Keratoconus Patients Exhibit a Distinct Ocular Surface Immune Cell and Inflammatory Profile

Overview

Journal Sci Rep

Specialty Science

Date 2021 Oct 23

PMID 34686755

Citations 16

Authors

Sharon DSouza

Archana Padmanabhan Nair

Ganesh Ram Sahu

Tanuja Vaidya

Rohit Shetty

Pooja Khamar

Ritika Mullick

Sneha Gupta

Mor M Dickman

Rudy M M A Nuijts

Rajiv R Mohan

Arkasubhra Ghosh

Swaminathan Sethu

Affiliations

Soon will be listed here.

Abstract

Inflammatory factors have been considered to contribute to keratoconus (KC) pathogenesis. This study aims to determine the immune cells subsets and soluble inflammatory factor profile on the ocular surface of KC patients. 32 KC subjects (51 eyes) across different grades of severity and 15 healthy controls (23 eyes) were included in the study. Keratometry and pachymetry measurements were recorded. Ocular surface immune cells (collected by ocular surface wash) immunophenotyped using flow cytometry include leukocytes, neutrophils, macrophages, natural killer (NK) cells, pan-T cells, gamma delta T (γδT) cells and NKT cells. Tear fluid collected using Schirmer's strip was used to measure 50 soluble factors by multiplex ELISA. Proportions of activated neutrophils, NK cells and γδT cells were significantly increased in KC patients. Significantly higher levels of tear fluid IL-1β, IL-6, LIF, IL-17A, TNFα, IFNα/β/γ, EPO, TGFβ1, PDGF-BB, sVCAM, sL-selectin, granzyme-B, perforin, MMP2, sFasL and IgE, along with significantly lower levels of IL-1α and IL-9 were observed in KC patients. Alterations observed in few of the immuno-inflammatory parameters correlated with grades of disease, allergy, eye rubbing and keratometry or pachymetry measurements. The observation implies a distinct immuno-inflammatory component in KC pathogenesis and its potential as an additional therapeutic target in KC management.

Citing Articles

Untargeted Tear Proteomics in a Large South-Asian Cohort Reveals Inflammatory Signaling, ECM Remodeling, and Altered Metabolism in Keratoconus.

Kannan R, Shetty R, Panigrahi T, Koh S, Khamar P, Deshpande V Invest Ophthalmol Vis Sci. 2025; 66(2):60.

PMID: 39992672 PMC: 11878249. DOI: 10.1167/iovs.66.2.60.

The cellular response of lipopolysaccharide-induced inflammation in keratoconus human corneal fibroblasts to RB-PDT: Insights into cytokines, chemokines and related signaling pathways.

Chai N, Stachon T, Hacker S, Berger T, Li Z, Amini M PLoS One. 2025; 20(1):e0318132.

PMID: 39869570 PMC: 11771863. DOI: 10.1371/journal.pone.0318132.

Distinct Ocular Surface Microbiome in Keratoconus Patients Correlate With Local Immune Dysregulation.

Kumar N, Khamar P, Kannan R, Padmanabhan A, Shetty R, DSouza S Invest Ophthalmol Vis Sci. 2025; 66(1):60.

PMID: 39869087 PMC: 11771523. DOI: 10.1167/iovs.66.1.60.

PI3K signaling and lysyl oxidase is critical to corneal stroma fibrosis following mustard gas injury.

Sinha N, Hofmann A, Suleiman L, Laub R, Tripathi R, Chaurasia S Exp Eye Res. 2024; 251:110213.

PMID: 39706242 PMC: 11798705. DOI: 10.1016/j.exer.2024.110213.

Mendelian randomization reveals that abnormal lipid metabolism mediates the causal relationship between body mass index and keratoconus.

Wang J, Liu F, Gong D, Su J, Zheng F, Ding S Sci Rep. 2024; 14(1):23698.

PMID: 39390037 PMC: 11467444. DOI: 10.1038/s41598-024-74455-9.

References

Shetty R, Deshmukh R, Ghosh A, Sethu S, Jayadev C . Altered tear inflammatory profile in Indian keratoconus patients - The 2015 Col Rangachari Award paper. Indian J Ophthalmol. 2017; 65(11):1105-1108. PMC: 5700575. DOI: 10.4103/ijo.IJO_233_17. View

Smith V, Matthews F, Majid M, Cook S . Keratoconus: matrix metalloproteinase-2 activation and TIMP modulation. Biochim Biophys Acta. 2006; 1762(4):431-9. DOI: 10.1016/j.bbadis.2006.01.010. View

Reyes N, Mayhew E, Chen P, Niederkorn J . γδ T cells are required for maximal expression of allergic conjunctivitis. Invest Ophthalmol Vis Sci. 2011; 52(5):2211-6. PMC: 3080177. DOI: 10.1167/iovs.10-5959. View

Pahuja N, Kumar N, Shroff R, Shetty R, Nuijts R, Ghosh A . Differential Molecular Expression of Extracellular Matrix and Inflammatory Genes at the Corneal Cone Apex Drives Focal Weakening in Keratoconus. Invest Ophthalmol Vis Sci. 2016; 57(13):5372-5382. DOI: 10.1167/iovs.16-19677. View

Osei E, Mostaco-Guidolin L, Hsieh A, Warner S, Al-Fouadi M, Wang M . Epithelial-interleukin-1 inhibits collagen formation by airway fibroblasts: Implications for asthma. Sci Rep. 2020; 10(1):8721. PMC: 7250866. DOI: 10.1038/s41598-020-65567-z. View

Kenney M, Nesburn A, Burgeson R, Butkowski R, Ljubimov A . Abnormalities of the extracellular matrix in keratoconus corneas. Cornea. 1997; 16(3):345-51. View

Loh I, Sherwin T . Is Keratoconus an Inflammatory Disease? The Implication of Inflammatory Pathways. Ocul Immunol Inflamm. 2020; 30(1):246-255. DOI: 10.1080/09273948.2020.1780271. View

Chaerkady R, Shao H, Scott S, Pandey A, Jun A, Chakravarti S . The keratoconus corneal proteome: loss of epithelial integrity and stromal degeneration. J Proteomics. 2013; 87:122-31. PMC: 3721369. DOI: 10.1016/j.jprot.2013.05.023. View

Feng M, Jing L, Cheng J, An S, Huang J, Yan Q . Circ_0020093 ameliorates IL-1β-induced apoptosis and extracellular matrix degradation of human chondrocytes by upregulating SPRY1 via targeting miR-23b. Mol Cell Biochem. 2021; 476(10):3623-3633. PMC: 8382646. DOI: 10.1007/s11010-021-04186-2. View

10.

Blackburn B, Jenkins M, Rollins A, Dupps W . A Review of Structural and Biomechanical Changes in the Cornea in Aging, Disease, and Photochemical Crosslinking. Front Bioeng Biotechnol. 2019; 7:66. PMC: 6459081. DOI: 10.3389/fbioe.2019.00066. View

11.

Smith V, Rishmawi H, Hussein H, Easty D . Tear film MMP accumulation and corneal disease. Br J Ophthalmol. 2001; 85(2):147-53. PMC: 1723854. DOI: 10.1136/bjo.85.2.147. View

12.

Dudakova L, Sasaki T, Liskova P, Palos M, Jirsova K . The presence of lysyl oxidase-like enzymes in human control and keratoconic corneas. Histol Histopathol. 2015; 31(1):63-71. DOI: 10.14670/HH-11-649. View

13.

Pasztor D, Kolozsvari B, Csutak A, Berta A, Hassan Z, Ujhelyi B . Tear Mediators in Corneal Ectatic Disorders. PLoS One. 2016; 11(4):e0153186. PMC: 4830513. DOI: 10.1371/journal.pone.0153186. View

14.

Lema I, Sobrino T, Duran J, Brea D, Diez-Feijoo E . Subclinical keratoconus and inflammatory molecules from tears. Br J Ophthalmol. 2009; 93(6):820-4. DOI: 10.1136/bjo.2008.144253. View

15.

Karaca E, Ozmen M, Ekici F, Yuksel E, Turkoglu Z . Neutrophil-to-lymphocyte ratio may predict progression in patients with keratoconus. Cornea. 2014; 33(11):1168-73. DOI: 10.1097/ICO.0000000000000260. View

16.

Shetty R, Ghosh A, Lim R, Subramani M, Mihir K, Reshma A . Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci. 2015; 56(2):738-50. DOI: 10.1167/iovs.14-14831. View

17.

Ferrari G, Rama P . The keratoconus enigma: A review with emphasis on pathogenesis. Ocul Surf. 2020; 18(3):363-373. DOI: 10.1016/j.jtos.2020.03.006. View

18.

Velotti F, Barchetta I, Cimini F, Cavallo M . Granzyme B in Inflammatory Diseases: Apoptosis, Inflammation, Extracellular Matrix Remodeling, Epithelial-to-Mesenchymal Transition and Fibrosis. Front Immunol. 2020; 11:587581. PMC: 7686573. DOI: 10.3389/fimmu.2020.587581. View

19.

Barabino S, Montaldo E, Solignani F, Valente C, Mingari M, Rolando M . Immune response in the conjunctival epithelium of patients with dry eye. Exp Eye Res. 2010; 91(4):524-9. DOI: 10.1016/j.exer.2010.07.008. View

20.

Paul S, Singh A, Shilpi , Lal G . Phenotypic and functional plasticity of gamma-delta (γδ) T cells in inflammation and tolerance. Int Rev Immunol. 2013; 33(6):537-58. DOI: 10.3109/08830185.2013.863306. View