Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology
Abstract
1. Introduction
2. Emerging Immunological Markers
2.1. Importance of Immune Processes in Cornea Transplantation
2.2. In Vivo Confocal Microscopy Evaluation of Immune Cells in the Corneal Graft
2.3. Cytokines and Regulatory T cells
2.4. Major Histocompatibility Complex and Antigen-Presenting Cells
3. Endothelial Cell Density and Morphological Indicators as Graft Response Predictors
4. Vascular Dynamics and Graft Survival
4.1. Prior to Transplantation
Antiangiogenic | Proangiogenic |
---|---|
IFN-γ [83] | VEGF-A, C, D [22,85,89,90,91,98,99,100] |
sVEGFR-1,2,3 [92,93,94,95,96,97,98,99,100] | bFGF [22,85,86,87,88,89] |
PEDF [94,95,96,97] | VLA-1 [102] |
Endostatin [94,95,96,97] | PDGF [105,106] |
ANG2 [107,108] |
4.2. After Transplantation
5. Physical Properties of the Cornea as Biomarkers of Graft Survival
6. Markers of Wound Healing
Markers of Wound Healing | Clinical Significance | References |
---|---|---|
IL-1α, IL-1β | Paracrine regulation of myofibroblasts apoptosis | [143,145,147] |
TNF-α | Triggers stromal keratocytes responses, including IL-1-mediated synthesis of Fas ligand | [144,145] |
EGF | Reflects level of intrastromal inflammation. Responds to key inflammatory mediators including IL-1 and TNF. Observed as early as 2 months before rejection. Levels decreased as immunosuppressant treatment progresses. | [145] |
PDGF | Sub-basal and endothelial immune cell density increases associated with graft rejection. Reflects levels of stromal inflammation by responding to inflammatory mediators. | [145,151] |
aFGF, bFGF | Binds to VEGF-A; VEGF-C; VEGF-C and D, respectively. Can act as anti-angiogenic factors in the corneal epithelial cells. | [151] |
uPA | Corneal epithelial cells migration and proliferation | [159] |
7. Future Directions
Author Contributions
Conflicts of Interest
References
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Biomarkers | Clinical Significance | References |
---|---|---|
ABO Blood Group | Minor histocompatibility complex antigen mismatch implicated in allograft rejection. | [3,4] |
HLA-DR | Major histocompatibility complex antigen mismatch implicated in allograft rejection for high-risk bed. | [5,6,7,8] |
Activated Keratocytes | Reflect level of intrastromal inflammation. Respond to key inflammatory mediators including IL-1 and TNF-α. Observed as early as 2 months before rejection. Levels decrease as immunosuppressant treatment progresses. | [9,10,11,12,13,14,15] |
Immune Cell Density | Sub-basal and endothelial immune cell density increase associated with graft rejection. Reflects levels of stromal inflammation by responding to inflammatory mediators. | [10,16] |
Angio-/Lymphangiogenic Markers VEGFR-1, 2, 3 | Binds to VEGF-A; VEGF-C; VEGF-D, respectively. Can act as anti-angiogenic factors in the corneal epithelial cells. | [17,18,19,20,21,22] |
VEGF-A, C, D | Directly promotes corneal angio/lymphangiogenesis in the absence of above anti-angiogenic receptor. | |
Inflammatory Markers IL-1, IL-6, IL-8, IL-17A, TNF-α | Proinflammatory cytokines upregulated post-transplantation. | [13,23,24,25,26,27] |
MIP-1α, MIP-1β, MIP-2, RANTES, CCL2, CCL20, CCL21 | Proinflammatory chemokines upregulated post-transplantation. Promote corneal acquisition of MHC class II cells and APC. | [21,24,28,29,30,31] |
IL-2, IL-4, IL-5, IFN-γ | Protective factors (IL-2 and IL-5) and hazardous factors (IL-4 and IFN-γ) within the AqH. Candidate markers for prognosticating post-operative immune responses. | [27] |
C3a | Complement pathway product. High levels in the AqH associated with graft rejection. | [32] |
MHC class I-related chain A (MICA) | Expression induced by IFN-γ in corneal epithelial and endothelial cells. Connection to stimulation of CD8+ cells and subsequent promotion of immune response. | [33] |
ICAM-1, VLA-1 | Adhesion molecules targeted by immune cells. Expression upregulated in inflammatory states and promote acquisition of MHC class II cells and APC in the cornea. | [34,35,36,37] |
Antigen Presenting Cells and Surface Proteins CD11c+(Dendritic cells) | Upregulation within 24 h of inflammation. Showed increased expression of MHC class II molecules in inflammatory states. | [38] |
CD11c−/CD11b+ (Monocyte/Macrophage) | Migrates throughout the stroma (normally confined to posterior stroma) during inflammatory states. | [38] |
CD80, CD86, CD40 | Co-stimulatory molecules expressed on APCs, of which their expression is increased due to increased proinflammatory cytokines post-transplantation. | [7,38,39] |
CCR7 | Promotes CCL21-dependent APC migration to the cornea through afferent lymphatics. | [30] |
T Cells and Surface Proteins Foxp3 (Treg) | Releases IL-10 and TGF. Correlated with reduced allograft rejection. | [16,40,41] |
CD8+/IFN-γ+ | High levels in the AqH associated with prognostication of allograft rejection. | [32] |
Biomarkers | Clinical Significance | References |
---|---|---|
Endothelial cell density (ECD, cell counts/mm2) | Lower ECD preoperatively and 2 months postoperatively was significantly correlated with the development of late endothelial failure after PKP. The lower ECD at 6 months postoperatively showed strong correlation with graft failure from endothelial decompensation. | [63,65] [66,67] |
Lower graft ECD was identified as a significant predisposing factor for lower postoperative ECD, but not for graft failure after DSAEK. Lower graft ECD was found as a significant risk factor for higher postoperative ECD loss by multinominal regression analysis after DMEK. | [70] [71] | |
Endothelial cell morphology Polymegethism (coefficient of variation of cell area, %) | Clinically valuable marker of the state of the endothelium | [15] |
Pleomorphism (hexagonality, %) Spring constant K * | Valuable morphometric parameter of the state of the endothelium Lower hexagonality at 6 months after PKP showed a suggestive trend of higher graft failure. Positive correlation with CD166+/CD24–/CD105–/CD44– effector cell fraction for injection of cultured HCECs with a ROCK inhibitor. Preoperative K showed best classification accuracy with ECD at postoperative 6 months compared with other parameters, including effector cell fraction, preoperative ECD, and preoperative hexagonality. | [15] [67] [61] |
Genes ANAPC1 | A cell cycle-regulated E3 ubiquitin ligase which controls progression through mitosis and the G1 phase of the cell cycle. An intergenic variant (rs78658973[A]) close to ANAPC1 was found to have a strong association with decreased ECD. | [72] |
Associated Factors | Clinical Significance | References |
---|---|---|
Graft Failure | CCT was associated with graft failure independent of the prediction made through ECD. The possibility of an unknown mechanism connecting CCT to graft failure has been posited. | [116,117] |
Diabetes and Hyperglycemia | Associated with corneal endothelial dysfunction and resultant stromal hydration of the cornea. Osmotic fluid shifts and collagen cross-linkage are likely etiologies. | [118,119] |
Endothelial Decompensation, Corneal Edema | Diseases involving endothelial dysfunction, such as Fuchs’ endothelial corneal dystrophy, progress into corneal edema. Resultant increase in CCT is a reliable method to measure disease progression. | [120,121,122] |
ΔIOP > 25 mmHg (post-operation) | CCT was predictive of IOP increase 1 month postoperatively. Preoperative glaucoma was associated with early graft failure. CCT may represent the underlying physiologic link that connects glaucoma and graft failure. | [116,117] |
GenesZNF469 | Possible regulator of collagen synthesis and/or organization. Implicated in the development of Brittle Cornea syndrome, which exhibits markedly reduced CCT. | [123] |
COL5A1 | Encodes for the alpha-1 chain of type V collagen. Associated with a variation of Ehlers–Danlos syndrome, which also exhibits reduced CCT. | [124,125] |
COL8A2 | Encodes for the alpha-2 chain of type VIII collagen. Associated with posterior polymorphous corneal dystrophy and Fuchs’ endothelial corneal dystrophy, characterized by changes in the endothelial layer and Descemet’s membrane. | [124,125] |
ZFP106 | Contains an mHag loci which encodes for H-3a epitopes. These loci were previously shown to mediate corneal graft allograft rejection. | [126] |
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Di Zazzo, A.; Lee, S.-M.; Sung, J.; Niutta, M.; Coassin, M.; Mashaghi, A.; Inomata, T. Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology. J. Clin. Med. 2020, 9, 586. https://doi.org/10.3390/jcm9020586
Di Zazzo A, Lee S-M, Sung J, Niutta M, Coassin M, Mashaghi A, Inomata T. Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology. Journal of Clinical Medicine. 2020; 9(2):586. https://doi.org/10.3390/jcm9020586
Chicago/Turabian StyleDi Zazzo, Antonio, Sang-Mok Lee, Jaemyoung Sung, Matteo Niutta, Marco Coassin, Alireza Mashaghi, and Takenori Inomata. 2020. "Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology" Journal of Clinical Medicine 9, no. 2: 586. https://doi.org/10.3390/jcm9020586
APA StyleDi Zazzo, A., Lee, S.-M., Sung, J., Niutta, M., Coassin, M., Mashaghi, A., & Inomata, T. (2020). Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology. Journal of Clinical Medicine, 9(2), 586. https://doi.org/10.3390/jcm9020586