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![The central corneal stromal opacities in the right and left eye of 3 new patients with keratitis fugax hereditaria. (A and B) Patient 15-01 (56 years of age, best corrected visual acuity [BCVA] 20/40 OU). (C and D) Patient 15-04 (68 years of age, BCVA 20/32 OD, 20/40 OS). (E and F) Patient 17-01 (46 years of age, BCVA 20/20 OD, 20/16 OS).](publication/339203447/figure/fig1/AS:871218735501313@1584726141653/The-central-corneal-stromal-opacities-in-the-right-and-left-eye-of-3-new-patients-with.png)
The central corneal stromal opacities in the right and left eye of 3 new patients with keratitis fugax hereditaria. (A and B) Patient 15-01 (56 years of age, best corrected visual acuity [BCVA] 20/40 OU). (C and D) Patient 15-04 (68 years of age, BCVA 20/32 OD, 20/40 OS). (E and F) Patient 17-01 (46 years of age, BCVA 20/20 OD, 20/16 OS).
Source publication
Purpose:
To apply in vivo corneal confocal microscopy (IVCM) to study the pathogenesis of keratitis (keratoendotheliitis) fugax hereditaria, an autosomal dominant cryopyrin-associated periodic keratitis, associated with the c.61G>C pathogenic variant in the NLRP3 gene, in its acute and chronic phase, and to report histopathological findings after...
Citations
... Previous studies have also documented the presence of such cell types in the corneal stroma of patients with keratitis fugax hereditaria, an autosomal dominant cryopyrin-associated periodic keratitis. During acute episodes, hyperreflective cellular structures indicative of inflammatory cells were observed transiently within the anterior to middle layers of the corneal stroma [15]. Instances of "microdots" were reported in the central cornea, with their prevalence increasing from preoperative (50%) to postoperative (90.9%) stages in patients undergoing femtosecond laser-assisted keratoplasty [16]. ...
... Using IVCM, NLS has been described in a variety of settings of corneal diseases, including femtosecond laserassisted keratoplasty [15,16,19], generally interpreted as activated keratocytes [42]. In our study these structures were seen in all groups, indicating no direct impact on corneal fibrosis, at least not clinically evident. ...
Purpose
This study investigates immune cell (ICs) infiltration in advanced keratoconus patients undergoing autologous adipose-derived adult stem cell (ADASC) therapy with recellularized human donor corneal laminas (CL).
Methods
A prospective clinical trial included fourteen patients divided into three groups: G-1, ADASCs; G-2, decellularized CL (dCL); and G-3, dCL recellularized with ADASCs (ADASCs-rCL). Infiltrated ICs were assessed using in vivo confocal microscopy (IVCM) at 1,3,6, and12 months post-transplant.
Results
Infiltrated ICs, encompassing granulocytes and agranulocytes, were observed across all groups, categorized by luminosity, structure, and area. Stromal ICs infiltration ranged from 1.19% to 6.62%, with a consistent increase in group-related cell density ( F = 10.68, P < .0001), independent of post-op time ( F = 0.77, P = 0.511); the most substantial variations were observed in G-3 at 6 and 12 months (2.0 and 1.87-fold, respectively). Similarly, significant size increases were more group-dependent ( F = 5.76, P < .005) rather than time-dependent ( F = 2.84, P < .05); G-3 exhibited significant increases at 6 and 12 months (3.70-fold and 2.52-fold, respectively). A lamina-induced shift in IC size occurred ( F = 110.23, P < .0001), primarily with 50–100 μm ² sizes and up to larger cells > 300μm ² , presumably macrophages, notably in G-3, indicating a potential role in tissue repair and remodeling, explaining reductions in cells remnants < 50μm ² .
Conclusions
ADASCs-rCL therapy may lead to increased IC infiltration compared to ADASCs alone, impacting cell distribution and size due to the presence of the lamina. The findings reveal intricate immune patterns shaped by the corneal microenvironment and highlight the importance of understanding immune responses for the development of future therapeutic strategies.
... [2][3][4] The attacks usually last for 1-3 days, leaving blurry vision for several weeks and the corneal stroma is invaded by inflammatory cells during the acute attacks. 2 5 Repeated attacks result in bilateral horizontally oval central stromal corneal opacities in approximately half of the patients with KFH, some of whom experience permanently reduced vision. 5 We identified a heterozygous pathogenic variant c.61G>C, p.(Asp21His) in the NLRP3 gene as the cause of KFH. 2 NLRP3 is a nod-like receptor and a key component of NLRP3 inflammasome. 6 NLRP3 Inflammasome is a protein complex that recognises pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). ...
... 22 23 Histopathological studies suggest deposition of lipids in corneas with permanent opacities in patients with KFH, and clinical confocal microscopy shows needle-shaped elements in corneal stroma. 5 It might be necessary to prevent the recurrent attacks rather than to alleviate them to be able to prevent opacities from developing. ...
... 21 A similar invasion of inflammatory cells into the stroma is observed during the acute attacks in KFH. 5 However, no significant difference in NLRP3 baseline expression was observed between the control and patient-derived ...
Aims
To elucidate the effect of NLRP3 variant c.61G>C on interleukin-1β (IL-1β) secretion in keratitis fugax hereditaria (KFH), a cryopyrin-associated periodic syndrome limited to the eye, and to probe the potential modifying role of prednisolone.
Methods
Peripheral blood mononuclear cells (PBMCs) isolated from whole blood of patients with KFH and healthy controls were grown under steady-state conditions or primed with lipopolysaccharide (LPS) with or without prednisolone, and subsequently activated with ATP. Cell lysates and proteins precipitated from the cell culture media were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. NLRP3, procaspase-1, and IL-1β were visualised by western blotting. The concentration of secreted IL-1β in the culture media was quantified by ELISA.
Results
Following priming of the NLRP3 inflammasome with LPS, a lower threshold for IL-1β secretion was observed in patient-derived PBMCs, compared with healthy controls (median, 124 vs 10 pg/mL, respectively). Interestingly, in PBMCs derived from patients with frequent KFH symptoms, LPS priming alone was able to trigger substantial IL-1β secretion (median, 522 pg/mL), whereas those of patients experiencing occasional KFH attacks showed a subtler release of IL-1β (median, 85 pg/mL). NLRP3 expression was significantly enhanced with LPS stimulation (p=0.03) whereas procaspase-1 expression was not affected. LPS and ATP treated PBMCs from patients with KFH showed significantly diminished IL-1β secretion with prednisolone treatment (p=0.04).
Conclusions
PBMCs from patients with KFH are more prone to secrete IL-1β, confirming the presumption that the c.61G>C is a gain-of-function variant. Furthermore, prednisolone is confirmed as a potent drug to reduce IL-1β secretion in KFH.
... In 1964, Olavi Valle, then a Finnish resident in ophthalmology, described in ten members of one family a recurrent unilateral keratitis that he named keratitis fugax hereditaria (KFH, MIM 148200). 1 The second Finnish family was reported in 1987, whereupon the disease was renamed keratoendotheliitis fugax hereditaria 2 based on misinterpretation of specular endothelial microscopy findings. 3 We recently discovered in 23 showed that endothelial cells were uninvolved. 3,4 Unilateral ocular pain, conjunctival injection, photophobia, and tearing characterize the acute inflammatory attacks of KFH that last for 1 to 3 days and leave a blurry vision for several weeks. ...
... 3 We recently discovered in 23 showed that endothelial cells were uninvolved. 3,4 Unilateral ocular pain, conjunctival injection, photophobia, and tearing characterize the acute inflammatory attacks of KFH that last for 1 to 3 days and leave a blurry vision for several weeks. 1,2,4 Our confocal microscopy suggests influx of leukocytes into the corneal stroma during the attack. ...
... 1,2,4 Our confocal microscopy suggests influx of leukocytes into the corneal stroma during the attack. 3 The attacks begin at the median age of 11 years, and recur 1 to 6 times a year. Repeated attacks result in one half of the patients in bilateral horizontally oval central stromal opacities that can reduce visual acuity. ...
PURPOSE
To chart clinical findings in individuals with keratitis fugax hereditaria (KFH) and geographic distribution of their ancestors.
DESIGN
A prospective cross-sectional study.
METHODS
Setting: Tertiary referral center. Patient population: 84 Finnish patients (55% female) from 25 families with the pathogenic NLRP3 variant c.61G>C. Observation Procedures and Main Outcome Measures: Sanger sequencing, clinical examination, corneal imaging, and a questionnaire regarding symptoms, quality-of-life, treatment, and comorbidities.
RESULTS
The oldest members in each family were born in Ostrobothnia in Western Finland or in Southwestern Finland with historical ties to Sweden. One carrier was asymptomatic. Most (77%) experienced their first attack between 6 and 20 years of age. Three quarters had unilateral attacks 3-5 times annually, primarily triggered by cold wind or air, or stress. Eighty percent reported ocular pain (median, 7 on scale 1-10), conjunctival injection, photophobia, foreign body sensation, and tearing during attacks. Visual blur occurred 75% and 91% during and after the attack, respectively, for 1 day to 2 months (median, 10 days). Forty-seven percent had corneal oval opacities with irregular tomography patterns and mild to moderate decrease (20/60 or better) in best-corrected visual acuity that improved with scleral contact lenses. Except for headache in 40%, systemic symptoms were absent during the attacks.
CONCLUSIONS
Symptoms and signs of KFH are restricted to the anterior segment of the eye, and they vary widely between individuals. We recommend scleral contact lenses as first-line treatment for reduced vision. Allele frequencies suggest that KFH goes unrecognized in Sweden and populations with Scandinavian heritage.
... e highly reflective microdots and needle-shaped structures found in the stromal layers by IVCM had been observed in several different corneal inflammations. It is deduced to correspond to disorganized extracellular material, hyperreflective extracellular matrix, around degenerated collagen fiber bundles associated with deposition of lipid [14]. ...
Purpose. To investigate the effects of pterygium on corneal cell and nerve density in patients with unilateral pterygium using in vivo laser scanning confocal microscopy (LSCM). Methods. In this cross-sectional study, 24 patients with unilateral pterygium who were treated in the Department of Ophthalmology of the Second People’s Hospital of Wuxi City from April 2018 to July 2018 were analyzed. Each eye with pterygium and its fellow eye were imaged by LSCM. The density of basal corneal epithelial cells, anterior stromal cells, posterior stromal cells, dendritic cells, and endothelial cells in pterygium and adjacent clear cornea was measured. In the fellow eyes, the central cornea, nasal cornea, nasal mid-peripheral cornea, and temporal cornea were imaged. The difference in the density of cells and subepithelial nerve fibers in different corneal regions of eyes with pterygium was analyzed. The cell and nerve density of the fellow cornea were also measured to exclude the influencing factors. Results. The density of corneal basal epithelial cells in the central corneas of eyes with pterygium was 6497 ± 1776 cells/mm2, which was higher than that in the area near the head of pterygium (5580 ± 1294 cells/mm2, P
Purpose
The aim of this study was to report a novel heterozygous variant c.1712G>T (p.Gly571Val) in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain–containing 3 gene ( NLRP3 ) in a previously unreported non-Finnish individual with keratitis fugax hereditaria (KFH).
Methods
Ophthalmologic examination of the proband was performed with slit-lamp biomicroscopy and anterior segment optical coherence tomography. Saliva was collected as a source of DNA, after which targeted exome sequencing of candidate genes was performed using a commercially available panel. Identified presumed pathogenic variants were confirmed by Sanger sequencing.
Results
Slit-lamp examination of the 52-year-old female proband revealed peripheral arcus-like degeneration and bilateral central corneal opacification, observed on anterior segment optical coherence tomography to involve the anterior half of the corneal stroma. Examination of the proband's parents revealed clear corneas in each eye. Genetic testing of the proband identified the presence of a novel heterozygous NLRP3 missense mutation (c.1712G>T, p.Gly571Val), which was confirmed by Sanger sequencing. This mutation was absent in the proband's parents.
Conclusions
Although KFH has been reported only in individuals of Finnish descent and only in association with a missense mutation in exon 1 of NLRP3 , we report an individual of non-Finnish descent with KFH associated with a novel heterozygous variant in exon 2 of NLRP3 . Thus, ophthalmologists should be aware of the ethnic and genetic heterogeneity associated with KFH.
The NLRP3 inflammasome is one of the NOD-like receptor family members with the most functional characterization and acts as a key player in innate immune system, participating in several physiological processes including, among others, the modulation of the immune system response and the coordination of host defences. Activation of the inflammasome is a crucial signaling mechanism that promotes both an acute and a chronic inflammatory response, which can accelerate the production of pro-inflammatory cytokines, mainly Interleukin (IL)-1β and IL-18, leading to an exacerbated inflammatory network. Cryopyrin associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder, clinically characterized by cutaneous and systemic, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients, in which an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies. During recent years, two new hereditary NLRP3-related disorders have been described, deafness autosomal dominant 34 (DFN34) and keratitis fugax hereditaria (KFH), with an exclusive cochlear- and anterior eye- restricted autoinflammation, respectively, and caused by mutations in NLRP3 gene, thus expanding the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases. Several crucial mechanisms involved in the control of activation and regulation of the NLRP3 inflammasome have been identified and researchers took advantage of this to develop novel target therapies with a significant improvement of clinical signs and symptoms of NLRP3-associated diseases. This review provides a broad overview of NLRP3 inflammasome biology with particular emphasis on CAPS, whose clinical, genetic, and therapeutic aspects will be explored in depth. The latest evidence on two “new” diseases, DFN34 and KFH, caused by mutations in NLRP3 is also described.
