Eyeworld

39 EW CORNEA August 2016 Contact information Asbell: penny.asbell@mssm.edu Hamm-Alvarez: Sherri.Snelling@med.usc.edu 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 col- leagues 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 re- sponse by proinflammatory cyto- kines, 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 in- creased 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 con- tinued. "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, how- ever, is when things in the body go wrong. "What we think is happening somehow in the Sjögren's syn- drome 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 ac- tivate other signaling pathways that are inflammatory. "We are starting a fire in the lacrimal gland and it's continu- ing 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 contribu- tion for understanding Sjögren's and potentially looking at targets for treating it more effectively, particularly the dry eye part of the disease." EW 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.

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