Dysregulation of CXCR3 Expression on Peripheral Blood Leukocytes in Patients With Neovascular Age-Related Macular Degeneration

Falk, Mads Krüger; Singh, Amardeep; Faber, Carsten; Nissen, Mogens Holst; Hviid, Thomas Vauvert F.; Sørensen, Torben Lykke

doi:10.1167/iovs.14-14107

Cited by 29 publications

(33 citation statements)

References 31 publications

(53 reference statements)

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“…In line with our previous findings in patients with neovascular AMD, 17,33 we find association between neovascular AMD and lower CD4 þ CXCR3 þ and CD4 þ CXCR3 þ CCR6 þ . CXCR3 þ T cells are particularly interesting since they migrate toward areas of inflammation, 34 CXCR3-CXCL10 interaction activates downstream pathways that inhibits VEGF-induced endothelial motility and tube formation, 35 and age-related parainflammation in RPE leads to downregulation of CXCL10 expression.…”

Section: Discussionsupporting

confidence: 93%

Polypoidal Choroidal Vasculopathy Associate With Diminished Regulatory T Cells That Are Polarized Into a T Helper 2-Like Phenotype

Subhi

Nielsen

Molbech

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Subhi Y, Krogh Nielsen M, Molbech CR, et al. Polypoidal choroidal vasculopathy associate with diminished regulatory t cells that are polarized into a T helper 2-like phenotype. Invest Ophthalmol Vis Sci. 2019;60:2583-2590. https://doi.org/ 10.1167/iovs.19-26882 PURPOSE. To investigate possible roles of T helper (Th) cells, regulatory T cells (Tregs), and the recently mapped Th-like Tregs in patients with polypoidal choroidal vasculopathy (PCV). METHODS.In this prospective case-control study, we obtained fresh venous blood from patients with PCV (n ¼ 24), age-matched healthy controls (n ¼ 32), and patients with neovascular AMD (n ¼ 45). All participants underwent a comprehensive ocular examination including fluorescein and indocyanine green angiography for where retinal disease was suspected. Using flow cytometry, we identified Th subsets, Tregs, and Th-like Tregs. Plasma samples were stored at À808C to investigate plasma cytokines of interest.RESULTS. Compared to healthy controls, patients with PCV had lower percentages of Tregs (8.7% 6 2.8% vs. 7.3% 6 1.7%, P ¼ 0.027), which were significantly more Th2-like polarized (42.6% 6 13.3% vs. 50.5% 6 13.0%, P ¼ 0.029). These changes differed from that observed in neovascular AMD, which compared to healthy controls had fewer Th1/Th17 cells (3.6% 6 2.7% vs. 2.4% 6 2.5%, P ¼ 0.049), comparable Treg levels, and no distinct polarization of Thlike Tregs. Because of these findings, we measured plasma IL-4 and IL-33 levels. Plasma IL-33 in patients with PCV (median 0.30 pg/mL) was twice as high compared to healthy controls (median 0.16 pg/mL; P ¼ 0.037).CONCLUSIONS. PCV associate with diminished Tregs that are polarized more into a Th2-like phenotype. This is correlated to IL-33 levels, which we also find increased in patients with PCV. Our findings suggest a possible role for Th2-like Tregs and IL-33 in PCV.

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Section: Discussionsupporting

confidence: 93%

Polypoidal Choroidal Vasculopathy Associate With Diminished Regulatory T Cells That Are Polarized Into a T Helper 2-Like Phenotype

Subhi

Nielsen

Molbech

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Many studies in animal models have established causal links between retinal damage and proinflammatory pathways [20][21][22]. In humans, many studies have shown that AMD patients presented higher expression of proinflammatory cytokines and altered phenotype and functions of immune cells [16,23,24]. This study demonstrated that AMD patients also presented an imbalance in the composition of CD4 + T …”

Section: Discussionmentioning

confidence: 60%

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

Chen

Wang

2017

Cell Physiol Biochem

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Background/Aims: Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. Methods: We examined the CD4 + T cell compartments and their functions in AMD patients. Results: AMD patients presented significantly higher frequencies of interferon (IFN)-γ-expressing and interleukin (IL)-17-expressing CD4 + T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4 + T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3 + and CCR4 + CCR6 + expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. Conclusions: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ-and IL-17-dependent fashion, and could potentially serve as therapeutic targets.

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“…We have recently demonstrated a trend towards lower CXCR3 expression on circulating CD4 + CD69 + T cells (activated T-cells) in patients with exudative AMD compared to age-matched controls without AMD (p = 0.07) 12 . In this current study, we confirm the results from our previous study and report a lower expression of CXCR3 on CD4 + cells in patients with exudative AMD (p = 0.012) compared to controls without AMD.…”

Section: Discussionmentioning

confidence: 96%

“…This was an intentional strategy to better match the control group. Since this was a hypothesis-driven study, our aim for the number of participants was based on our previous experience with studies of systemic lymphocytes in patients with AMD rather than a power calculation, which is at least 20 individuals in each group 9, 12, 30 . We thus recruited at least 20 individuals in each group and stopped including further participants after recruiting a total of 90.…”

Section: Methodsmentioning

confidence: 99%

Systemic frequencies of T helper 1 and T helper 17 cells in patients with age-related macular degeneration: A case-control study

Singh

Subhi

Nielsen

et al. 2017

Sci Rep

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Age-related macular degeneration (AMD) is a degenerative disease of the retina and a leading cause of irreversible vision loss. We investigated the systemic differences in the frequency of T helper (Th) 1 and Th17 cells in patients with non-exudative and exudative AMD and compared to age-matched controls. Flow cytometry was used to determine the systemic frequency of Th1 (CD4+CXCR3+IL12RB2+) and Th17 (CD4+CCR6+IL23R+) cells, and percentage of CD4+ T-cells expressing CXCR3, IL12RB2, CCR6, IL23R, and co-expressing CXCR3 and CCR6. The frequency of Th1 cells and CXCR3+ CD4+ T-cells was lower in patients with exudative AMD. A significant age-dependent decrement in Th1 was observed in controls, but not in non-exudative or exudative AMD. This may be related to the CXCR3+ CD4+ T-cells, which showed similar pattern in controls, but not in non-exudative or exudative AMD. No significant group differences were observed for the frequency of Th17 cells. Correlation networks found several differences between controls and AMD. These data suggests the involvement of the adaptive immune system in AMD and supports the notion of AMD as a systemic disease. Our observations warrant further investigation into the role of the adaptive immune system in the pathogenesis of AMD.

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Dysregulation of CXCR3 Expression on Peripheral Blood Leukocytes in Patients With Neovascular Age-Related Macular Degeneration

Cited by 29 publications

References 31 publications

Polypoidal Choroidal Vasculopathy Associate With Diminished Regulatory T Cells That Are Polarized Into a T Helper 2-Like Phenotype

Polypoidal Choroidal Vasculopathy Associate With Diminished Regulatory T Cells That Are Polarized Into a T Helper 2-Like Phenotype

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

Systemic frequencies of T helper 1 and T helper 17 cells in patients with age-related macular degeneration: A case-control study

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