Nous avons sélectionné des patients atteints d’une TO biologiquement confirmée et avons exploré les différences cliniques et biologiques de deux groupes de patients, l’un en France, l’autre en Colombie. Dans notre hypothèse de départ, les souches sud-américaines, seraient plus virulentes et elles pourraient jouer un rôle crucial dans la sévérité et l’évolution de la TO. Nous avons constaté, chez les patients colombiens, de plus grandes lésions de la rétine et une plus grande proportion de lésions maculaires, dans un contexte inflammatoire vitréen plus sévère. Le cytoquinome oculaire confirme une forte réponse inflammatoire chez les patients européens centrée sur l’IL-17, mais cette réponse Th17 est absente chez les sujets colombiens. L’IL-6 et l’IL-13 sont au contraire fortement augmentées chez ces derniers. Nous avons également démontré que certaines cytokines étaient associées à certaines caractéristiques cliniques comme la sévérité de l’inflammation ou la récurrence. Des travaux préliminaires nous ont permis de débuter une modélisation de ces affactions oculaires en employant une souche de type II et une souche atypique de T. gondii. Nous avons aussi évalué la possibilité d’effectuer des traitements ciblés en intraoculaires par transfection in vivo. Conclusion: Nous avons constaté des différences cliniques et biologiques entre les patients colombien et français. Il semble y avoir une régulation souche dépendante de la production d’IFN-y et d’IL-17. Ces différences pourraient contribuer à expliquer la plus grande sévérité des toxoplasmoses oculaires en Colombie. En se basant sur nos résultats nous pouvons envisager d’explorer des traitements immunomodulateurs plus ciblés. / Ocular involvement, mainly retinochoroiditis, is one of the most severe sequelae of Toxoplasma gondii infection. However, the pathophysiological mechanisms of retinal destruction are poorly understood. Several studies suggested a more frequent and more severe ocular involvement in South American infections compared with European infections, probably due to different T. gondii strains (Type I/III, and atypical vs. Type II). To compare the clinical characteristics and biological and immunological responses in a single study and using the same parameters, in Colombian and French patients with active ocular toxoplasmosis (OT), as well as to study the local cytokinome in aqueous humor of these patients and correlate it with the clinical features. We prospectively collected and compared the clinical features of patients with active OT, evaluated at the Department of Ophthalmology of Strasbourg University Hospital and of Quindio University Health-Center. Results of biological tests in the collected aqueous humor samples were compared between Colombian and French patients: the pattern of protein recognition by immunoblotting (IB); the relative diagnostic sensitivities of IB and Polymerase Chain Reaction (PCR); and the cytokine and chemokine profiles. We found that Colombian and French OT patients presented not only different clinical characteristics but also biological characteristics, and that more virulent South American strains might be responsible for these differences, due to a disruption of the protective effects of interferon gamma (IFN-γ). Retinal lesions were 50% greater in Colombian patients. Macular localization leading to visual impairment was observed in 56% of Colombian cases, compared with 13% of French patients. Moreover, more vitreous inflammation and vasculitis were observed in Colombian patients. However, cytokine assays of the aqueous humor showed upregulation of inflammatory responses in European patients, notably IL-17, which we did not observe in Colombian patients. In a mouse model, intraocular tachyzoite injection of type II and atypical T. gondii strains resulted in differences in parasite multiplication and pathology similar to those observed in human infections. Production of IL-17 and other inflammatory markers, like IL-6, MCP-1, and the Th17 transcription factor ROR-γt was observed upon infection with the type II PRU strain, but was much less with the atypical LEF strain. In a previous work, the cytokine and mRNA patterns showed an upregulation of Th1 responses, notably IFN-γ production, in French patients, and anti-IL-17A antibody markedly diminished clinical damage and retinal inflammation, and also diminished parasite proliferation. In contrast to these previous findings in French patients, the cytokinome of aqueous humor of OT Colombian patients showed a downregulation of Th1 and Th17 responses and an upregulation of the Th2 response. Correlation between the clinical characteristics of Colombian patients with active OT and the levels of cytokines in aqueous humor (AH) showed that local production of cytokines differed between patients with OT, and particular cytokine levels were related to more severe clinical characteristics. Some cytokines were related to a higher number of recurrences.There are clinical and biological differences between Colombian and French patients with OT. There seem to be strain-specific differences in IL-17 and IFN-γ induction, which play an important role in the pathogenesis of this disease. These differences should be considered when thinking in perspectives of any possible immune-modulatory treatment in OT.
| Identifer | oai:union.ndltd.org:theses.fr/2013STRAJ043 |
| Date | 18 September 2013 |
| Creators | De la Torre Cifuentes, Ligia Alejandra |
| Contributors | Strasbourg, Universidad del Quindío (Armenia, Colombie), Candolfi, Ermanno, Gomez-Marin, Jorge |
| Source Sets | Dépôt national des thèses électroniques françaises |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation, Text |
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