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Chlamydia trachomatis infections demonstrate remarkable differences in clinical course that are approximately 40% based on host genetic variation. Here, we study the single nucleotide polymorphisms (SNPs) and their haplotypes in TLR2, TLR4 and TLR9 (TLR2+2477G > A; TLR2 -16934T > A; TLR4+896A > G; TLR9-1237T > C and TLR9 +2848G > A) in relation to the susceptibility to, and severity of C. trachomatis infections. We analysed the five SNPs in a cohort of 770 Dutch Caucasian women either attending a sexually transmitted diseases outpatient clinic (n = 731) or having complaints of subfertility (n = 39). Haplotype analyses showed a trend for TLR2 haplotype I (-16934T/+2477G) to protect against the development of symptoms and tubal pathology (P-trend = 0.03) after Chlamydia infection. In the susceptibility cohort, TLR9 haplotype III (-1237C/+2848A) showed a significant decreasing trend in the development of symptoms after C. trachomatis infection (P = 0.02, OR: 0.55, 95% CI: 0.33-0.91). Logistic regression of the TLR2 haplotypes, TLR4+896A > G, and TLR9 haplotypes showed that the TLR2 haplotype combinations AG-TA and AG-TG confer risk (OR 3.4 (P = 0.01) and 1.6 (P = 0.03)), while the TLR9 haplotype combination TG-TA protects against C. trachomatis infections (OR: 0.4, P = 0.004). Our study shows that both TLR2 and TLR9 genes and SNP combinations do influence the clinical course of Chlamydia infections.

Background: As peroxisome proliferator–activated receptor–gamma (PPAR-γ) is frequently expressed in colon, its genetic polymorphism may play a role in the etiology of inflammatory bowel disease (IBD). The aims of the present study were to determine the distribution of PPAR-γ polymorphisms Pro12Ala and C161T and to explore the association between the PPAR-γ genotypes and phenotypes of IBD patients. Methods: A total of 244 IBD patients [212 ulcerative colitis (UC) and 32 Crohn's disease (CD)] and 220 controls in the Chinese population and 603 IBD patients (302 UC and 301 CD) and 180 controls in the white Dutch population were enrolled in the study. The phenotypes of Chinese IBD patients were grouped according to disease location. The PPAR-γ polymorphisms Pro12Ala and C161T were genotyped by PCR-based methods. Results: In the Chinese population, T carriers of the PPAR-γ C161T polymorphism were more common in UC patients than in the controls [37.7% vs. 25.5%, odds ratio 1.77, 95% confidence interval 1.18–2.68, P = 0.007], whereas Ala carriers of the Pro12Ala polymorphism showed no significant association in UC patients, but there was a significant association of Ala carriers with more extensive disease among the UC patients (P = 0.002); Pro12Ala and C161T genotypes did not show any associations with CD patients. No associations were found for the PPAR-γ C161T SNP studied in the Dutch IBD population. Conclusions: Our study showed the potential association between the PPAR-γ C161T polymorphism and UC patients in the central Chinese population. This finding was not replicated in the Dutch population. Further studies are necessary to explore the functional implication of the PPAR-γ C161T polymorphism in Chinese UC patients. (Inflamm Bowel Dis 2009;)

Granule cell neuronopathy (GCN) is a rare JC virus (JCV)-related disease in immunocompromised patients, characterized by lytic infection of the cerebellar granule cell layer. To enable early diagnosis and intervention, we identify features of GCN and describe possible aspects of disease heterogeneity. We report on two new cases of GCN in HIV-infected patients of whom we retrospectively assessed clinical and radiologic data. In addition, we carried out a literature search and review of clinical, radiologic and histopathologic findings of all published GCN cases. Including the two new cases reported here, a total of 18 GCN cases were included in this study. HIV infection, present in 12 of the cases, was the most common underlying condition, followed by monoclonal antibody treatment which was present in three cases. Cerebellar atrophy was detected in all except two cases. In 12 patients a heterogeneous distribution pattern of white matter changes in the cerebellum and brainstem was observed. Imaging findings in GCN are remarkably heterogeneous; exhibiting cerebellar atrophy, as well as white matter pathology, particularly in the adjacent infratentorial white matter. This suggests an overlap of GCN with other JCV-related diseases, such as progressive multifocal leukoencephalopathy.

Background: Regulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection.Methodology and Principal Findings: Disruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5-/- mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5-/- mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFN gamma, CD4-IL-17, CD4-IL-10 & CD8-TNF alpha) in the oviducts. NKT cell depletion in vitro reduced IL-17 alpha and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d-/- mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922).Conclusions/Significance: These experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.

Probiotics are useful in mild enteric disorders that are limited to the presence of individual symptoms such as diarrhoea, constipation, and bloating. More controversial is their use in colonic diverticular disease or in one of the most common disorders, namely the irritable bowel syndrome. With few exceptions and in a limited well defined patients’ group, no evidence exists that probiotics induce and maintain remission in patients with inflammatory bowel disease. In this chapter we review the current evidence of the value of probiotics in clinical practice of the following enteric disorders as well as the formulations and compositions of specific probiotics. It will be clear that most of the compositions used are not classified as medicaments, and most of them are free to obtain as “over-the-counter” preparations administered without medical prescriptions. Therefore, their use as therapeutics is very limited at present. This situation is likely to change in coming years. As shown in other chapters of this book a multidisciplinary approach is bringing scientific protocols to the field of probiotics and new technology to study the complicated field of gut microbiology and ecology is being applied to the study of functional and inflammatory diseases of the gut.

The aim of this review is to present a concise overview of all data available on the immunogenetics of Chlamydia trachomatis infections, both sexually transmitted urogenital and ocular infections. Currently, candidate gene approaches are used to identify genes related to the susceptibility to and severity of C. trachomatis infections. The main focus in the review will be on data obtained by the study of human cohorts.

Arthralgia and spondyloarthropathy of the peripheral and the axial joints are common in patients with inflammatory bowel diseases. Evidence for this association has been provided by clinical, epidemiologic, and immunologic studies confirming the presence of shared inflammatory pathways in gut and joint. Bacterial gut infections such as Salmonella typhimurium, Yersinia enterocolitica, Shigella, Campylobacter jejuni may induce reactive peripheral arthritis and 20% of these patients may develop chronic spondyloarthropathy. It is not certain that arthralgias in inflammatory bowel diseases are more frequent than in the general population but clinical articular manifestations compatible with spondyloarthropathy are present in 10% to 40% of patients with inflammatory bowel diseases. These enteropathic peripheral arthropathies without axial involvement are subdivided into a pauciarticular of large joints and a bilateral symmetrical polyarthropathy. The rationale and the challenges of using prebiotics, probiotics, and synbiotics in the management of patients with inflammatory bowel diseases with arthralgias and spondyloarthropathy are briefly reviewed. The rationale is based on the modulation of the ubiquitous intestinal flora by bacteria and their products that have been proven to be safe. The challenge is to find the "window of opportunity" to treat the evolutionary stage of joint inflammation. It seems to us that the major aim is not to treat patients who have a self-limited inflammatory joint disorder, but those patients with persistent arthralgias in an early phase of the disease. Seronegative and seropositive patients with early arthritis, before damage may occur, could be managed by this approach to improve the quality of life and to positively influence the natural course of the disease.

Probiotics are cultures of beneficial bacteria from the healthy gut microflora that improve the balance of the intestinal milieu by modifying the intestinal microflora and suppressing enhanced inflammatory responses. Probiotics are currently the subject of intense and widespread research as functional foods since they are known to induce health benefits, may be used as pharmaceutical preparations, and have achieved a "generally recognized as safe" (GRAS) status. Lactobacillus strains can also be genetically engineered for use in oral immunotherapeutic applications, such as vaccination and delivery of immunoregulatory substances. In the present review we evaluate the two different approaches to the therapeutic use of probiotics. We also focus on recent findings in the field of molecular biology and genetics of the intestinal immune response related to the microflora and intestinal ecology, in order to understand the mechanisms of action of probiotics and their present indications in gastrointestinal diseases. Finally, with a view to future perspectives we provide some examples of probiotics that are being assessed and have great potential in improving the health of animals and man.