Impact of mast cells in fibromyalgia and low-grade chronic inflammation: Can IL-37 play a role?

Fibromyalgia (FM) is a disease characterized by chronic widespread pain, fatigue, aches, joint stiffness, depression, cognitive dysfunction, and nonrestorative sleep. In FM, neurotransmission and glial activation can occur with an increase in inflammatory cytokines and involvement of mast cells (MCs) in the skin. FM skin biopsies show an increase in the number of MCs, as well as the production of corticotropin releasing hormone and substance P (SP) by the neurons, which in turn activate MCs to release neurosensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low-grade inflammation. In fact, certain proinflammatory cytokines are higher in FM and mediate muscle pain, the mechanism of which is not yet clear. MC-derived tumor necrosis factor (TNF) induces nerve growth factor (NGF) and participates in nerve fiber elongation in skin hypersensitivity. IL-37 is an inhibitor of proinflammatory IL-1 family members, which are generated and released by MCs. The goal of this article is to demonstrate that inflammatory cytokines and MC products play a role in FM and that inflammation may be inhibited by IL-37. Here, we propose IL-37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL-1 family members.

Activation of mast cells mediates inflammatory response in psoriasis: Potential new therapeutic approach with IL-37.

Psoriasis (PS) is an autoimmune disorder characterized by chronic inflammatory skin immune-mediated disease which occurs in 2-4% of the worldwide population. PS is associated with an increased risk of cardiovascular disease and depression, and 30% of PS patients are affected with psoriatic arthritis. PS presents excessive keratinocyte proliferation, abnormal differentiation, and elevated mast cell (MC) number. In PS, there are enhanced type I interferon (IFN), angiogenesis, and over-expression of several proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1 family members generated by several immune cells including MCs. MCs are hematopoietic cells that reside in vascularized tissues, which, upon appropriate activation, release proinflammatory cytokines, an effect worsened by acute stress and PS. In recent years, IL-37 emerged as an anti-inflammatory cytokine which binds to alpha chain of the IL-18 receptor alpha (IL-18Rα) and downregulates MyD88. This effect leads to the inhibition of nuclear factor-κB (NF-κB) and mitogen activation protein kinase, with the suppression of inflammatory response. These observations candidate IL-37 as a potential new therapeutic cytokine for inflammatory disorders including PS.

Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration.

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.

Inflammaging: should this term be suitable for age related macular degeneration too?

INTRODUCTION: Inflammaging is a phenomenon triggered by the conjunction of chronic repetitive and subclinical inflammation from external aggressors and internal inflammatory mechanisms due to the progressive degradation of systems such as the mitochondrial function. Age-related macular degeneration is the leading cause of blindness and visual impairment in patients older than 60 years in developed countries. DISCUSSION: Remarkable correlations have been documented between common or rare immunological/inflammatory gene polymorphisms and AMD, unequivocally indicating the involvement of inflammation and immune-mediated processes (complement activation) in the pathogenesis of this disease. CONCLUSION: Altogether these factors also drive this pathologic condition under the general heading of "Inflammaging".

About Chlamydia trachomatis. Reply to Garcia-Teillard et al. Trachoma and the Importance of Sexual Infective Route in Developed Countries. Comment on "Gallenga et al. Why the SAFE-S Strategy for Trachoma? Are Musca sorbens or Scatophaga stercoraria Really the Culprit?-A Brief Historical Review from an Italian Point of View. Pathogens 2023, 12, 1419".

The confirmatory comment of Garcia-Teillard et al [...].

Short term effects of extremely low irradiance photobiomodulation on retinal function, in age related macular degeneration.

BACKGROUND: recently much studies evidenced the potential role of photo-biomodulation (PBM) in patients affected by Age-related Macular Degeneration (AMD). We designed a new wearable device for self-medication that employs the same broadband red light described in literature, but with extremely low irradiance. AIM: to demonstrate the safety and effectiveness of low-fluence light stimulations emitted by a LED source with appropriate wavelengths through our new device in improving short-term visual function in patients affected by severe non neovascular AMD. MATERIALS AND METHODS: we prospectively enrolled patients affected by severe non-neovascular AMD with a relative sparing of the foveal region. All the patients were randomly assigned in placebo or in treatment group. The treatment consisted of 10 sessions of 10-min each, using the new device comprised of micro-LEDs that emitted light onto an amorphous support assembled within Metallic eyeglasses. The placebo group blindly underwent the same number of PBM sessions with the micro-LED turned off. Before and after each placebo/treatment sessions all the patients received: optical coherence tomography (OCT), Best-Corrected Visual Acuity (BCVA) and Microperimetry (MP). RESULTS: no significant differences in the anatomical parameters were observed in the two groups. The MP mean sensitivity and the central visual function both far and near significantly improved in the treated group (respectively p < 0.001, p < 0.001). CONCLUSIONS: our pivotal demonstrated that the LED PBM delivered through our new device is a safe and effective tool for improving short-term visual function in patients affected by severe non-neovascular AMD.

Macrophage Activation in Follicular Conjunctivitis during the COVID-19 Pandemic.

Among the symptoms of SARS-CoV-2, follicular conjunctivitis has become relevant. The conjunctiva acts as an open lymph node, reacting to the viral antigen that binds the epithelial cells, forming follicles of B cells with activated T cells and NK cells on its surface, which, in turn, talk to monocyte-derived inflammatory infected macrophages. Here, the NLRP3 inflammasome is a major driver in releasing pro-inflammatory factors such as IL-6 and caspase-1, leading to follicular conjunctivitis and bulbar congestion, even as isolated signs in the 'asymptomatic' patient.

Why the SAFE-S Strategy for Trachoma? Are Musca sorbens or Scatophaga stercoraria Really the Culprit?-A Brief Historical Review from an Italian Point of View.

The biological history of Chlamydia trachomatis is intertwined with the evolution of the man. Infecting Elemental Bodies (EBs), having penetrated mucosal epithelial cells, wrap themselves in a cloak (ĸλαµÎ¹ς) of glycogen that ensures their obligatory intracellular survival and protects this differentiation into Reticulate Bodies (RBs) that feed on cellular ATP. Multiple chemokines and cytokines are involved under the direction of IL-6 in the florid phase and IL-17A in the scar phase. The WHO has successfully identified the SAFE strategy against trachoma (Surgery, Antibiotics, Facial cleansing, Environment) as the blueprint to eliminate the disease by 2020. Recently, interest has been increasingly focused on changing sexual attitudes in different areas of the world, leaving Musca sorbens, Scatophaga stercoraria, and stepsisters fairly blameless, but extolling the role of Chlamydia trachomatis in apparently "sterile" chronic prostatitis or conjunctivitis or, less frequently, in oropharyngitis and proctitis. The addition of an S (SAFE-S) standing for "sexual behavior" was then proposed to also attract the interest and attention not only of Ophthalmologists and Obstetricians/Gynecologists, Urologists/Andrologists, and the School Authorities for information on the prevention of sexually transmitted diseases, but also of Social Physicians and Pediatricians. This means that sexually transmitted infections should be screened in asymptomatic patients with risky sexual behavior or sexual contact with people diagnosed with a transmitted infection.

Genetic Basis and Molecular Mechanisms of Uveal Melanoma Metastasis: A Focus on Prognosis.

Uveal melanoma (UM) is the most frequently found primary intraocular tumor, although it accounts for only 5% of all melanomas. Despite novel systemic therapies, patient survival has remained poor. Indeed, almost half of UM patients develop metastases from micro-metastases which were undetectable at diagnosis. Genetic analysis is crucial for metastatic risk prediction, as well as for patient management and follow-up. Several prognostic parameters have been explored, including tumor location, basal dimension and thickness, histopathologic cell type, vascular mimicry patterns, and infiltrating lymphocytes. Herein, the Authors review the available literature concerning cytogenetic prognostic markers and biochemical pathways correlated to UM metastasis development.

Advanced Molecular and Immunological Diagnostic Methods to Detect SARS-CoV-2 Infection.

COVID-19 emerged in late 2019 in China and quickly spread across the globe, causing over 521 million cases of infection and 6.26 million deaths to date. After 2 years, numerous advances have been made. First of all, the preventive vaccine, which has been implemented in record time, is effective in more than 95% of cases. Additionally, in the diagnostic field, there are numerous molecular and antigenic diagnostic kits that are equipped with high sensitivity and specificity. Real Time-PCR-based assays for the detection of viral RNA are currently considered the gold-standard method for SARS-CoV-2 diagnosis and can be used efficiently on pooled nasopharyngeal, or oropharyngeal samples for widespread screening. Moreover, additional, and more advanced molecular methods such as droplet-digital PCR (ddPCR), clustered regularly interspaced short palindromic repeats (CRISPR) and next-generation sequencing (NGS), are currently under development to detect the SARS-CoV-2 RNA. However, as the number of subjects infected with SARS-CoV-2 continuously increases globally, health care systems are being placed under increased stress. Thus, the clinical laboratory plays an important role, helping to select especially asymptomatic individuals who are actively carrying the live replicating virus, with fast and non-invasive molecular technologies. Recent diagnostic strategies, other than molecular methods, have been adopted to either detect viral antigens, i.e., antigen-based immunoassays, or human anti-SARS-CoV-2 antibodies, i.e., antibody-based immunoassays, in nasal or oropharyngeal swabs, as well as in blood or saliva samples. However, the role of mucosal sIgAs, which are essential in the control of viruses entering the body through mucosal surfaces, remains to be elucidated, and in particular the role of the immune response in counteracting SARS-CoV-2 infection, primarily at the site(s) of virus entry that appears to be promising.

Virtual learning solutions in COVID-19 era: University Italian Ophthalmology department perspective.

INTRODUCTION: Few months after the COVID-19 pandemic burst, many aspects of the human life, including education, dramatically changed. Because of the lockdown measures taken to limit the virus spread in Italy, in-person teaching and learning have been interrupted in all health care disciplines and readapted in virtual formulae. METHODS: As academic ophthalmology departments, we had to maintain the educational needs of medical and orthoptic students, internships, surgical training of residents, as well as to cover the scientific update of health care personnel (HCPs), and the continuation of research and academic activities. To assure these needs we ideated an educational strategy and a team, which was then translated on a multichannel virtual platform created with Microsoft Teams. RESULTS: In this platform there were 21 channels organized in a public view mode, open to all Team members, or in private view mode to separate non-permanent HCPs, internships, residents, and students' tasks, from permanent HCPs tasks. Virtual channels were dedicated to provide theoretical lessons, clinical cases, surgical video, internal meetings and webinar, to offer news from scientific societies, requests of appointments from biomedical companies, links with ophthalmological websites, to move forward research projects, to participate at institutional academic duties, and to obtain feedbacks from users. Residents continued their training on surgery using a surgical simulator, after consulting an agenda uploaded into the dedicated virtual channel. CONCLUSION: These positive initial results should represent a boost to rapidly proceed with the development of even more versatile virtual learning solutions, given that the forecasts for the duration of the COVID-19 pandemic are not encouraging.

Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor's daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.

Visual Performance and Quality of Life after Femtosecond Laser-Assisted Cataract Surgery with Trifocal IOLs Implantation.

PURPOSE: To assess visual performance and quality of life after implantation of diffractive trifocal IOLs with enhanced depth of focus (Acriva Reviol Tri-ED) compared to monofocal IOLs. SETTING: Ophthalmology Clinic, Department of Medicine and Science of Ageing, University "G. d'Annunzio" Chieti-Pescara, Italy. DESIGN: Prospective clinical study. METHODS: This study comprised 36 eyes of 18 patients with senile cataract candidates for phacoemulsification and implantation of the Acriva Reviol Tri-ED (Group 1-18 eyes) and the AcrySof IQ Monofocal IOL SN60WF (Group 2-18 eyes). The main outcome measures, over a 6-month follow-up period, were uncorrected and corrected visual acuity at different distances (40, 60 cm and 4 m), defocus curve, contrast sensitivity and wavefront error. Patient satisfaction was evaluated by means of the NEI-RQL-42 questionnaire. RESULTS: At 180 days postoperatively, the difference of the UCDVA and CDVA between the groups was not statistically significant (p = 0.888 and p = 0.843, respectively). The difference between the groups was statistically significant for UCIVA (p = 0.019) and UCNVA (p = 0.036). The mean values of contrast sensitivity under photopic and mesopic conditions were not significantly different between the groups. The RMS of spherical aberration was significantly lower in Group 1 compared to Group 2. The NEI-RQL-42 questionnaire showed statistically significant differences between the groups for the dependence on correction (p < 0.001). CONCLUSIONS: The diffractive trifocal IOL with enhanced depth of focus Acriva Reviol Tri-ED was effective in improving functional capacity for intermediate and near vision compared to monofocal IOLs and provided a good quality of vision due to a significant reduction in spherical aberration.

Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37.

Brain microglia cells are responsible for recognizing foreign bodies and act by activating other immune cells. Microglia react against infectious agents that cross the blood-brain barrier and release pro-inflammatory cytokines including interleukin (IL)-1ß, IL-33 and tumor necrosis factor (TNF). Mast cells (MCs) are immune cells also found in the brain meninges, in the perivascular spaces where they create a protective barrier and release pro-inflammatory compounds, such as IL-1ß, IL-33 and TNF. IL-1ß binds to the IL-1R1 receptor and activates a cascade of events that leads to the production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activation of the immune system. IL-33 is a member of the IL-1 family expressed by several immune cells including microglia and MCs and is involved in innate and adaptive immunity. IL-33 is a pleiotropic cytokine which binds the receptor ST2 derived from TLR/IL-1R super family and is released after cellular damage (also called "alarmin"). These cytokines are responsible for a number of brain inflammatory disorders. Activated IL-1ß in the brain stimulates microglia, MCs, and perivascular endothelial cells, mediating various inflammatory brain diseases. IL-37 also belongs to the IL-1 family and has the capacity to suppress IL-1ß with an anti-inflammatory property. IL-37 deficiency could activate and enhance myeloid differentiation (MyD88) and p38-dependent protein-activated mitogenic kinase (MAPK) with an increase in IL-1ß and IL-33 exacerbating neurological pathologies. In this article we report for the first time that microglia communicate and collaborate with MCs to produce pro-inflammatory cytokines that can be suppressed by IL-37 having a therapeutic potentiality.

New Insights into Molecular Oncogenesis and Therapy of Uveal Melanoma.

Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep process of oncogenesis, whereas novel therapeutic approaches gave significant results in the clinical applications. Uveal melanoma-affected patients greatly benefited from recent advances of the research in this eye cancer. Tumour biology, genetics, epigenetics and immunology contributed significantly in elucidating the role of different genes and related pathways during uveal melanoma onset/progression and UM treatments. Indeed, these investigations allowed identification of new target genes and to develop new therapeutic strategies/compounds to cure this aggressive melanoma of the eye. Unfortunately, the advances reported in the treatment of cutaneous melanoma have not produced analogous benefits in metastatic uveal melanoma. Nowadays, no systemic adjuvant therapy has been shown to improve overall survival or reduce the risk of metastasis. However, the increasing knowledge of this disease, and the encouraging results seen in clinical trials, offer promise for future effective therapies. Herein, different pathways/genes involved in uveal melanoma onset/progression were taken into consideration, together with novel therapeutic approaches.

Progression in migraine: Role of mast cells and pro-inflammatory and anti-inflammatory cytokines.

Migraine is a common painful neurovascular disorder usually associated with several symptoms, such as photophobia, phonophobia, nausea, vomiting and inflammation, and involves immune cells. Mast cells (MCs) are immune cells derived from hematopoietic pluripotent stem cells which migrate and mature close to epithelial, blood vessels, and nerves. In almost all vascularized tissues there are MCs that produce, contain and release biologically active products including cytokines, arachidonic acid compounds, and proteases. In addition, MCs participate in innate and adaptive immune responses. Innate responses in the central nervous system (CNS) occur during neuroinflammatory phenomena, including migraine. Antigens found in the environment have a crucial role in inflammatory response, causing a broad range of diseases including migraine. They can be recognized by several innate immune cells, such as macrophages, microglia, dendritic cells and MCs, which can be activated trough Toll-like receptor (TLR) signaling. MCs reside close to primary nociceptive neurons, associate with nerves, and are capable of triggering local inflammation. MCs are involved in the pathophysiology of various tissues and organs, especially where there is an increase of angiogenesis. Activated MCs release preformed mediators include histamine, heparin, proteases (tryptase, chimase), hydrolases, cathepsin, carboxypeptidases, and peroxidase, and they also generate pro-inflammatory cytokines/chemokines. In addition, activated macrophages, microglia and MCs in the CNS release pro-inflammatory cytokines which provoke an increase of arachidonic acid product levels and lead to migraine and other neurological manifestations including fatigue, nausea, headaches and brain fog. Innate immunity and pro-inflammatory interleukin (IL)-1 cytokine family members can be inhibited by IL-37, a relatively new member of the IL-1 family. In this article, we report that some pro-inflammatory cytokines inducing migraine may be inhibited by IL-37, a natural suppressor of inflammation, and innate and acquired immunity.

New insight into systemic mastocytosis mediated by cytokines IL-1ß and IL-33: Potential inhibitory effect of IL-37.

Systemic mastocytosis in various forms is characterized by mast cell (MC) infiltration of the bone marrow and other internal organs. The most common form is the indolent one with life expectancy similar to the normal population, while the systemic aggressive myeloproliferative type presents serious damage to various organs and is associated with mature and immature atypical mast cells. In systemic mastocytosis patients, MCs could be activated with consequent severe anaphylactic reactions, along with other symptoms. MCs, which are reactive to a variety of external factors such as allergens or other inflammatory or physical stimuli, derive from pluripotent cellular progenitor CD34+ which leaves the bone marrow as CD34+/CD17+ for implantation in the tissues where they reach maturation. MCs participate in the innate and adaptive immune system where they play a role in host defense. Activation of MCs occurs through the binding of IgE to FcεRI receptor, and initiates the phosphorylation and activation of the p38 tyrosine MAP kinase. After various reactions there is a subsequent translation and generation of pro-inflammatory cytokines which are strongly linked to allergic inflammation and mastocytosis. Human cytokine interleukin-37 (IL-37), a unique IL-1ß family member, has strong protective and anti-inflammatory properties, influencing cellular metabolism. We investigated the effect of IL-37 on inflammation in mastocytosis and report that the hematopoietic expression of IL-37 can reduce the inflammatory state in this disease. IL-37 limits excessive inflammation, which suggests that IL-37 may be beneficial to the metabolic and inflammatory process and is a candidate as a potential new therapeutic agent.

Impact of methylenetetrahydrofolate reductase C677T polymorphism on the efficacy of photodynamic therapy in patients with neovascular age-related macular degeneration.

The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12-0.32] and 0.09 [95% CI, 0.04-0.21] (P < 0.001), and odd ratios of 0.24 [95% CI, 0.15-0.39] and 0.03 [95% CI, 0.01-0.11] (P < 0.001). These pharmacogenetic findings indicate a rational basis to optimize the future clinical application of PDT-V during the combined treatments of AMD-related CNV, highlighting the role of thrombophilia to be aware of the efficacy profile of photodynamic therapy.