Research Article: Role of Secreted Conjunctival Mucosal Cytokine and Chemokine Proteins in Different Stages of Trachomatous Disease

Date Published: July 16, 2008

Publisher: Public Library of Science

Author(s): Troy A. Skwor, Berna Atik, Raj Prasad Kandel, Him Kant Adhikari, Bassant Sharma, Deborah Dean, Albert I. Ko

Abstract: BackgroundChlamydia trachomatis is responsible for trachoma, the primary cause of preventable blindness worldwide. Plans to eradicate trachoma using the World Health Organization’s SAFE program (Surgery, Antibiotics, Facial Cleanliness and Environment Improvement) have resulted in recurrence of infection and disease following cessation of treatment in many endemic countries, suggesting the need for a vaccine to control infection and trachomatous disease. Vaccine development requires, in part, knowledge of the mucosal host immune responses in both healthy and trachomatous conjuctivae—an area of research that remains insufficiently studied.Methodology/Principal FindingsWe characterized 25 secreted cytokines and chemokines from the conjunctival mucosa of individuals residing in a trachoma endemic region of Nepal using Luminex X100 multiplexing technology. Immunomodulating effects of concurrent C. trachomatis infection were also examined. We found that proinflammatory cytokines IL-1β (r = 0.259, P = 0.001) and TNFα (r = 0.168, P<0.05) were significantly associated with trachomatous disease and concurrent C. trachomatis infection compared with age and sex matched controls from the same region who did not have trachoma. In support of these findings, anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) was negatively associated with chronic scarring trachoma (r = −0.249, P = 0.001). Additional cytokines (Th1, IL-12p40 [r = −0.212, P<0.01], and Th2, IL-4 and IL-13 [r = −0.165 and −0.189, respectively, P<0.05 for both]) were negatively associated with chronic scarring trachoma, suggesting a protective role. Conversely, a pathogenic role for the Th3/Tr1 cytokine IL-10 (r = 0.180, P<0.05) was evident with increased levels for all trachoma grades. New risk factors for chronic scarring trachoma included IL-6 and IL-15 (r = 0.259 and 0.292, respectively, P<0.005 for both) with increased levels for concurrent C. trachomatis infections (r = 0.206, P<0.05, and r = 0.304, P<0.005, respectively). Chemokine protein levels for CCL11 (Eotaxin), CXCL8 (IL-8), CXCL9 (MIG), and CCL2 (MCP-1) were elevated in chronic scarring trachoma compared with age and sex matched controls (P<0.05, for all).Conclusions/SignificanceOur quantitative detection of previously uncharacterized and partially characterized cytokines, a soluble cytokine receptor, and chemokines for each trachoma grade and associations with C. trachomatis infections provide, to date, the most comprehensive immunologic evaluation of trachoma. These findings highlight novel pathologic and protective factors involved in trachomatous disease, which will aid in designing immunomodulating therapeutics and a vaccine.

Partial Text: Trachoma, the leading global cause of preventable blindness, has plagued populations for thousands of years [1]. There are over 360 million trachoma cases of whom ∼6 million are blind [2],[3]. Limited access to clean water and inadequate sanitary conditions provides ideal conditions for the persistence of this endemic disease caused by the obligate intracellular bacterium Chlamydia trachomatis. Additionally, C. trachomatis is the leading bacterial cause of sexually transmitted diseases (STD) throughout the world [4], causing chronic conditions such as arthritis [5], infertility and ectopic pregnancy [6]. The economics and health burden from trachoma alone claims billions of dollars in productivity loss in already poverty stricken countries [7]. Recognizing this, the World Health Organization (WHO) proposed the SAFE program (Surgery, Antibiotics, Facial cleanliness and Environmental improvement) in 2001 with the goal of eradicating blinding trachoma by the year 2020.

While there is some important research on cytokine mRNA expression in association with trachoma, our fundamental knowledge of the host immune response has been limited by a lack of quantitative protein data, especially for those cytokines and chemokines that are post-transcriptionally and –translationally modified, in association with each grade of trachoma. The goal of this study was to validate previous gene expression findings and to characterize novel inflammatory cytokine and chemokine protein concentrations in mucosal conjunctival secretions and how each may influence inflammation for the different grades of trachomatous disease. Additionally, we further characterized immuno-regulatory effects induced by concurrent C. trachomatis infection.



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