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Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to Staphylococcus aureus infections accompanied by local necrosis and systemic inflammation. The pathogenesis observed in haploinsufficient patients differs from the hyperinflammation seen in classical OTULIN-related autoinflammatory syndrome (ORAS) patients and is characterized by increased susceptibility of dermal fibroblasts to S. aureus alpha toxin-inflicted cytotoxic damage. Immunological abnormalities were not observed in OTULIN haploinsufficient patients, suggesting a non-hematopoietic basis. In this research report, we investigated an Otulin +/− mouse model after in vivo provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked Otulin +/− mice, which was driven by CD64 + monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of Otulin +/− mice demonstrated higher proinflammatory cytokine secretion after in vitro stimulation with LPS or polyinosinic:polycytidylic acid (Poly(I:C)). Our experiments in full and mixed bone marrow chimeric mice suggest that, in contrast to humans, the observed inflammation was mainly driven by the hematopoietic compartment with cell-extrinsic effects likely contributing to inflammatory outcomes. Using an OTULIN haploinsufficient mouse model, we validated the role of OTULIN in the regulation of environmentally directed inflammation.

FOXP3+ regulatory T cells (Treg) are indispensable for immune homoeostasis and for the prevention of autoimmune diseases. Interleukin-2 (IL-2) signalling is critical in all aspects of Treg biology. Consequences of defective IL-2 signalling are insufficient numbers or dysfunction of Treg and hence autoimmune disorders in human and mouse. The restoration and maintenance of immune homoeostasis remain central therapeutic aims in the field of autoimmunity. Historically, broadly immunosuppressive drugs with serious side-effects have been used for the treatment of autoimmune diseases or prevention of organ-transplant rejection. More recently, ex vivo expanded or in vivo stimulated Treg have been shown to induce effective tolerance in clinical trials supporting the clinical benefit of targeting natural immunosuppressive mechanisms. Given the central role of exogenous IL-2 in Treg homoeostasis, a new and promising focus in drug development are IL-2-based approaches for in vivo targeted expansion of Treg or for enhancement of their suppressive activity. In this review, we summarise the role of IL-2 in Treg biology and consequences of dysfunctional IL-2 signalling pathways. We then examine evidence of efficacy of IL-2-based biological drugs targeting Treg with specific focus on therapeutic candidates in clinical trials and discuss their limitations.

Diseases caused by Dengue (DENV) and Zika (ZIKV) viruses cause significant mortality and illness globally. Due to the high sequence similarity of the viral proteins and the purported cross-reactive immune responses against the viruses, we envisioned a common multi-epitope vaccine (MEV) against both viruses by adopting a novel approach of identifying “immunogenic hotspots”. These stretches of the structural and non-structural proteins are enriched with MHC class I and class II supertype-restricted T cell epitopes, and B cell epitopes, in addition to being highly conserved between different DENV serotypes and ZIKV. Such an approach ensures inclusion of multiple overlapping T and B cell epitopes common to both viruses, and also warrants high population coverage. Importantly, epitopes known to cause antibody-dependent-enhancement of infection have been excluded. These immunogenic hotspots have then been stitched together with linkers in-silico along with an adjuvant, CTxB to develop the MEV candidate. Four structural models of the MEV were selected on the basis of conformational preservation of CTxB, and their biophysical parameters, which also conserved the immunogenicity of the multiple epitopes. Importantly, each of the MEV candidates were found to interact with TLR4-MD2 complex by molecular docking studies, indicative of their ability to induce TLR-mediated immune responses. Competing Interest Statement The authors have declared no competing interest.

Background Nanotechnology's rapid development has been in great demand, particularly for silver nanoparticles, which are useful in a variety of industries including medicine, textiles, and home appliances. Silver nanoparticles are extremely essential due to their unique physicochemical and antibacterial properties, which can be used in a variety of applications. Green synthesis is an environmentally friendly alternative to conventional synthesis because it uses fewer chemical reagents and lowers temperature and pressure. Aloe vera and Thuja orientalis have a wide medical use because it contains a large number of compounds derived and was decided to use for the synthesis of nanoparticles. Main text The combination of silver nanoparticles has a wide range of applications, which has encouraged researchers to focus on the methods for the synthesis of silver nanoparticles from Aloe vera and Thuja orientalis leaves extract, characterization techniques of synthesized silver nanoparticles, and evaluation of their antimicrobial and antifungal activities. The synthesized AgNPs can be characterized by using various analytical techniques including UV–visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), etc. The various types of silver nanoparticles, various strategies for silver nanoparticle synthesis, nano-based drug delivery systems, taxonomy and chemical constituents of Aloe vera and Thuja orientalis plants, the general mechanism of action of silver nanoparticles in bacteria, and various applications of silver nanoparticles have also been discussed. Conclusion This review covers a wide range of research on silver nanoparticles to gain a better understanding of their physicochemical feature characterization, production, mechanisms of action, and applications. Various AgNP factors, such as size, surfactant, and structural shape, influence the unique physicochemical properties of these nanoparticles. Even though there are a variety of ways to make AgNPs, green synthesis has a high yield and biocompatibility because it uses natural agents and harmless chemicals. In this paper, we describe the green manufacture of silver nanoparticles utilizing Aloe vera and Thuja orientalis leaf extracts, as well as the method to test their antimicrobial and antifungal activity .