Inflammation and scarring form a positive feedback loop in trachoma
Results from two Fight for PhD students take us closer to developing treatment to prevent blindness from a widespread tropical condition
New research sheds light on how scarring trachoma can continue long after the infection that starts it has cleared. Results from 2 studies suggest that the body’s defence against infection – the immune system – stays active. The results also point to a potential target for treatment.
Trachoma is the world’s leading infectious cause of blindness. It begins with repeated childhood infection of the lining of the eyelid (the conjunctiva) by Chlamydia trachomatis bacteria. It can continue on into adulthood with long-term (chronic) inflammation and scarring, even when the infection can’t be detected.
Scarring tightens the eyelids and turns the lashes inward (trichiasis), where they scratch the eye’s surface. This is painful and eventually leads to blindness.
Trachoma’s molecular footprint
Dr Maryse Bailly at UCL Institute of Ophthalmology led the study published today in the journal Scientific Reports. The team has shown that connective tissue cells (fibroblasts) grown from patients’ conjunctiva biopsies produce more of a molecule called interleukin 6 (IL-6) compared to fibroblasts from healthy conjunctiva.
“IL-6 is an important mediator of inflammation and a previously suggested risk factor for scarring trachoma,” said Dr Jenny Kechagia, who is first author of the study and did the research for her Fight for Sight PhD studentship.
“Our results show that although IL-6 does not stimulate tissue contraction directly, it activates immune cells (macrophages), which in turn stimulates fibroblast contraction and may drive local inflammation. This positive feedback loop between scarring and inflammation may contribute to chronic scarring and suggests that the conjunctival stroma (connective tissue) itself may play a more central role in scarring trachoma than previously thought.”
Recent Fight for Sight PhD student Dr Tamsyn Derrick is first author of the second study, published in PLOS. It was led by Dr Matthew Burton at the London School of Hygiene and Tropical Medicine.
Target connective tissue growth factor
The team found that compared to healthy controls, eyelid tissue from people with scarring trachoma contains significantly more of the pro-inflammatory signalling molecules IL-1Beta and S100A7 and pro-scarring connective tissue growth factor (CTGF). There was evidence of ongoing inflammation in the stroma of individuals with trichiasis even when this inflammation was not externally visible on the patient’s eyelid. This is consistent with the local inflammatory feedback loop proposed by Dr Kechagia.
“CTGF modulates the interaction between cells and the connective tissue, and over activity of CTGF is known to drive scarring disease in the heart, lung and kidney, said Dr Derrick. “Our data suggest that ongoing inflammation in the conjunctiva is associated with CTGF activation, which in turn drives fibrosis and scarring. As a potential direct mediator of inflammation-induced scarring in the conjunctiva, CTGF could be a suitable target for treatment to halt the progression of scarring trachoma.”
Dr Dolores M Conroy is Director of Research at Fight for Sight. She said: “The World Health Organisation estimates that 231 million people live in the regions where trachoma is widespread. Trachoma control programmes do a good job of treating the active infection with antibiotics, however there are a great many people still at risk of progressing to scarring trachoma given that the condition can persist once the infection has gone. In order to develop a treatment that can prevent the chronic inflammation and scarring that lead to blindness, we need to understand how the two are linked. Results from both these studies take us an important step in the right direction.”
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