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International audience; PurposeTo conduct a systematic review and meta-analysis on the levels of oxidative stress markers and antioxidants in keratoconus compared to healthy subject.MethodThe PubMed, Cochrane Library, Embase, Science Direct and Google Scholar databases were searched on 1st June 2020 for studies reporting oxidative and antioxidative stress markers in keratoconus and healthy controls. Main meta-analysis was stratified by type of biomarkers, type of samples (tears, cornea, aqueous humour and blood) and type of corneal samples (stromal cells, epithelium and endothelium).ResultsWe included 36 articles, for a total of 1328 keratoconus patients and 1208 healthy controls. There is an overall increase in oxidative stress markers in keratoconus compared with healthy controls (standard mean deviation (SMD) = 0.94, 95% confidence interval (95% CI) 0.55–1.33), with a significant increase in reactive oxygen and nitrogen species (1.09, 0.41–1.78) and malondialdehyde (1.78, 0.83–2.73). There is an overall decrease in antioxidants in keratoconus compared with healthy controls (−0.63, −0.89 to −0.36), with a significant decrease in total antioxidant capacity/status (−1.65, −2.88 to −0.43), aldehyde/NADPH dehydrogenase (−0.77, −1.38 to −0.17), lactoferrin/transferrin/albumin (−1.92, −2.96 to −0.89) and selenium/zinc (−1.42, −2.23 to −0.61). Oxidative stress markers were higher in tears and in cornea of keratoconus than in aqueous humour, and antioxidants were decreased in tears, aqueous humour and blood without difference between sample type. Oxidative stress markers increased in stromal cells and antioxidants decreased in endothelium.ConclusionOxidative stress markers and antioxidants were dysregulated in keratoconus, involving an imbalance of redox homeostasis in tears, cornea, aqueous humour and blood.

Indexation en cours.; International audience; PURPOSE: Contact lens (CL)-related microbial keratitis (MK) has major public health implications, with about 300 million wearers worldwide, and certain potentially modifiable risk factors. This study aimed to identify the risk factors of CL-related MK. METHODS: A multicenter case-control study was conducted between 2014 and 2017. Cases presenting with CL-related MK were submitted to an anonymous 52-item questionnaire, which was also completed by healthy controls. Univariate followed by multivariate logistic regression analysis was performed. Risk factors for CL-related MK were given as odds ratio (OR) with 95% confidence interval and P-value. RESULTS: The study included a total of 2267 patients (1198 cases and 1069 controls). The MK risk factors for the daily disposable lenses group were exceeding the lens renewal period (OR = 9.16, P = 0.008) and occasionally wearing CL when sleeping (OR = 15.83, P = 0.035). The most important risk factors in the nondaily disposable lenses group were lens cleaning solution distributed by eye care brands (OR = 3.50, P < 0.001) and failure to renew lens cases (OR = 3.39, P = 0.001). Statistically and clinically significant variables were used to establish the MK risk equation for CL wearers, allowing an individual calculation of the risk of MK under lenses. CONCLUSIONS: The MK risk equation is a valuable tool for educating patients about the risks associated with wearing CL. It allows the patient to be informed about their overall risk of infection while detailing the precipitating elements of the infectious risk with the aim of modifying risk behavior.

Purpose To compare the outcomes of transepithelial photorefractive intrastromal corneal crosslinking (CXL) and photorefractive keratectomy (PRK) in eyes with low myopia. Setting Purpan Hospital, Toulouse, France. Design Prospective case series. Methods Myopic patients with a manifest refraction spherical equivalent (MRSE) of −1.00 to −2.50 diopters (D) and a cylindrical component of plano to −0.75 D were included. The dominant eye had PRK (PRK eyes). The nondominant eye had transepithelial photorefractive intrastromal CXL with riboflavin (ParaCel Part 1 and 2), 30 mW/cm2 pulsed ultraviolet-A irradiation centered on the pupil (Mosaic System) for 16 minutes and 40 seconds, and a supplemental oxygen delivery mask (CXL eyes). The primary outcome measure was the change in the MRSE. Other outcome measures were the uncorrected (UDVA) and corrected (CDVA) distance visual acuities, mean keratometry, and endothelial cell count (ECC) over a 6-month follow-up. Adverse events were assessed. Results Nineteen patients were included. By 6 months, the mean MRSE had decreased by 0.72 D ± 0.42 (SD) in CXL eyes and by 1.35 ± 0.46 D in PRK eyes (P Conclusions Photorefractive keratectomy provided better visual and refractive outcomes than transepithelial photorefractive intrastromal CXL. Transepithelial photorefractive intrastromal CXL, however, showed the potential refractive effect of CXL but with a limited magnitude of myopic correction.

International audience; Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

International audience; Purpose: We compared an iontophoresis riboflavin delivery technique for transepithelial corneal collagen crosslinking (I-CXL) with a conventional CXL (C-CXL).Methods: We designed three experimental sets using 152 New Zealand rabbits to study riboflavin application by iontophoresis using charged riboflavin solution (Ricrolin+) with a 1-mA current for 5 minutes. The first set was to compare riboflavin concentration measured by HPLC in corneas after iontophoresis or conventional riboflavin application. The second set was to analyze autofluorescence and stromal collagen modification immediately and 14 days after I-CXL or C-CXL, by using nonlinear two-photon microscopy (TP) and second harmonic generation (SHG). In the third set, physical modifications after I-CXL and C-CXL were evaluated by stress-strain measurements and by studying corneal resistance against collagenase digestion. Results: Based on HPLC analysis, we found that iontophoresis allowed riboflavin diffusion with 2-fold less riboflavin concentration than conventional application (936.2 ± 312.5 and 1708 ± 908.3 ng/mL, respectively, P < 0.05). Corneal TP and SHG imaging revealed that I-CXL and C-CXL resulted in a comparable increased anterior and median stromal autofluorescence and collagen packing. The stress at 10% strain showed a similar stiffness of corneas treated by I-CXL or C-CXL (631.9 ± 241.5 and 680.3 ± 216.4 kPa, respectively, P = 0.908). Moreover, we observed an increased resistance against corneal collagenase digestion after I-CXL and C-CXL (61.90% ± 5.28% and 72.21% ± 4.32% of remaining surface, respectively, P = 0.154).Conclusions: This experimental study suggests that I-CXL is a promising alternative methodology for riboflavin delivery in crosslinking treatments, preserving the epithelium.

BACKGROUND/AIMS: To compare the efficacy and safety of intracameral (IC) administration at the beginning of cataract surgery, of Mydrane, a standardised ophthalmic combination of tropicamide 0.02%, phenylephrine 0.31% and lidocaine 1%, to a standard topical regimen. METHODS: In this international phase III, prospective, randomised study, the selected eye of 555 patients undergoing phacoemulsification with intraocular lens (IOL) implantation received 200 μL of Mydrane (Mydrane group) just after the first incision or a topical regimen of one drop each of tropicamide 0.5% and phenylephrine 10% repeated three times (reference group). The primary efficacy variable was achievement of capsulorhexis without additional mydriatics. The non-inferiority of Mydrane to the topical regimen was tested. The main outcome measures were pupil size, patient perception of ocular discomfort and safety. RESULTS: Capsulorhexis without additional mydriatics was performed in 98.9% of patients and 94.7% in the Mydrane and reference groups, respectively. Both groups achieved adequate mydriasis (>7 mm) during capsulorhexis, phacoemulsification and IOL insertion. IOL insertion was classified as 'routine' in a statistically greater number of eyes in the Mydrane group compared with the reference group (p=0.047). Patients in the Mydrane group reported statistically greater comfort than the reference group before IOL insertion (p=0.034). Safety data were similar between groups. CONCLUSIONS: Mydrane is an effective and safe alternative to standard eye drops for initiating and maintaining intraoperative mydriasis and analgesia. Patients who received IC Mydrane were significantly more comfortable before IOL insertion than the reference group. Surgeons found IOL insertion less technically challenging with IC Mydrane. TRIAL REGISTRATION NUMBER: NCT02101359; Results. info:eu-repo/semantics/publishedVersion

International audience; Purpose: To characterize the expression of the bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases (collectively called BTPs), which include BMP-1, mammalian tolloid (mTLD), and mammalian tolloid-like 1 (mTLL-1) and 2 (mTLL-2), as well as the associated proteins procollagen C-proteinase enhancers (PCPE-1 and -2), in corneal scarring. Methods: Using a mouse full-thickness corneal excision model, wound healing was followed for up to 28 days by transmission electron microscopy, immunohistology (BMP-1/mTLD and PCPE-1), and quantitative PCR (Q-PCR: collagen III, BMP-1/mTLD, mTLL-1, mTLL-2, PCPE-1, PCPE-2). Bone morphogenetic protein-1/mTLD and PCPE-1 were also immunolocalized in cases of human corneal scarring following injuries. Results: In the mouse model, throughout the follow-up period, there was a large increase in collagen III mRNA expression in the stroma. By transmission electron microscopy, there was marked cellular infiltration into the wound as well as disorganization of collagen fibrils, but no significant difference in fibril diameter. In control corneas, by Q-PCR, BMP-1/mTLD showed the highest expression, compared to low levels of mTLL-1 and undetectable levels of mTLL-2, in both epithelium and stroma. Following wounding, both BMP-1/mTLD and PCPE-1 mRNA and protein increased, while PCPE-2 mRNA decreased. Finally, by immunofluorescence, BMP-1/mTLD and PCPE-1 were strongly expressed in the scar region in both mouse and human corneas. Conclusions: Bone morphogenetic protein-1/mTLD and PCPE-1 are upregulated in corneal scars. Both proteins may therefore contribute to the process of corneal scarring.

International audience; The cornea is a transparent, avascular tissue that acts as the major refractive surface of the eye. Corneal transparency, assured by the inner stroma, is vital for this role. Disruption in stromal transparency can occur in some inherited or acquired diseases. As a consequence, light entering the eye is blocked or distorted, leading to decreased visual acuity. Possible treatment for restoring transparency could be via viral-based gene therapy. The stroma is particularly amenable to this strategy due to its immunoprivileged nature and low turnover rate. We assayed the potential of AAV vectors to transduce keratocytes following intra-stromal injection in vivo in the mouse cornea and ex vivo in human explants. In murine and human corneas, we transduced the entire stroma using a single injection, preferentially targeted keratocytes and achieved long-term gene transfer (up to 17 months in vivo in mice). Of the serotypes tested, AAV2/8 was the most promising for gene transfer in both mouse and man. Furthermore, transgene expression could be transiently increased following aggression to the cornea.

A monoclonal anti-CD160 antibody inhibits the growth of new vessels in pathological ocular and tumor neoangiogenesis but not in healthy tissues., Angiogenesis plays an essential role in several diseases of the eye and in the growth of solid tumors, but existing antiangiogenic therapies have limited benefits in several cases. We report the antiangiogenic effects of a monoclonal antibody, CL1-R2, in several animal models of neovascularization. CL1-R2 recognizes human CD160, a membrane receptor which is conserved in various mammal species. We show that CD160 is expressed on the endothelial cells of newly formed blood vessels in human colon carcinoma and mouse B16 melanoma but not in vessels of healthy tissues. CL1-R2 reduced fibroblast growth factor 2–induced neovascularization in the rabbit cornea, in a mouse model of oxygen-induced retinopathy, and in a mouse Matrigel plug assay. Treatment of B16 melanoma-bearing mice with CL1-R2 combined with cyclophosphamide chemotherapy caused regression of the tumor vasculature and normalization of the remaining vessels as shown by Doppler ultrasonography, intravital microscopy, and histology. These studies validate CD160 as a potential new target in cases of human pathological ocular and tumor neoangiogenesis that do not respond or become resistant to existing antiangiogenic drugs.

PURPOSE: To investigate the participation of interleukin-6 (IL-6) after photorefractive keratectomy (PRK) and its possible roles and sources in corneal wound healing. METHODS: IL-6, levels were measured in the tear fluids of patients before and after PRK and in conditioned media of human corneal epithelial cells and keratocytes. Its effects on total collagen and collagen-type synthesis by keratocytes were studied with a 3H-proline incorporation assay and Northern blot analysis. Zymography was used to evaluate the metalloproteinase content in the conditioned medium of IL-6-stimulated keratocytes. RESULTS: IL-6 is present in the tear fluid samples after photorefractive keratectomy, possibly synthesized by epithelial cells and keratocytes. CONCLUSIONS: IL-6 stimulates collagen synthesis in general and collagen type I in particular. Furthermore, it reduces the production of MMP-2, the latent form of the metalloproteinase, by cultured keratocytes. The results suggest that IL-6 might be regarded as a mediator involved in corneal healing after excimer laser.PURPOSE: To investigate the participation of interleukin-6 (IL-6) after photorefractive keratectomy (PRK) and its possible roles and sources in corneal wound healing. METHODS: IL-6, levels were measured in the tear fluids of patients before and after PRK and in conditioned media of human corneal epithelial cells and keratocytes. Its effects on total collagen and collagen-type synthesis by keratocytes were studied with a 3H-proline incorporation assay and Northern blot analysis. Zymography was used to evaluate the metalloproteinase content in the conditioned medium of IL-6-stimulated keratocytes. RESULTS: IL-6 is present in the tear fluid samples after photorefractive keratectomy, possibly synthesized by epithelial cells and keratocytes. CONCLUSIONS: IL-6 stimulates collagen synthesis in general and collagen type I in particular. Furthermore, it reduces the production of MMP-2, the latent form of the metalloproteinase, by cultured keratocytes. The results suggest that IL-6 might be regarded as a mediator involved in corneal healing after excimer laser.

The corneal epithelium and epidermis form a complex protective barrier against environmental aggressions. In the epidermis, the terminal differentiation program of keratinocytes is well known and largely provided by the stratum corneum, developed in the final stage of keratinocyte differentiation. In contrast, the differentiation of the corneal epithelial cells is yet poorly studied. Despite that, in some corneal disorders, the first manifestations appear in this tissue. Therefore, further research on the differentiation process of the corneal epithelial cells would significantly improve the early diagnosis and management of patients affected by corneal-related disorders like keratoconus. Keratoconus is a multifactorial corneal ectasia associated with numerous surface changes causing a gradual and irreversible degradation of vision. The aim of my work was to characterize the terminal differentiation program of the corneal epithelium in controls versus patients with keratoconus. Firstly, I analyzed the expression of three groups of genes involved in various steps of the corneal epidermal differentiation: 1) genes that encoded keratins, 2) genes that encoded junctional complex proteins and 3) genes that coded for components of the cornified envelope, a pericellular and highly resistant structure that replaces the plasma membrane of keratinocytes during the last step of their differentiation, by means of RT-qPCR, Western Blot and immunohistology. Previous studies demonstrated that many of these genes were shown to be expressed in the cornea; however no data was available for those encoding corneodesmosin, filaggrin, hornerin and keratins 1/10. In parallel, I investigated the differential expression of the selected genes in the corneal epithelium in two cohorts of keratoconus patients (mild versus severe). I showed that the expression of keratin 16 was absent in the corneas of patients with keratoconus in comparison to controls. In line with this, I discovered that the expression and localization of several genes encoding cornified envelope components (such as involucrin, the Small Proline-Rich Proteins (SPRRs) and proteins of desmosomal plaques) was down-regulated and abnormal, respectively, in keratoconus. Surprisingly, cornified envelopes are not produced by the differentiated corneal epithelial cells. SPRRs have been reported to quench the reactive oxygen species in vitro, therefore we hypothesized that they might play a role in the corneal epithelium. Subsequently, I analyzed the expression of the main genes involved in the NRF2-pathway of oxidative stress protection such as the heme oxygenases 1 and 2, the nuclear factor erythroid 2-related factor 2, the lysyl oxidase, KEAP1, among others. Many of them were under-expressed in the keratoconus cornea epitheliums, finding that supports the involvement of oxidative stress in the progression of the disease. My findings allowed, on one hand, the characterization of the differentiation program of corneal epithelial cells and, on the other hand, the better understanding of the pathophysiology of keratoconus by proposing the involvement of mechanical weakness and a deficit in the oxidative stress response.This could improve the management of the keratoconic patients and may provide new insights for its prevention and treatment in the future., L'épithélium cornéen, tout comme l'épiderme, forme une barrière complexe qui protège l'organisme contre les agressions de l'environnement. Dans l'épiderme, cette fonction est assurée en grande partie par la couche cornée qui correspond à l'étape finale, de mieux en mieux caractérisée, de la différenciation du kératinocyte. Par contre, le programme de différenciation de l'épithélium de la cornée est peu étudié. Pourtant, les premières manifestations de diverses pathologies cornéennes apparaissent au niveau de l'épithélium, et leur dépistage précoce pourrait modifier notablement leur prise en charge. Cela pourrait être le cas du kératocône, une ectasie cornéenne plurifactorielle et rare, associée à de nombreux remaniements de surface engendrant une dégradation progressive et irréversible de la vision. L'objectif de mon travail de thèse a été de caractériser le programme de différenciation terminale de l'épithélium cornéen en situation normale et dans le cas du kératocône en prenant comme référence les gènes de différenciation tardive de l' épiderme. Tout d'abord, j'ai analysé l'expression de 3 groupes de gènes représentatifs des étapes de la différenciation épidermique (gènes des kératines, des protéines des complexes jonctionnels et des composants de l'enveloppe cornée, une structure péricellulaire résistante qui remplace la membrane plasmique des kératinocytes épidermiques lors de l'étape ultime de leur différenciation) dans l'épithélium cornéen contrôle en utilisant des techniques de RT-qPCR, Western Blot et immunohistologie. J'ai montré que l'épithélium de la cornée exprime un grand nombre des gènes de l'épiderme, mais pas ceux de la cornéodesmosine, la filaggrine, l'hornerine et des kératines 1/10. En parallèle, j'ai recherché les mêmes gènes dans l'épithélium de la cornée de deux cohortes de patients atteints de kératocône. J'ai montré que la kératine 16 est exprimée dans les cornées contrôles et disparaît dans le kératocône. Curieusement, de nombreux gènes codant pour les composants de l'enveloppe cornée sont exprimés dans l'épithélium cornéen comme ceux de l'involucrine, des Small Proline- Rich Proteins (SPRRs) et des protéines de la plaque desmosomale. De plus leur expression diminue dans l'épithélium cornéen kératoconique, avec une localisation subcellulaire différente pour l'involucrine. Pourtant, l'enveloppe cornée n'est pas produite par les cellules épithéliales différenciées de la cornée. Les protéines SPRRs étant aussi impliquées dans la détoxification des espèces réactives de l'oxygène in vitro, nous avons supposé qu'elles jouent ce rôle dans l'épithélium cornéen. Enfin, j'ai complété mes analyses avec l'étude des principaux éléments de la voie NRF2 de protection au stress oxydatif : heme oxygenases 1 et 2, nuclear factor erythroid 2-related factor 2, lysyl oxydase, KEAP1, etc. Plusieurs de ces gènes sont exprimés plus faiblement dans les cornées du kératocône par rapport aux cornées contrôles. Ces résultats ont permis, d'une part, de caractériser le programme de différenciation des cellules épithéliales de la cornée et, d'autre part, de mieux comprendre la physiopathologie du kératocône en proposant l'implication d'un déficit de la réponse au stress oxydatif.

The corneal epithelium and epidermis form a complex protective barrier against environmental aggressions. In the epidermis, the terminal differentiation program of keratinocytes is well known and largely provided by the stratum corneum, developed in the final stage of keratinocyte differentiation. In contrast, the differentiation of the corneal epithelial cells is yet poorly studied. Despite that, in some corneal disorders, the first manifestations appear in this tissue. Therefore, further research on the differentiation process of the corneal epithelial cells would significantly improve the early diagnosis and management of patients affected by corneal-related disorders like keratoconus. Keratoconus is a multifactorial corneal ectasia associated with numerous surface changes causing a gradual and irreversible degradation of vision. The aim of my work was to characterize the terminal differentiation program of the corneal epithelium in controls versus patients with keratoconus. Firstly, I analyzed the expression of three groups of genes involved in various steps of the corneal epidermal differentiation: 1) genes that encoded keratins, 2) genes that encoded junctional complex proteins and 3) genes that coded for components of the cornified envelope, a pericellular and highly resistant structure that replaces the plasma membrane of keratinocytes during the last step of their differentiation, by means of RT-qPCR, Western Blot and immunohistology. Previous studies demonstrated that many of these genes were shown to be expressed in the cornea; however no data was available for those encoding corneodesmosin, filaggrin, hornerin and keratins 1/10. In parallel, I investigated the differential expression of the selected genes in the corneal epithelium in two cohorts of keratoconus patients (mild versus severe). I showed that the expression of keratin 16 was absent in the corneas of patients with keratoconus in comparison to controls. In line with this, I discovered that the expression and localization of several genes encoding cornified envelope components (such as involucrin, the Small Proline-Rich Proteins (SPRRs) and proteins of desmosomal plaques) was down-regulated and abnormal, respectively, in keratoconus. Surprisingly, cornified envelopes are not produced by the differentiated corneal epithelial cells. SPRRs have been reported to quench the reactive oxygen species in vitro, therefore we hypothesized that they might play a role in the corneal epithelium. Subsequently, I analyzed the expression of the main genes involved in the NRF2-pathway of oxidative stress protection such as the heme oxygenases 1 and 2, the nuclear factor erythroid 2-related factor 2, the lysyl oxidase, KEAP1, among others. Many of them were under-expressed in the keratoconus cornea epitheliums, finding that supports the involvement of oxidative stress in the progression of the disease. My findings allowed, on one hand, the characterization of the differentiation program of corneal epithelial cells and, on the other hand, the better understanding of the pathophysiology of keratoconus by proposing the involvement of mechanical weakness and a deficit in the oxidative stress response.This could improve the management of the keratoconic patients and may provide new insights for its prevention and treatment in the future.; L'épithélium cornéen, tout comme l'épiderme, forme une barrière complexe qui protège l'organisme contre les agressions de l'environnement. Dans l'épiderme, cette fonction est assurée en grande partie par la couche cornée qui correspond à l'étape finale, de mieux en mieux caractérisée, de la différenciation du kératinocyte. Par contre, le programme de différenciation de l'épithélium de la cornée est peu étudié. Pourtant, les premières manifestations de diverses pathologies cornéennes apparaissent au niveau de l'épithélium, et leur dépistage précoce pourrait modifier notablement leur prise en charge. Cela pourrait être le cas du kératocône, une ectasie cornéenne plurifactorielle et rare, associée à de nombreux remaniements de surface engendrant une dégradation progressive et irréversible de la vision. L'objectif de mon travail de thèse a été de caractériser le programme de différenciation terminale de l'épithélium cornéen en situation normale et dans le cas du kératocône en prenant comme référence les gènes de différenciation tardive de l' épiderme. Tout d'abord, j'ai analysé l'expression de 3 groupes de gènes représentatifs des étapes de la différenciation épidermique (gènes des kératines, des protéines des complexes jonctionnels et des composants de l'enveloppe cornée, une structure péricellulaire résistante qui remplace la membrane plasmique des kératinocytes épidermiques lors de l'étape ultime de leur différenciation) dans l'épithélium cornéen contrôle en utilisant des techniques de RT-qPCR, Western Blot et immunohistologie. J'ai montré que l'épithélium de la cornée exprime un grand nombre des gènes de l'épiderme, mais pas ceux de la cornéodesmosine, la filaggrine, l'hornerine et des kératines 1/10. En parallèle, j'ai recherché les mêmes gènes dans l'épithélium de la cornée de deux cohortes de patients atteints de kératocône. J'ai montré que la kératine 16 est exprimée dans les cornées contrôles et disparaît dans le kératocône. Curieusement, de nombreux gènes codant pour les composants de l'enveloppe cornée sont exprimés dans l'épithélium cornéen comme ceux de l'involucrine, des Small Proline- Rich Proteins (SPRRs) et des protéines de la plaque desmosomale. De plus leur expression diminue dans l'épithélium cornéen kératoconique, avec une localisation subcellulaire différente pour l'involucrine. Pourtant, l'enveloppe cornée n'est pas produite par les cellules épithéliales différenciées de la cornée. Les protéines SPRRs étant aussi impliquées dans la détoxification des espèces réactives de l'oxygène in vitro, nous avons supposé qu'elles jouent ce rôle dans l'épithélium cornéen. Enfin, j'ai complété mes analyses avec l'étude des principaux éléments de la voie NRF2 de protection au stress oxydatif : heme oxygenases 1 et 2, nuclear factor erythroid 2-related factor 2, lysyl oxydase, KEAP1, etc. Plusieurs de ces gènes sont exprimés plus faiblement dans les cornées du kératocône par rapport aux cornées contrôles. Ces résultats ont permis, d'une part, de caractériser le programme de différenciation des cellules épithéliales de la cornée et, d'autre part, de mieux comprendre la physiopathologie du kératocône en proposant l'implication d'un déficit de la réponse au stress oxydatif.