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Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma.

ABSTRACT: Trachoma is the most common infectious cause of blindness and a major public health problem in many developing countries. It is caused by recurrent ocular infection with Chlamydia trachomatis in childhood, with conjunctival scarring seen later in life. The pathogenesis of trachomatous scarring, however, is poorly understood, and this study was carried out to investigate the immunofibrogenic correlates of trachomatous conjunctival scarring. A case-control study of 363 cases with conjunctival scarring and 363 control participants was conducted. Investigations included in vivo confocal microscopy (IVCM) assessment, quantitative real-time PCR gene expression, C. trachomatis detection, and nonchlamydial bacterial culture. Trachomatous scarring was found to be strongly associated with a proinflammatory, innate immune response with increased expression of psoriasin, interleukin-1?, tumor necrosis factor alpha, defensin-?4A, chemokine ligand 5, and serum amyloid A1. There was also differential expression of various modifiers of the extracellular matrix, including metalloproteinases 7, 9, 10, and 12, tissue inhibitor of matrix metalloproteinase 1, and secreted protein acidic cystein-rich-like 1. The expression of many of these genes was also significantly associated with the presence of nonchlamydial bacterial infection. These infections had a marked effect on conjunctival immune processes, including an increased inflammatory infiltrate and edema seen with IVCM. This study supports the possibility that the immunofibrogenic response in scarring trachoma is partly stimulated by nonchlamydial bacterial infection, which is characterized by the expression of innate factors.

SUBMITTER: Hu VH

PROVIDER: S-EPMC3255692 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma.

Hu Victor H VH Weiss Helen A HA Ramadhani Athumani M AM Tolbert Sonda B SB Massae Patrick P Mabey David C W DC Holland Martin J MJ Bailey Robin L RL Burton Matthew J MJ

Infection and immunity 20111028 1

Trachoma is the most common infectious cause of blindness and a major public health problem in many developing countries. It is caused by recurrent ocular infection with Chlamydia trachomatis in childhood, with conjunctival scarring seen later in life. The pathogenesis of trachomatous scarring, however, is poorly understood, and this study was carried out to investigate the immunofibrogenic correlates of trachomatous conjunctival scarring. A case-control study of 363 cases with conjunctival scar ...[more]

PMID: 22038912

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Project description:Trachoma is a poorly understood immuno-fibrogenic disease process, initiated by Chlamydia trachomatis (Ct). Differences in conjunctival gene expression profiles between Ethiopians with trachomatous trichiasis (with (TTI) and without (TT) inflammation) and controls (NC) were investigated to identify relevant host responses. Tarsal conjunctival swab samples were collected for RNA isolation and Ct PCR. Transcriptome-wide microarray experiments were conducted on 42 samples (TTI 13, TT 15, NC14). Specific results were confirmed using multiplex quantitative RT-PCR for 16 mRNA targets in an independent collection of case-control samples: 386 case-control pairs (TTI 244, TT 142, NC 386). The gene expression profiles of cases were consistent with: squamous metaplasia (Keratins, SPRR), pro-inflammatory cytokine production (IL-1β, CXCL5, S100A7) and tissue remodelling (MMP7, MMP9, MMP12, HAS3). There was no difference in the level of IFNG between cases and controls. However, cases had increased INDO, NOS2A, and IL13RA2 and reduced IL13. Ct was detected in 1/772. Cases show evidence of ongoing inflammation and tissue remodelling, which were more marked where clinical inflammation was also present. Significantly, these processes appear to be active in the absence of current Ct infection. There was limited evidence of a TH1 response (INDO, NOS2A) and no association between a TH2 response and cases. The epithelium appears actively involved in late cicatricial stages of trachoma through production of pro-inflammatory factors (IL-1β, CXCL5, S100A7). Longitudinal studies are needed to investigate which aetiological factors and pathways are associated with progressive scarring and whether simply controlling chlamydial infection will halt progression in people with established cicatricial disease. Case - control study. Conjunctival swab samples were collected from people with trachomatous trichiasis with (TTI) and without (TT) clinically visable inflammation compared to normal controls (C). Total RNA extracted and analysed on the Illumina WG-6 platrom. Additional extensive qRT-PCR work done on a large set of case-control pairs.

Project description:ObjectiveTo characterize the tissue and cellular changes found in trachomatous scarring (TS) and inflammation using in vivo confocal microscopy (IVCM).DesignTwo complimentary case-control studies.ParticipantsThe first study included 363 cases with TS (without trichiasis), of whom 328 had IVCM assessment, and 363 control subjects, of whom 319 had IVCM assessment. The second study included 34 cases with trachomatous trichiasis (TT), of whom 28 had IVCM assessment, and 33 control subjects, of whom 26 had IVCM assessment.MethodsAll participants were examined with ×2.5 loupes. The IVCM examination of the upper tarsal conjunctiva was carried out with a Heidelberg Retina Tomograph 3 with the Rostock Cornea Module (Heidelberg Engineering GmbH, Dossenheim, Germany).Main outcome measuresThe IVCM images were graded in a masked manner using a previously published grading system evaluating the inflammatory infiltrate density; the presence or absence of dendritiform cells (DCs), tissue edema, and papillae; and the level of subepithelial connective tissue organization.ResultsSubjects with clinical scarring had a characteristic appearance on IVCM of well-defined bands and sheets of scar tissue visible. Similar changes were also seen in some clinically normal subjects consistent with subclinical scarring. Scarred subjects had more DCs and an elevated inflammatory infiltrate, even after adjusting for other factors, including the level of clinical inflammation. Cellular activity was usually seen only in or just below the epithelium, rarely being seen deeper than 30 ?m from the surface. The presence of tissue edema was strongly associated with the level of clinical inflammation.ConclusionsIn vivo confocal microscopy can be quantitatively used to study inflammatory and scarring changes in the conjunctiva. Dendritic cells seem to be closely associated with the scarring process in trachoma and are likely to be an important target in antifibrotic therapies or the development of a chlamydial vaccine. The increased number of inflammatory cells seen in scarred subjects is consistent with the immunopathologic nature of the disease. The localization of cellular activity close to the conjunctival surface supports the view that the epithelium plays a central role in the pathogenesis of trachoma.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Project description:Ocular infection with Chlamydia trachomatis (trachoma) is the leading cause of blindness that results from infection. Chronic inflammation is believed to drive the scarring process and the progressive blinding disease, however the mechanisms by which this occurs are not completely understood. We hypothesized that Micro RNA (miRNA), as key regulators of genes in inflammatory pathways, are involved in the immunopathogenesis and tissue remodeling observed in trachoma. Conjunctival swabs were collected from a total of 63 individuals resident in trachoma endemic communities in The Gambia, West Africa. MiRNA was extracted from the conjunctival swabs of 23 healthy controls (N), 18 cases with trachomatous scarring (TS) and 22 cases with trachomatous scarring in the presence of clinically significant inflammation (TSI) using Qiagen Allprep DNA/RNA/protein kits. Following reverse transcription and pre-amplification, quantitative RT-PCR was performed using TaqMan Array Human MicroRNA genecards (Av2.0 and Bv3.0) on a 7900HT thermal cycler (Life Technologies, Inc). A total of 754 of the most well characterised unique human miRNA from miRBase (www.mirbase.org/) were screened. Data from each array were uploaded and analysed using the high throughput qPCR package in bioconductor R. Samples with a global miRNA median cycle threshold of 40 were filtered out. A and B cards were analysed separately due to differences in performance of samples on each card. In the A card group 40 samples were normalized and tested: 8 TSI, 16 TS and 16 N. In the B card group 29 samples were normalized and tested: 6 TSI, 13 TS and 10 N. Results were normalized by rank invariant normalization as it reduced the coefficient of variation and increased sample distribution homology more than any other normalization procedure tested. Data in each group were tested for differential expression by Limma. 63 total Samples. In the A card group 40 samples were normalized and tested: 8 TSI, 16 TS and 16 N. In the B card group 29 samples were normalized and tested: 6 TSI, 13 TS and 10 N. Results were normalized by rank invariant normalization as it reduced the coefficient of variation and increased sample distribution homology more than any other normalization procedure tested.

Dataset Information

Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma.

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Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma.

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