Trained innate immunity and diseases: Bane with the boon

Emerging research shows that innate immunity can also keep the memory of prior experiences, challenging the long-held notion that immunological memory is only the domain of the adaptive immune cells. However, the absence of immunological memory in innate immune responses has recently been brought into question. Now it is known that after a few transient activations, innate immune cells may acquire immunological memory phenotype, resulting in a stronger response to a subsequent secondary challenge. When exposed to particular microbial and/or inflammatory stimuli, trained innate immunity is characterized by the enhanced non-specific response, which is regulated by substantial metabolic alterations and epigenetic reprogramming. Trained immunity is acquired by two main reprogramming, namely, epigenetic reprogramming and metabolic adaptation/reprogramming. Epigenetic reprogramming causes changes in gene expression and cell physiology, resulting in internal cell signaling and/or accelerated and amplified cytokine release. Metabolic changes due to trained immunity induce accelerated glycolysis and glutaminolysis. As a result, trained immunity can have unfavorable outcomes, such as hyper inflammation and the development of cardiovascular diseases, autoinflammatory diseases, and neuroinflammation. In this review, the current scenario in the area of trained innate immunity, its mechanisms, and its involvement in immunological disorders are briefly outlined.Copyright © 2022

Teledermatology for Common Inflammatory Skin Conditions: The Medicine of the Future?

BACKGROUND: The COVID-19 pandemic period revolutionized daily clinical practice. Several strategies were adopted by clinicians to avoid reducing treatment for diseases without the risk of spreading the infection. Among the adopted strategies, telemedicine played a key role. In this scenario, several tools were used, including e-mails, phone calls, video calls, support groups, and messages. Fortunately, the COVID-19 pandemic period seems to be at an end. However, the use of teledermatology appears to be an excellent strategy for the future as well. Indeed, several patients may benefit from teledermatology. OBJECTIVE: In this manuscript, we aim to investigate the use of telemedicine in the dermatological field to point out how this tool may become the mainstay of future medicine. Only the use of teledermatology with common inflammatory skin conditions have been reported herein. MATERIALS AND METHODS: Investigated manuscripts included metanalyses, reviews, letters to the editor, real-life studies, case series, and reports. Manuscripts were identified, screened, and extracted for relevant data following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. RESULTS: A total of 121 records were identified from the analyzed databases. However, only 110 articles were assessed for eligibility. Finally, 92 articles were selected at the end of the literature research for our review. CONCLUSIONS: Teledermatology should be considered as a viable option for the dermatologist for the future. We believe that the pandemic has strengthened this service, and this will allow for ever better development in the future. Guidelines regarding the use of teledermatology are required as well as additional improvements for the future.

Dantrolene and ryanodine receptors in COVID-19: The daunting task and neglected warden.

Dantrolene (DTN) is a ryanodine receptor (RyR) antagonist that inhibits Ca2+ release from stores in the sarcoplasmic reticulum. DTN is mainly used in the management of malignant hyperthermia. RyRs are highly expressed in immune cells and are involved in different viral infections, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), because Ca2+ is necessary for viral replication, maturation and release. DTN can inhibit the proliferation of SARS-CoV-2, indicating its potential role in reducing entry and pathogenesis of SARS-CoV-2. DTN may increase clearance of SARS-CoV-2 and promote coronavirus disease 2019 (COVID-19) recovery by shortening the period of infection. DTN inhibits N-methyl-D-aspartate (NMDA) mediated platelets aggregations and thrombosis. Therefore, DTN may inhibit thrombosis and coagulopathy in COVID-19 through suppression of platelet NMDA receptors. Moreover, DTN has a neuroprotective effect against SARS-CoV-2 infection-induced brain injury through modulation of NMDA receptors, which are involved in excitotoxicity, neuronal injury and the development of neuropsychiatric disorders. In conclusion, DTN by inhibiting RyRs may attenuate inflammatory disorders in SARS-CoV-2 infection and associated cardio-pulmonary complications. Therefore, DNT could be a promising drug therapy against COVID-19. Preclinical and clinical studies are warranted in this regards.

Medicinal chemistry perspective on cGAS-STING signaling pathway with small molecule inhibitors.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway serves as a pivotal mediator of innate immunity by triggering the secretion of type I interferons and other proinflammatory cytokines. In view of the immune-related diseases caused by abnormal activity of the cGAS-STING signaling pathway, considerable progress in this field has encouraged the discovery of cGAS-STING inhibitors in the past five years. In this review, we will focus on the link between the cGAS-STING signaling pathway and autoimmune and inflammatory disorders, summarize the development and optimization of cGAS-STING signaling pathway inhibitors, discuss the therapeutic effects on inflammatory diseases and propose suggestions and insights for future exploitation.

Immunogenetic perspective of inflammatory disorders

Understanding of the genetic basis underlying inflammatory disorders has progressed in recent years. Contribution of proinflammatory cytokines, human leukocyte antigen (HLA), and non-HLA polymorphisms in the pathogenesis of several autoimmune and immune-mediated inflammatory disorder is critical. HLA plays a central role in disease pathology. Harmful stimuli triggering the signaling mechanisms including nuclear factor-kappa B pathway, Janus kinase-signal transducer and activator of transcription pathway, and mitogen-activated protein kinase pathway results in the release of inflammatory mediators. From acute to chronic inflammation, the etiology of various inflammatory disorders is poorly understood. Inflammatory disorder such as COVID 19 is a devastating havoc to the world. As we reach the end of 2020, >1 million people have succumbed to death worldwide. Disease-manifesting clinical features include mild to severe pneumonia, loss of respiratory function progressing to acute respiratory distress syndrome with occasional multiorgan failure. Cytokine storm, decreased T cell count, and insufficient immune response are conducive issues to COVID 19 pandemic. Varied immune responses to the same antigen across different individuals determine the genetic perspective of disease susceptibility. Through genome-wide association studies, next-generation sequencing and other genetic techniques, several genetic risk loci associated with various inflammatory diseases such as inflammatory bowel disease, psoriasis, sclerosis, and systemic lupus erythematosus (SLE) have been identified. Dysregulated inflammatory pathways, gene mutation, or elevated cytokine level may lead to the disease progression. However, the production of autoantibodies against the nuclear antigens is a hallmark of diseases like SLE and rheumatoid arthritis. Moreover, environmental factors like smoking also increase the risk of inflammatory disorders. Understanding the functional aspects of casual genetic factors underlying the disease pathogenesis greatly facilitates the ability to identify the therapeutic targets relevant to disease. The current chapter deals with the idea of genetic perspective associated with various inflammatory disorders and their potential therapeutic targets along with the factors contributing to disease susceptibility. © 2022 Elsevier Inc. All rights reserved.

Eosinophilic Ascites: An Infrequent Presentation of Eosinophilic Gastroenteritis.

Eosinophilic gastroenteritis (EGE) is an unusual and benign inflammatory disorder that mainly affects the digestive tract. Its main symptoms are cramp-like abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, and weight loss. Laboratory results show peripheral eosinophilia. This disease generally affects patients with a personal history of atopy and drug or food intolerance. The etiology remains unknown, the diagnosis is challenging, and the treatment depends on the severity of the disease and can range from supportive therapy to corticosteroid therapy. We report a case of a 24-year-old female known to have a history of iron deficiency anemia who was brought to the emergency department with an intense colicky abdominal pain, fatigue, diarrhea, and vomit right after a mild coronavirus disease 2019 (COVID-19) infection. The clinical investigation revealed moderate ascites identified in abdominal computed tomography (CT) scan, peripheral blood eosinophil count, and elevation of inflammatory parameters. An ultrasound-guided diagnostic paracentesis was performed, showing ascitic fluid with a clear predominance of eosinophils (57%). To confirm the diagnosis of EGE, an upper digestive endoscopy (UDE) was performed. The biopsies of the esophagus and gastric body revealed polymorphonuclear eosinophils and colonic mucosal biopsies revealed eosinophils (20 eosinophils per 10 fields). After reviewing the clinical history, we concluded that the patient was taking iron supplements due to her iron deficiency anemia, whose onset coincided with the symptoms presented. Exploring the clinical history a little more, the patient mentioned that in the past, she already had some intolerance to oral iron supplements, manifested by gastrointestinal symptoms, although milder. Approximately three weeks after suspending the supplements, we have seen an analytical improvement that was accompanied by clinical improvement. The patient was discharged with the resolution of abdominal pain.

The Prospective Effect of Allopurinol on the Oxidative Stress Index and Endothelial Dysfunction in Covid-19.

SARS-CoV-2 by the direct cytopathic effect or indirectly through the propagation of pro-inflammatory cytokines could cause endothelial dysfunction (ED) and oxidative stress (OS). It has been reported that OS is triggered by various types of viral infections, including SARS-CoV-2. Into the bargain, allopurinol is regarded as a potent antioxidant that acts through inhibition of xanthine oxidase (XO), which is an essential enzyme of purine metabolism. Herein, the present study aimed to find the potential protective effects of allopurinol on the biomarkers of OS and ED in patients with severe Covid-19. This single-center cohort study recruited 39 patients with mild-moderate Covid-19 compared with 41 patients with severe Covid-19. Nineteen patients with severe Covid-19 were on the allopurinol treatment because of underlying chronic gout 3 years ago compared with 22 Covid-19 patients not on this treatment. The recruited patients were allocated into three groups: group I, mild-moderate Covid-19 on the standard therapy (n = 39); group II, severe Covid-19 patients on the standard therapy only (n = 22); and group III, severe Covid-19 patients on the standard therapy plus allopurinol (n = 19). The duration of the study was 3 weeks from the time of hospitalization till the time of recovery. In addition, inflammatory biomarkers (D-dimer, LDH, ferritin, CRP, procalcitonin), neutrophil-lymphocyte ratio (NLR), endothelin-1 (ET-1), uric acid and oxidative stress index (OSI), CT scan score, and clinical score were evaluated at the time of admission and discharge regarding the effect of allopurinol treatment adds to the standard treatment of Covid-19. Allopurinol plus standard treatment reduced LDH, ferritin, CRP, procalcitonin, and ET-1 serum level significantly (P < 0.05) compared with Covid-19 patients on standard treatment. Besides, neutrophil (%), lymphocyte (%), and neutrophil-lymphocyte ratio (NLR) were reduced in patients with severe Covid-19 on standard treatment plus allopurinol compared with Covid-19 patients on standard treatment alone (P < 0.01). OSI was higher in patients with severe Covid-19 than mild-moderate Covid-19 patients (P = 0.00001) at admission. At the time of discharge, the oxidative status of Covid-19 patients was significantly improved compared with that at admission (P = 0.01). In conclusion, Covid-19 severity is linked with high OS and inflammatory reaction with ED development. High uric acid in patients with severe Covid-19 is correlated with high OS and inflammatory biomarkers. Allopurinol with standard treatment in patients with severe Covid-19 reduced oxidative and inflammatory disorders with significant amelioration of ED and clinical outcomes.

Targeting DCs for Tolerance Induction: Don't Lose Sight of the Neutrophils.

Chronic inflammatory disorders (CID), such as autoimmune diseases, are characterized by overactivation of the immune system and loss of immune tolerance. T helper 17 (Th17) cells are strongly associated with the pathogenesis of multiple CID, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. In line with the increasingly recognized contribution of innate immune cells to the modulation of dendritic cell (DC) function and DC-driven adaptive immune responses, we recently showed that neutrophils are required for DC-driven Th17 cell differentiation from human naive T cells. Consequently, recruitment of neutrophils to inflamed tissues and lymph nodes likely creates a highly inflammatory loop through the induction of Th17 cells that should be intercepted to attenuate disease progression. Tolerogenic therapy via DCs, the central orchestrators of the adaptive immune response, is a promising strategy for the treatment of CID. Tolerogenic DCs could restore immune tolerance by driving the development of regulatory T cells (Tregs) in the periphery. In this review, we discuss the effects of the tolerogenic adjuvants vitamin D3 (VD3), corticosteroids (CS), and retinoic acid (RA) on both DCs and neutrophils and their potential interplay. We briefly summarize how neutrophils shape DC-driven T-cell development in general. We propose that, for optimization of tolerogenic DC therapy for the treatment of CID, both DCs for tolerance induction and the neutrophil inflammatory loop should be targeted while preserving the potential Treg-enhancing effects of neutrophils.

Role of Extracellular Vesicles in Cell Death and Inflammation.

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions, such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.

Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies.

The Coronavirus disease 2019 (COVID-19) pandemic has represented an unprecedented challenge for humankind from health, economic, and social viewpoints. In February 2020, Italy was the first western country to be deeply hit by the pandemic and suffered the highest case/fatality rate among western countries. Brand new anti-COVID-19 vaccines have been developed and made available in <1-year from the viral sequence publication. Patients with compromised immune systems, such as autoimmune-autoinflammatory disorders (AIAIDs), primary (PIDs) and secondary (SIDs) immunodeficiencies, have received careful attention for a long time regarding their capacity to safely respond to traditional vaccines. The Italian Immunological Societies, therefore, have promptly faced the issues of safety, immunogenicity, and efficacy/effectiveness of the innovative COVID-19 vaccines, as well as priority to vaccine access, in patients with AIADs, PIDs, and SIDs, by organizing an ad-hoc Task Force. Patients with AIADs, PIDs, and SIDs: (1) Do not present contraindications to COVID-19 vaccines if a mRNA vaccine is used and administered in a stabilized disease phase without active infection. (2) Should usually not discontinue immunosuppressive therapy, which may be modulated depending on the patient's clinical condition. (3) When eligible, should have a priority access to vaccination. In fact, immunizing these patients may have relevant social/health consequences, since these patients, if infected, may develop chronic infection, which prolongs viral spread and facilitates the emergence of viral variants.

Erythema ab igne in pediatric patients remote schooling during the COVID-19 pandemic: A case series.

Erythema ab igne is an uncommon dermatosis characterized by erythematous or hyperpigmented reticular patches that appear after prolonged localized heat exposure. We present three cases of erythema ab igne in pediatric patients who presented in March and April of 2021 and share a history of space heater usage while engaging in remote schooling during the COVID-19 pandemic.

Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases.

Exaggerated oxidative stress and hyper-inflammation are essential features of oxidative/inflammatory diseases. Simultaneously, both processes may be the cause or consequence of mitochondrial dysfunction, thus establishing a vicious cycle among these three factors. However, several natural substances, including melatonin and micronutrients, may prevent or attenuate mitochondrial damage and may preserve an optimal state of health by managing the general oxidative and inflammatory status. This review aims to describe the crucial role of mitochondria in the development and progression of multiple diseases as well as the close relationship among mitochondrial dysfunction, oxidative stress, and cytokine storm. Likewise, it attempts to summarize the main findings related to the powerful effects of melatonin and some micronutrients (vitamins and minerals), which may be useful (alone or in combination) as therapeutic agents in the treatment of several examples of oxidative/inflammatory pathologies, including sepsis, as well as cardiovascular, renal, neurodegenerative, and metabolic disorders.

COVID-19 with dermatologic manifestations and implications: An unfolding conundrum.

The novel coronavirus SARS-CoV-2 has caused Coronavirus Disease 2019, widely known as COVID-19, now a pandemic with extraordinary infectivity, mortality, and fomite adhesiveness. We delineate cutaneous manifestations of COVID-19, some of which may represent adverse cutaneous drug reactions, and skin changes associated with COVID-19 lifestyle alterations in patients and health care workers. We review COVID-19 from both a dermatologic and public health perspective.

Systemic immunosuppressive therapy for inflammatory skin diseases in children: Expert consensus-based guidance for clinical decision-making during the COVID-19 pandemic.

BACKGROUND/OBJECTIVES: The COVID-19 pandemic has raised questions about the approach to management of systemic immunosuppressive therapies for dermatologic indications in children. Change to: Given the absence of data to address concerns related to SARS-CoV-2 infection and systemic immunosuppressive therapies in an evidence-based manner, a Pediatric Dermatology COVID-19 Response Task Force (PDCRTF) was assembled to offer time-sensitive guidance for clinicians. METHODS: A survey was distributed to an expert panel of 37 pediatric dermatologists on the PDCRTF to assess expert opinion and current practice related to three primary domains of systemic therapy: initiation, continuation, and laboratory monitoring. RESULTS: Nearly all respondents (97%) reported that the COVID-19 pandemic had impacted their decision to initiate immunosuppressive medications. The majority of pediatric dermatologists (87%) reported that they were pausing or reducing the frequency of laboratory monitoring for certain immunosuppressive medications. In asymptomatic patients, continuing therapy was the most popular choice across all medications queried. The majority agreed that patients on immunosuppressive medications who have a household exposure to COVID-19 or test positive for new infection should temporarily discontinue systemic and biologic medications, with the exception of systemic steroids, which may require tapering. CONCLUSIONS: The ultimate decision regarding initiation, continuation, and laboratory monitoring of immunosuppressive therapy during the pandemic requires careful deliberation, consideration of the little evidence available, and discussion with families. Consideration of an individual's adherence to COVID-19 preventive measures, risk of exposure, and the potential severity if infected must be weighed against the dermatological disease, medication, and risks to the patient of tapering or discontinuing therapies.