continued. “Tears [are] the first line of defense against pathogens or viruses or other foreign bodies that may touch the eye. So one of the things that this paper in American Journal of Physiology – Cell Physiology did is look at the different ways that some of the more destructive proteases like cathepsin S might be able to reach the tear film.”2

Dr. Hamm-Alvarez explained that she and her colleagues think there is a normal process in the body that uses a small amount of these proteases in response to pathogens. When their release goes awry, however, is when things in the body go wrong.

“What we think is happening somehow in the Sjögren’s syndrome lacrimal gland is that there is a normal process in the healthy lacrimal gland that is responsible for recruiting cathepsin S into tears at low levels, but somehow this process gets turned on and/or increased to a higher level and you can’t turn it off. Thus, you end up with a much more proteolytic and damaging tear film,” she said of her team’s theory. This most recent research involved Rab proteins, which are involved in the secretory pathway, in genetically altered mice. The team found mice lacking Rab3D showed elevated cathepsin S in their tears, while mice lacking Rab27a and Rab27b had reduced cathepsin S activity. “We propose that a loss of Rab3D from secretory vesicles, leading to disproportionate Rab27-to-Rab3D activity, may contribute to enhanced release of [cathepsin S] in tears of [Sjögren’s syndrome] patients,” Hamm-Alvarez et al. wrote in the study’s abstract. On top of that, Dr. Hamm-Alvarez said cathepsin S, in addition to degrading other proteins, can activate other signaling pathways that are inflammatory. “We are starting a fire in the lacrimal gland and it’s continuing to burn out of control on the ocular surface,” Dr. Hamm-Alvarez explained. “We think that if we can regulate its activity back to normal levels in tears, that is going to have a beneficial effect on the whole inflammatory cycle.” Dr. Asbell praised this research for trying to find a biomarker and to better understand the mechanism behind it, saying it is “definitely a step forward,” but she noted that these conclusions are still based on an animal model. “Animal models we can control, so that’s the good part about using an animal model, but they’re not people,” Dr. Asbell said. “I am sure [Dr. Hamm-Alvarez] will be taking the information she found and some of the previous information and looking at people. If we find out that cathepsin S in tears is really a good biomarker for Sjögren’s, I think that’s going to be a terrific contribution for understanding Sjögren’s and potentially looking at targets for treating it more effectively, particularly the dry eye part of the disease.”

References

1. Hamm-Alvarez SF, et al. Tear cathepsin S as a candidate biomarker for Sjögren’s syndrome. Arthritis Rheumatol. 2014;66:1872–81.

2. Meng Z, et al. Imbalanced Rab3D versus Rab27 increases cathepsin S secretion from lacrimal acini in a mouse model of Sjögren’s Syndrome. Am J Cell Physiol. 2016;310:C942–54.

Editors’ note: Dr. Hamm-Alvarez and Dr. Asbell have no financial interests related to their comments.

Contact information

Asbell: penny.asbell@mssm.edu
Hamm-Alvarez: Sherri.Snelling@med.usc.edu

Research identifies powerful indicator of Sjögren’s syndrome Research identifies powerful indicator of Sjögren’s syndrome
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