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Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured by interferon-γ production) and Th2-skewed (measured by interleukin-4 production) developed comparable ocular surface inflammation and conjunctival CD4+ T cell recruitment but no appreciable corneal epithelial changes upon repeated local antigenic challenge. Th1-skewed mice showed decreased corneal mechanical sensitivity and altered corneal nerve morphology (signs of corneal neuropathy) upon antigenic challenge. However, Th2-skewed mice also developed milder corneal neuropathy immediately after immunization and independently of ocular challenge, suggestive of adjuvant-induced neurotoxicity. All these findings were confirmed in wild-type mice. To circumvent unwanted neurotoxicity, CD4+ T cells from immunized mice were adoptively transferred to T cell-deficient mice. In this setup, only Th1-transferred mice developed corneal neuropathy upon antigenic challenge. To further delineate the contribution of each profile, CD4+ T cells were polarized in vitro to either Th1, Th2, or Th17 cells and transferred to T cell-deficient mice. Upon local antigenic challenge, all groups had commensurate conjunctival CD4+ T cell recruitment and macroscopic ocular inflammation. However, none of the groups developed corneal epithelial changes and only Th1-transferred mice showed signs of corneal neuropathy. Altogether, the data show that corneal nerves, as opposed to corneal epithelial cells, are sensitive to immune-driven damage mediated by Th1 CD4+ T cells in the absence of other pathogenic factors. These findings have potential therapeutic implications for ocular surface disorders.

Corneal neurosensory abnormalities cause pain and discomfort in ocular surface disease, yet their pathophysiology is poorly understood. Here we show that in a mouse dry eye model, the ocular (over)activation of transient receptor potential vanilloid 1 (TRPV1) channels in response to tear deficiency and tissue damage promotes neuroinflammatory gene expression and macrophage reactivity in the trigeminal ganglion, where the cornea-innervating sensory neurons are located. This is accompanied by ocular surface macrophage activation, impaired corneal sensitivity to mechanical and non-TRPV1-mediated chemical stimulation, reduced corneal nerve density and the sensitization of ocular TRPV1 channels, thus establishing a vicious neurosensory cycle. Isolated corneal TRPV1 activation without ocular desiccation recapitulates macrophage reactivity, corneal nerve degeneration and trigeminal neuroinflammation, whereas the ocular substance P blockade reverts most of the TRPV1-driven corneal neurosensory abnormalities. Our study identifies a corneal–trigeminal axis that facilitates corneal neurosensory dysfunction and suggests potential targets for the treatment of ocular surface disease-associated corneal neuropathy. Neuroinflammation links corneal sensitivity and tear deficiency The cornea needs to stay healthy for good vision. It has many nerve fibers that help protect the eye by sensing changes and triggering immune responses. However, problems with these nerves, known as corneal neuropathy, are common in conditions such as dry eye disease (DED), where tears are insufficient or poor in quality. Researchers explored how DED affects corneal nerves and the role of a protein called TRPV1. The researchers used mice to study DED by removing a tear gland from one eye, creating a model of unilateral (one-sided) DED. They found that TRPV1 is crucial in spreading inflammation and nerve damage from the affected eye to the other eye. They also discovered that blocking a substance called substance P, which is released during nerve activation, can reduce nerve damage. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Background and Objectives: To evaluate whether regional climatic factors, particularly relative humidity (RH) and temperature, are associated with geographic variation in dry eye disease (DED) prevalence in Argentina. Materials and Methods: A secondary analysis of a nationwide voluntary online cross-sectional survey of DED in Argentina (April 2022; non-probability sample; n = 10,812) was performed. Participants were assigned to one of five standard geopolitical regions. DED prevalence (%) was estimated at regional levels. Monthly mean, maximum, and minimum temperature and RH for April 2022 were obtained from the National Meteorological Service; for each province/region, data corresponded to the principal synoptic station in the provincial capital. Because the survey and climate data were restricted to April, seasonal effects could not be evaluated. Region-level analyses of climate–DED patterns were prespecified as exploratory and descriptive given the small number of regional units (n = 5). Weighted descriptive models were used to compare RH–DED patterns while accounting for regional age and sex distributions. Results: Regional DED prevalence ranged from 37.7% (Northwest) to 49.8% (Cuyo). RH showed a clear inverse pattern with regional DED prevalence, whereas temperature showed no consistent relationship. Weighted descriptive models showed a similar qualitative RH–DED pattern, although residual confounding cannot be excluded. Conclusions: DED prevalence in Argentina shows geographic variability and a descriptive inverse pattern with ambient RH. These ecological findings are hypothesis-generating and must be interpreted cautiously due to sampling bias. Future seasonal, longitudinal, or individual-level studies are needed to confirm and quantify these preliminary signals.

Immunological interdependence between the two eyes has been reported for the cornea and the retina but not for the ocular mucosal surface. Intriguingly, patients frequently report ocular surface-related symptoms in the other eye after unilateral ocular surgery. Here we show how unilateral eye injuries in mice affect the mucosal immune response of the opposite ocular surface. We report that, despite the lack of lymphatic cross-drainage, a neurogenic inflammatory reflex in the contralateral conjunctiva is sufficient to increase, first, epithelial nuclear factor kappa B signaling, then, dendritic cell maturation, and finally, expansion of effector, instead of regulatory, T cells in the draining lymph node, leading to disrupted ocular mucosal tolerance. We also show that damage to ocular surface nerves is required. Using pharmacological inhibitors and agonists, we identified transient receptor potential vanilloid 1 (TRPV1) channel as the receptor sensing tissue damage in the injured eye and substance P released in the opposite ocular surface as the effector of the sympathetic response. Finally, blocking either step prevented subsequent ocular allergic reactions in the opposite eye in a unilateral corneal alkali burn model. This study demonstrates that both ocular surfaces are immunologically linked and suggests potential therapeutic targets for intervention.

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1β) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1β) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1β is processed by caspase-1 upon inflammasome activation. Here we employed neutrophils from both healthy donors and patients with a gain-of-function (GOF) NLRP3- mutation to dissect IL-1β processing in these cells. We found that although caspase-1 is required for IL-1β secretion, it undergoes rapid inactivation, and instead, neutrophil serine proteases play a key role in pro-IL-1β processing. Our findings bring to light distinctive features of the regulation of caspase-1 activity in human neutrophils and reveal new molecular mechanisms that control human neutrophil IL-1β secretion.

Purpose. To thoroughly analyze corneal deformation responses curves obtained by Ocular Response Analyzer (ORA) testing in order to improve subclinical keratoconus detection. Methods. Observational case series of 87 control and 73 subclinical keratoconus eyes. Examination included corneal topography, tomography, and biomechanical testing with ORA. Factor analysis, logistic regression, and receiver operating characteristic curves were used to extract combinations of 45 corneal waveform descriptors. Main outcome measures were corneal-thickness-corrected corneal resistance factor (ccCRF), combinations of corneal descriptors, and their diagnostic performance. Results. Thirty-seven descriptors differed significantly in means between groups, and among them ccCRF afforded the highest individual diagnostic performance. Factor analysis identified first- and second-peak related descriptors as the most variable one. However, conventional biomechanical descriptors corneal resistance factor and hysteresis differed the most between control and keratoconic eyes. A combination of three factors including several corneal descriptors did not show better diagnostic performance than a combination of conventional indices. Conclusion. Multivariate analysis of ORA signals did not surpass simpler models in subclinical keratoconus detection, and there is considerable overlap between normal and ectatic eyes irrespective of the analysis model. Conventional biomechanical indices seem to already provide the best performance when appropriately considered.

To evaluate intereye corneal asymmetry in Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany) indices as a diagnostic method between normal patients and patients with keratoconus. A retrospective, observational case series of 177 healthy, 44 indeterminate, and 121 patients with keratoconus classified by Pentacam ectasia detection indices, randomized to analysis and validation datasets. Intereye asymmetry in 20 Scheimpflug tomography corneal descriptors was calculated and compared to develop diagnostic models. Intereye asymmetry was not correlated with anisometropia in healthy controls but was correlated with the ectasia grade of the worse eye in patients with keratoconus. Patients with keratoconus had significantly greater intereye asymmetry in all descriptors except for relational thickness indices. Intereye asymmetry in front elevation at the thinnest corneal location afforded the single highest diagnostic performance (71% sensitivity and 85% specificity), whereas the best multivariate model combining intereye asymmetry in anterior and posterior keratometry, corneal thickness, and front and back elevation at the thinnest point provided 65% sensitivity and 97% specificity. Multivariate models upheld their performance in the validation dataset. Most (more than 90%) indeterminate patients, according to conventional Pentacam analysis, showed within-normal-range corneal asymmetry. Healthy corneas are markedly symmetric irrespective of anisometropia, but corneal asymmetry analysis does not provide sufficient sensitivity to be used alone for detecting keratoconus. However, its remarkable specificity suggests that it could be used combined with conventional single cornea Pentacam analysis to reduce the false-positive rate or in dubious cases.

The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells, which differentiate from CD14 + monocytes and have been identified as tumor-associated macrophages (TAMs). The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro , but only recently has been investigated in in vivo models. We here discuss how the cellular and molecular interactions that physiologically occur between B cells and macrophages can be subverted in chronic B lymphoid malignancies. Clinical approaches for the therapeutic targeting of TAMs are under evaluation. Promising strategies, along with a direct impact on the malignant cells, affect crucial pathways involved in the interaction of leukemic cells with TAMs. As an example, ibrutinib reduces CLL cell chemoattraction by inhibiting macrophage secretion of CXCL13. Lenalidomide and trabectedin prevent TAM recruitment mainly through CCL2 blockade. Most advanced strategies aim at depleting macrophages by targeting the CSF1/CSF1R pathway, which is fundamental for TAM survival. Of note, CSF1 transcripts are significantly more abundant in progressive CLL patients when compared with stable CLL and the frequency of CSF1R + TAMs correlates with poor survival in hematological malignancies. The successful combination of CSF1R inhibition with currently available agents targeting malignant cells might represent the next therapeutic frontier in CLL. Conceivably these approaches may become applicable to numerous chronic B lymphoid malignancies.

Background To evaluate the prevalence of dry eye disease (DED) and its associated risk factors in a sample of the Argentine population. Methods A prospective cross-sectional population-based study was conducted in Argentina during April 2022 through an anonymous electronic survey that included participants aged 12 years old or older. The prevalence of symptomatic DED was evaluated using the Women's Health Study (WHS) dry eye questionnaire. In addition, a list of conditions possibly related to dry eye were evaluated in the questionnaire to assess the prevalence of potential risk factors. A multivariate logistic regression analysis was performed. Results 10,812 subjects (mean age 44.1 ± 13.9, range 12–94 years old) answered the survey. Overall prevalence of DED was 42.1%. DED prevalence in women was 45.1% (3848 out of 8525) and in men was 30.8% (704 out of 2287). Risk factors were female sex (OR 2.78; p < 0.001), age > 60 years (OR 2.92), rheumatologic disease (OR 2.80, CI 1.62–3.13), use of digital screens for more than 6 h per day (OR 2.62; CI 1.43–2.80), glaucoma topical treatment (OR 2.05; CI 1.20–3.01), dysthyroidism (2.03; CI 1.48–2.51), and sleeping less than 7 h per day (OR 1.92; CI 1.30–2.51). Conclusion DED was found to be a prevalent condition among Argentine participants, the main risk factors were determined by sex, age, and especially those related to lifestyle in South America.

Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in glaucoma, retina, and neuroscience. Recently, neurotrophin analogs with panTrk activity and TrkC selectivity have shown promise as novel drugs for treating dry eye disease. In this review, we discuss the biology of the neurotrophin family, its role in corneal homeostasis, and its use in treating ocular surface diseases. There is an unmet need to investigate parenteral neurotrophins and its analogs that activate TrkB and TrkC selectively.