Murine Model of Primary Acquired Ocular Toxoplasmosis: Fluorescein Angiography and Multiplex Immune Mediator Profiles in the Aqueous Humor

Purpose. To compare the intraocular cytokine and chemokine profiles in patients with acute primary acquired ocular toxoplasmosis (pOT) or recurrent ocular toxoplasmosis (rOT) and to correlate them with their clinical characteristics.Methods. Aqueous humor samples were collected from 62 consecutive patients (21 pOT, 30 rOT, and 11 noninfected controls) and analyzed by multiplex assay. Correlations were assessed between cytokine/chemokine levels, type of inflammatory response (Th1, Th2, and Th17), and clinical characteristics. In all OT patients, the clinical diagnosis of either pOT or rOT was confirmed by positive intraocular Goldmann/Witmer-Desmonts coefficient. Correlations were assessed between a preselected panel of immune mediators and the clinical characteristics of OT.Results. In pOT patients, increased levels of IL-2, IFN-γ, TNF-α, IL-15, IL-4, IL-5, IL-9, IL-13, IL-17, IL-1Rα, IL-6, IL-1β, and chemokines MIP-1α, MIP-1β, IP-10, Eotaxin, IL-8, RANTES, PDGF-bb, GM-CSF, G-CSF, and MCP-1 were found in comparison to those in controls (p<0.05). Patients with rOT showed elevated levels of IL-2, IFN-γ, TNF-α, IL-15, IL-4, IL-5, IL-9, IL-17, IL-1Rα, IL-6, IL-1β, and chemokines MIP-1α, IP-10, Eotaxin, IL-8, RANTES, PDGF-bb, G-CSF, and MCP-1 compared to controls (p<0.05). In addition, IL-7 (p=0.028) differed between pOT and rOT; IL-9 (p=0.054) and IL-13 (p=0.051) showed a tendency of higher concentration in pOT than in rOT. A negative correlation was found between IL-7 (p=0.017) as well as IL-9 (p=0.008) and the number of recurrences. Cytokine ratios showed no difference between pOT and rOT, indicating a dominant Th1-type response in both infectious groups. Moreover, a positive correlation was detected between IL-7, VEGF, IL-13 and age at aqueous humor sampling (p<0.05).Conclusions. This study for the first time shows subtle differences between the intraocular cytokine profiles in patients with either acute pOT or rOT.

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Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice

Science Advances ◽

10.1126/sciadv.aaz5195 ◽

2020 ◽

Vol 6 (20) ◽

pp. eaaz5195 ◽

Cited By ~ 1

Author(s):

Takefumi Yamaguchi ◽

Kazunari Higa ◽

Yukari Yagi-Yaguchi ◽

Koji Ueda ◽

Hisashi Noma ◽

...

Keyword(s):

Clinical Outcomes ◽

Aqueous Humor ◽

Murine Model ◽

Graft Failure ◽

Cellular Response ◽

Energy Homeostasis ◽

Corneal Transplantation ◽

Full Spectrum ◽

Therapeutic Modalities ◽

Iris Atrophy

Corneal endothelial cell (CEnC) loss after corneal transplantation is the major cause of graft failure and remains a clinically relevant challenge to overcome. Accumulated knowledge derived from long-term clinical outcomes suggested that elevated protein levels in the aqueous humor are associated with CEnC loss. However, the full spectrum of driver proteins and molecular processes remains to be determined. Here, we defined the somatic microenvironmental landscape and cellular response across human aqueous humor in samples with poor corneal transplantation clinical outcomes using multiomics analyses and clarified specific driver alterations, including complement activation and disturbed energy homeostasis. These driver alterations were also confirmed in aqueous humor from a novel murine model that spontaneously develops iris atrophy, leading to CEnC loss. The application of the integrative multiomics performed in human samples to the novel murine model will help the development of therapeutic modalities for patients with CEnC loss after corneal transplantation.

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