Vitamin D-independent benefits of safe sunlight exposure.

This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathways is necessary to understand how they influence the course of many human diseases.

A century past the discovery of insulin: global progress and challenges for type 1 diabetes among children and adolescents in low-income and middle-income countries.

Type 1 diabetes is on the rise globally; however, the burden of mortality remains disproportionate in low-income and middle-income countries (LMICs). As 2021 marks 100 years since the discovery of insulin, we revisit progress, global burden of type 1 diabetes trends, and understanding of the pathogenesis and management practices related to the disease. Despite much progress, inequities in access and availability of insulin formulations persist and are reflected in differences in survival and morbidity patterns related to the disease. Some of these inequities have also been exacerbated by health-system challenges during the COVID-19 pandemic. There is a clear opportunity to improve access to insulin and related essential technologies for improved management of type 1 diabetes in LMICs, especially as a part of universal health coverage. These improvements will require concerted action and investments in human resources, community engagement, and education for the timely diagnosis and management of type 1 diabetes, as well as adequate health-care financing. Further research in LMICs, especially those in Africa, is needed to improve our understanding of the burden, risk factors, and implementation strategies for managing type 1 diabetes.

BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases.

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.

Natural Killer Cells as Key Mediators in Type I Diabetes Immunopathology.

The immunopathology of type I diabetes (T1D) presents a complicated case in part because of the multifactorial origin of this disease. Typically, T1D is thought to occur as a result of autoimmunity toward islets of Langerhans, resulting in the destruction of insulin-producing cells (ß cells) and thus lifelong reliance on exogenous insulin. However, that explanation obscures much of the underlying mechanism, and the actual precipitating events along with the associated actors (latent viral infection, diverse immune cell types and their roles) are not completely understood. Notably, there is a malfunctioning in the regulation of cytotoxic CD8+ T cells that target endocrine cells through antigen-mediated attack. Further examination has revealed the likelihood of an imbalance in distinct subpopulations of tolerogenic and cytotoxic natural killer (NK) cells that may be the catalyst of adaptive immune system malfunction. The contributions of components outside the immune system, including environmental factors such as chronic viral infection also need more consideration, and much of the recent literature investigating the origins of this disease have focused on these factors. In this review, the details of the immunopathology of T1D regarding NK cell disfunction is discussed, along with how those mechanisms stand within the context of general autoimmune disorders. Finally, the rarer cases of latent autoimmune, COVID-19 (viral), and immune checkpoint inhibitor (ICI) induced diabetes are discussed as their exceptional pathology offers insight into the evolution of the disease as a whole.

To Ki or Not to Ki: Re-Evaluating the Use and Potentials of Ki-67 for T Cell Analysis.

This study discusses substantive advances in T cell proliferation analysis, with the aim to provoke a re-evaluation of the generally-held view that Ki-67 is a reliable proliferation marker per se, and to offer a more sensitive and effective method for T cell cycle analysis, with informative examples in mouse and human settings. We summarize recent experimental work from our labs showing that, by Ki-67/DNA dual staining and refined flow cytometric methods, we were able to identify T cells in the S-G2/M phases of the cell-cycle in the peripheral blood (collectively termed "T Double S" for T cells in S-phase in Sanguine: in short "TDS" cells). Without our refinement, such cells may be excluded from conventional lymphocyte analyses. Specifically, we analyzed clonal expansion of antigen-specific CD8 T cells in vaccinated mice, and demonstrated the potential of TDS cells to reflect immune dynamics in human blood samples from healthy donors, and patients with type 1 diabetes, infectious mononucleosis, and COVID-19. The Ki-67/DNA dual staining, or TDS assay, provides a reliable approach by which human peripheral blood can be used to reflect the dynamics of human lymphocytes, rather than providing mere steady-state phenotypic snapshots. The method does not require highly sophisticated "-omics" capabilities, so it should be widely-applicable to health care in diverse settings. Furthermore, our results argue that the TDS assay can provide a window on immune dynamics in extra-lymphoid tissues, a long-sought potential of peripheral blood monitoring, for example in relation to organ-specific autoimmune diseases and infections, and cancer immunotherapy.

A dual antibody test for accurate surveillance of SARS-CoV-2 exposure rates.

Accurate population surveillance of SARS-CoV-2 infection has been hampered by limited testing and inadequate serological assays. In a recent issue of Med, Hippich et al.1 describe a two-step antibody test with 100% specificity, revealing higher-than-reported SARS-CoV-2 exposure rates in children.

Diabetic fibrosis.

Diabetes-associated morbidity and mortality is predominantly due to complications of the disease that may cause debilitating conditions, such as heart and renal failure, hepatic insufficiency, retinopathy or peripheral neuropathy. Fibrosis, the excessive and inappropriate deposition of extracellular matrix in various tissues, is commonly found in patients with advanced type 1 or type 2 diabetes, and may contribute to organ dysfunction. Hyperglycemia, lipotoxic injury and insulin resistance activate a fibrotic response, not only through direct stimulation of matrix synthesis by fibroblasts, but also by promoting a fibrogenic phenotype in immune and vascular cells, and possibly also by triggering epithelial and endothelial cell conversion to a fibroblast-like phenotype. High glucose stimulates several fibrogenic pathways, triggering reactive oxygen species generation, stimulating neurohumoral responses, activating growth factor cascades (such as TGF-ß/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs) and stimulating the AGE-RAGE axis, and upregulating fibrogenic matricellular proteins. Although diabetes-activated fibrogenic signaling has common characteristics in various tissues, some organs, such as the heart, kidney and liver develop more pronounced and clinically significant fibrosis. This review manuscript summarizes current knowledge on the cellular and molecular pathways involved in diabetic fibrosis, discussing the fundamental links between metabolic perturbations and fibrogenic activation, the basis for organ-specific differences, and the promises and challenges of anti-fibrotic therapies for diabetic patients.

Features of patients that died for COVID-19 in a hospital in the south of Mexico: A observational cohort study.

BACKGROUND: Due to the wide spread of SARS-CoV2 around the world, the risk of death in individuals with metabolic comorbidities has dangerously increased. Mexico has a high number of infected individuals and deaths by COVID-19 as well as an important burden of metabolic diseases; nevertheless, reports about features of Mexican individuals with COVID-19 are scarce. The aim of this study was to evaluate demographic features, clinical characteristics and the pharmacological treatment of individuals who died by COVID-19 in the south of Mexico. METHODS: We performed an observational study including the information of 185 deceased individuals with confirmed diagnoses of COVID-19. Data were retrieved from medical records. Categorical data were expressed as proportions (%) and numerical data were expressed as mean ± standard deviation. Comorbidities and overlapping symptoms were plotted as Venn diagrams. Drug clusters were plotted as dendrograms. RESULTS: The mean age was 59.53 years. There was a male predominance (60.1%). The mean hospital stay was 4.75 ± 4.43 days. The most frequent symptoms were dyspnea (88.77%), fever (71.42%) and dry cough (64.28%). Present comorbidities included diabetes (60.63%), hypertension (59.57%) and obesity (43.61%). The main drugs used for treating COVID-19 were azithromycin (60.6%), hydroxychloroquine (53.0%) and oseltamivir (27.3%). CONCLUSIONS: Mexican individuals who died of COVID-19 had shorter hospital stays, higher frequency of shortness of breath, and higher prevalence of diabetes than individuals from other countries. Also, there was a high frequency of off-label use of drugs for their treatment.

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update.

INTRODUCTION: G protein-coupled receptors (GPCRs) play key roles in many biological functions and are linked to many diseases across all therapeutic areas. As such, GPCRs represent a significant opportunity for antibody-based therapeutics. AREAS COVERED: The structure of the major GPCR families is summarized in the context of choice of antigen source employed in the drug discovery process and receptor biology considerations which may impact on targeting strategies. An overview of the therapeutic GPCR-antibody target landscape and the diversity of current therapeutic programs is provided along with summary case studies for marketed antibody drugs or those in advanced clinical studies. Antibodies in early clinical studies and the emergence of next-generation modalities are also highlighted. EXPERT OPINION: The GPCR-antibody pipeline has progressed significantly with a number of technical developments enabling the successful resolution of some of the challenges previously encountered and this has contributed to the growing interest in antibody-based therapeutics addressing this target class.