International Reviews of Immunology最新文献

Immunoglobulin D (IgD) is an enigmatic antibody and the least appreciated member of the immunoglobulin (Ig) family. Since its discovery over half a century ago, the essence of its function in the immune system has been somewhat enigmatic and less well-defined than other antibody classes. Membrane-bound IgD (mIgD) is mostly recognized as B-cell receptor (BCR) while secreted IgD (sIgD) has been recently implicated in 'arming' basophils and mast cells in mucosal innate immunity. Activations of immune responses via mIgD-BCR or sIgD by specific antigens or anti-IgD antibody thereby produce a broad and complex mix of cellular, antibody and cytokine responses from both the innate and adaptive immune systems. Such broadly activated immune responses via IgD were initially deemed to potentiate and exacerbate the onset of autoimmune and allergic conditions. Paradoxically, treatments with anti-IgD antibody suppressed and ameliorated autoimmune conditions and allergic inflammations in mouse models without compromising the host's general immune defence, demonstrating a unique and novel therapeutic application for anti-IgD antibody treatment. Herein, this review endeavored to collate and summarize the evidence of the unique characteristics and features of activated immune responses via mIgD-BCR and sIgD that revealed an unappreciated immune-regulatory function of IgD in the immune system via an amplifying loop of anti-inflammatory Th2 and tolerogenic responses, and highlighted a novel therapeutic paradigm in harnessing these immune responses to treat human autoimmune and allergic conditions.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in dramatic worldwide mortality. Along with developing vaccines, the medical profession is exploring new strategies to curb this pandemic. A better understanding of the molecular consequences of SARS-CoV-2 cellular infection could lead to more effective and safer treatments. This review discusses the potential underlying impact of SARS-CoV-2 in modulating interferon (IFN) secretion and in causing mitochondrial NAD⁺ depletion that could be directly linked to COVID-19's deadly manifestations. What is known or surmised about an imbalanced innate immune response and mitochondrial dysfunction post-SARS-CoV-2 infection, and the potential benefits of well-timed IFN treatments and NAD⁺ boosting therapies in the context of the COVID-19 pandemic are discussed.

Obesity is characterized by low-grade, chronic inflammation, which promotes insulin resistance and diabetes. Obesity can lead to the development and progression of many autoimmune diseases, including inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, thyroid autoimmunity, and type 1 diabetes mellitus (T1DM). These diseases result from an alteration of self-tolerance by promoting pro-inflammatory immune response by lowering numbers of regulatory T cells (T_regs), increasing Th1 and Th17 immune responses, and inflammatory cytokine production. Therefore, understanding the immunological changes that lead to this low-grade inflammatory milieu becomes crucial for the development of therapies that suppress the risk of autoimmune diseases and other immunological conditions. Cells generate extracellular vesicles (EVs) to eliminate cellular waste as well as communicating the adjacent and distant cells through exchanging the components (genetic material [DNA or RNA], lipids, and proteins) between them. Immune cells and adipocytes from individuals with obesity and a high basal metabolic index (BMI) produce also release exosomes (EXOs) and microvesicles (MVs), which are collectively called EVs. These EVs play a crucial role in the development of autoimmune diseases. The current review discusses the immunological dysregulation that leads to inflammation, inflammatory diseases associated with obesity, and the role played by EXOs and MVs in the induction and progression of this devastating conditi8on.

Engineered T cell therapies such as CAR-T cells and TCR-T cells have generated impressive patient responses in previously incurable diseases. In the past few years there have been a number of technical innovations that enable robust clinical manufacturing in functionally closed and often automated systems. Here we describe the latest technology used to manufacture CAR- and TCR-engineered T cells in the clinic, including cell purification, transduction/transfection, expansion and harvest. To help compare the different systems available, we present three case studies of engineered T cells manufactured for phase I clinical trials at the NIH Clinical Center (CD30 CAR-T cells for lymphoma, CD19/CD22 bispecific CAR-T cells for B cell malignancies, and E7 TCR T cells for human papilloma virus-associated cancers). Continued improvement in cell manufacturing technology will help enable world-wide implementation of engineered T cell therapies.

Neutrophil extracellular traps (NETs) are a defense mechanism against pathogens. They are composed of DNA and various proteins and have the ability to hinder microbial spreading and survival. However, NETs are not only related to infections but also participate in sterile inflammatory events. In addition to DNA, NETs contain histones, serine proteases, cytoskeletal proteins and antimicrobial peptides, all of which have immunomodulatory properties that can augment or decrease the inflammatory response. Extracellular localization of these molecules alerts the immune system of cellular damage, which is triggered by recognition of damage-associated molecular patterns (DAMPs) through specific pattern recognition receptors. However, not all of these molecules are DAMPs and may have other immunophysiological properties in the extracellular space. The release of NETs can lead to production of pro-inflammatory cytokines (due to TLR2/4/9 and inflammasome activation), the destruction of the extracellular matrix, activation of serine proteases and of matrix metallopeptidases (MMPs), modulation of cellular proliferation, induction of cellular migration and adhesion, promotion of thrombogenesis and angiogenesis and disruption of epithelial and endothelial permeability. Understanding the dynamics of NET-associated molecules, either individually or synergically, will help to unravel their role in inflammatory events and open novel perspectives for potential therapeutic targets. We here review molecules contained within NETS and their immunophysiological roles.

Several risk factors are known to be involved in the initiation and development of gastric cancer. Among them, H. pylori is one of the most prominent with multiple virulence factors contributing to its pathogenicity. In this study, we have discussed an interesting immunological cycle exploring the interplay between H. pylori, aryl hydrocarbon receptor (AHR), tryptophan, arginine, and the metabolites of these two amino acids in the development of gastric cancer. AHR is a ligand-activated transcription factor which acts as a regulator for a diverse set of genes and has various types of exogenous and endogenous ligands. The tryptophan metabolite, kynurenine, is one of these ligands that can interact with AHR, leading to immune suppression and subsequently, susceptibility to gastric cancer. On the other hand, H. pylori downregulates the expression of AHR and AHR repressor (AHRR), leading to increased inflammatory cytokine production. A metabolite of the kynurenine pathway, xanthurenic acid, is a potent inhibitor of a terminal enzyme in the synthetic pathway of tetrahydrobiopterin (BH4). BH4, itself, is a cofactor in the process of nitric oxide (NO) production from arginine that has been shown to have immune-enhancing properties. Arginine has also been evidenced to have anti-tumoral function through inducing apoptosis in gastric cell lines; however, controversy exists regarding the anti-tumor role of arginine and BH4, since they are also associated with increased NO production, subsequently promoting tumor angiogenesis. Hence, although several synergistic connections result in immunity improvement, these correlations can also act as a double-edged sword, promoting tumor development. This emphasizes on the need for further investigations to better understand this complex interplay.

Indoleamine 2, 3-dioxygenase (IDO) as an intracellular cytosolic enzyme converts tryptophan (Trp) to N-formyl kynurenine which leads to proinflammatory T-cell apoptosis and prevention of immune cells maturation via decreasing the level of cellular energy. Trp catabolism products such as kynurenine increase the recruitment of regulatory T cells and induce immune tolerance in dendritic cells. IDO expression can locally suppress immunity in the tumor microenvironment and tumor progression actively recruits IDO expressing cells in tumor-draining lymph nodes. Also, tumor infiltrating Tregs' activity leads to IDO expression in the tumor microenvironment. In this review, we described the immunomodulatory function of IDO and IDO-based therapeutic strategies for immune related diseases. According to positive-feedback loop between Tregs and IDO in the tumor microenvironment, IDO can be targeted as a promising immunostimulatory approach for immunotherapy of cancer. However, several studies revealed controversial consequences for influences of IDO in immunity. Considering the common concept, IDO1 and also IDO2 repress the function of T lymphocytes, while inactivation of IDO results in aggravation of some autoimmune diseases. Eventually, the extensive evaluation of IDO function in immunomodulatory procedure can help achieve IDO inhibitors as optimal drugs to inhibit tumor growth without motivating autoimmunity.

The immune system response of transplant recipients is the main cause of allograft rejection; therefore, its suppression seems crucial. Nevertheless, immunosuppressive agents are largely ineffective against innate immune response. Innate immunity is immediately activated after transplantation and contribute to allograft inflammation and rejection. In this regard, understanding the mechanism of activation and targeting the components of innate immunity could improve allograft survival time. In this review, we discuss two scenarios in the innate immunity, i.e., danger and allogeneic signals in the context of both allogeneic and syngeneic graft. Moreover, the mechanisms of innate allorecognition (i.e., signal regulatory protein α-CD47 and paired immunoglobulin-like receptors-MHC I axis) are described, which can improve our clinical decisions to use a better therapeutic strategy.

Immunological memory is critical for host immunity and decisive for individual to respond exponentially to previously encountered infection. Both T and B cell memory are known to orchestrate immunological memory with their central and effector memory arms contributing in prolonged immunity/defence mechanisms of host. While central memory helps in maintaining prolonged immunity for a particular infection, effector memory helps in keeping local/seasonal infection in control. In addition to this, generation of long-lived plasma cells is pivotal for generating neutralizing antibodies which can enhance recall and B cell memory to control re-infection. In view of this, scaling up memory response is one of the major objectives for the expected outcome of vaccination. In this line, this review deals with the significance of memory cells, molecular pathways of their development, maintenance, epigenetic regulation and negative regulation in various infections. We have also highlighted the significance of both T and B cell memory responses in the vaccination approaches against range of infections which is not fully explored so far.[Box: see text].