Advances in Immunology最新文献

Despite effective spike-based vaccines and monoclonal antibodies, the SARS-CoV-2 pandemic continues more than two and a half years post-onset. Relentless investigation has outlined a causative dynamic between host-derived antibodies and reciprocal viral subversion. Integration of this paradigm into the architecture of next generation antiviral strategies, predicated on a foundational understanding of the virology and immunology of SARS-CoV-2, will be critical for success. This review aims to serve as a primer on the immunity endowed by antibodies targeting SARS-CoV-2 spike protein through a structural perspective. We begin by introducing the structure and function of spike, polyclonal immunity to SARS-CoV-2 spike, and the emergence of major SARS-CoV-2 variants that evade immunity. The remainder of the article comprises an in-depth dissection of all major epitopes on SARS-CoV-2 spike in molecular detail, with emphasis on the origins, neutralizing potency, mechanisms of action, cross-reactivity, and variant resistance of representative monoclonal antibodies to each epitope.

Barrier tissues are the primary site of infection for pathogens likely to cause future pandemics. Tissue-resident lymphocytes can rapidly detect pathogens upon infection of barrier tissues and are critical in preventing viral spread. However, most vaccines fail to induce tissue-resident lymphocytes and are instead reliant on circulating antibodies to mediate protective immunity. Circulating antibody titers wane over time following vaccination leaving individuals susceptible to breakthrough infections by variant viral strains that evade antibody neutralization. Memory B cells were recently found to establish tissue residence following infection of barrier tissues. Here, we summarize emerging evidence for the importance of tissue-resident memory B cells in the establishment of protective immunity against viral and bacterial challenge. We also discuss the role of tissue-resident memory B cells in regulating the progression of non-infectious diseases. Finally, we examine new approaches to develop vaccines capable of eliciting barrier immunity.

Autoimmune diseases (ADs) often arise from a combination of genetic and environmental triggers that disrupt the immune system's capability to properly tolerate body self-antigens. Familial studies provided the earliest insights into the risk loci of such diseases, while genome-wide association studies (GWAS) significantly broadened the horizons. A drug targeting a prominent pathological pathway can be applied to multiple indications sharing overlapping mechanisms. Advances in genomic technologies used in genetic studies provide critical insights into future research on gene-environment interactions in autoimmunity. This Review summarizes the history and recent advances in the understanding of genetic susceptibility to ADs and related immune disorders, including coronavirus disease 2019 (COVID-19), and their indications for the development of diagnostic or prognostic markers for translational applications.

B cells are integral components of the mammalian immune response as they have the ability to generate antibodies against an almost infinite array of antigens. Over the past several decades, significant scientific progress has been made in understanding that this enormous B cell diversity contributes to pathogen clearance. However, our understanding of the humoral response to solid tumors and to tumor-specific antigens is unclear. In this review, we first discuss how B cells interact with other cells in the tumor microenvironment and influence the development and progression of various solid tumors. The ability of B lymphocytes to generate antibodies against a diverse repertoire of antigens and subsequently tailor the humoral immune response to specific pathogens relies on their ability to undergo genomic alterations during their development and differentiation. We will discuss key transforming events that lead to the development of B cell lymphomas. Overall, this review provides a foundation for innovative therapeutic interventions for both lymphoma and solid tumor malignancies.

The complement system consists of three pathways (alternative, classical, and lectin) that play a fundamental role in immunity and homeostasis. The multifunctional role of the complement system includes direct lysis of pathogens, tagging pathogens for phagocytosis, promotion of inflammatory responses to control infection, regulation of adaptive cellular immune responses, and removal of apoptotic/dead cells and immune complexes from circulation. A tight regulation of the complement system is essential to avoid unwanted complement-mediated damage to the host. This regulation is ensured by a set of proteins called complement regulatory proteins. Deficiencies or malfunction of these regulatory proteins may lead to pro-thrombotic hematological diseases, renal and ocular diseases, and autoimmune diseases, among others. This review focuses on the importance of two complement regulatory proteins of the alternative pathway, Factor H and properdin, and their role in human diseases with an emphasis on: (a) characterizing the main mechanism of action of Factor H and properdin in regulating the complement system and protecting the host from complement-mediated attack, (b) describing the dysregulation of the alternative pathway as a result of deficiencies, or mutations, in Factor H and properdin, (c) outlining the clinical findings, management and treatment of diseases associated with mutations and deficiencies in Factor H, and (d) defining the unwanted and inadequate functioning of properdin in disease, through a discussion of various experimental research findings utilizing in vitro, mouse and human models.

The term "lectin" is derived from the Latin word lego- (aggregate) (Boyd & Shapleigh, 1954). Indeed, lectins' folds can flexibly alter their pocket structures just like Lego blocks, which enables them to grab a wide-variety of substances. Thus, this useful fold is well-conserved among various organisms. Through evolution, prototypic soluble lectins acquired transmembrane regions and signaling motifs to become C-type lectin receptors (CLRs). While CLRs seem to possess certain intrinsic affinity to self, some CLRs adapted to efficiently recognize glycoconjugates present in pathogens as pathogen-associated molecular patterns (PAMPs) and altered self. CLRs further extended their diversity to recognize non-glycosylated targets including pathogens and self-derived molecules. Thus, CLRs seem to have developed to monitor the internal/external stresses to maintain homeostasis by sensing various "unfamiliar" targets. In this review, we will summarize recent advances in our understanding of CLRs, their ligands and functions and discuss future perspectives.

The cGAS-STING pathway is responsible for cytoplasmic double-stranded DNA (dsDNA) -triggered innate immunity and involved in the pathology of various diseases including infection, autoimmune diseases, neurodegeneration and cancer. Understanding the activation and regulatory mechanisms of this pathway is critical to develop therapeutic strategies toward these diseases. Here, we review the signal transduction, cellular functions and regulations of cGAS and STING, particularly highlighting the latest understandings on the activation of cGAS by dsDNA and/or Manganese (Mn²⁺), STING trafficking, sulfated glycosaminoglycans (sGAGs)-induced STING polymerization and activation, and also regulation of the cGAS-STING pathway by different biocondensates formed via phase separation of proteins from host cells and viruses.

The discovery that B cells and αβ T cells exist was predictable: These cells gave themselves away through their products and biological effects. In contrast, there was no reason to anticipate the existence of γδ T cells. Even the accidental discovery of a novel TCR-like gene (later named γ) that did not encode TCR α or β proteins did not immediately change this. TCR-like γ had no obvious function, and its early expression in the thymus encouraged speculation about a possible role in αβ T cell development. However, the identification of human PBL-derived cell-lines which expressed CD3 in complex with the TCR-like γ protein, but not the αβ TCR, first indicated that a second T cell-type might exist, and the TCR-like γ chain was observed to co-precipitate with another protein. Amid speculation about a possible second TCR, this potential dimeric partner was named δ. To determine if the δ protein was indeed TCR-like, we undertook to sequence it. Meanwhile, a fourth TCR-like gene was discovered and provisionally named x. TCR-like x had revealed itself through genomic rearrangements early in T cell development, and was an attractive candidate for the gene encoding δ. The observation that δ protein sequences matched the predicted amino acid sequences encoded by the x gene, as well as serological cross-reactivity, confirmed that the TCR-like x gene indeed encoded the δ protein. Thus, the γδ heterodimer was established as a second TCR, and the cells that express it (the γδ T cells) consequently represented a third lymphocyte-population with the potential of recognizing diverse antigens. Soon, it became clear that γδ T cells are widely distributed and conserved among the vertebrate species, implying biological importance. Consistently, early functional studies revealed their roles in host resistance to pathogens, tissue repair, immune regulation, metabolism, organ physiology and more. Albeit discovered late, γδ T cells have repeatedly proven to play a distinct and often critical immunological role, and now generate much interest.

In some cases, antibodies can enhance virus entry and replication in cells. This phenomenon is called antibody-dependent infection enhancement (ADE). ADE not only promotes the virus to be recognized by the target cell and enters the target cell, but also affects the signal transmission in the target cell. Early formalin-inactivated virus vaccines such as aluminum adjuvants (RSV and measles) have been shown to induce ADE. Although there is no direct evidence that there is ADE in COVID-19, this potential risk is a huge challenge for prevention and vaccine development. This article focuses on the virus-induced ADE phenomenon and its molecular mechanism. It also summarizes various attempts in vaccine research and development to eliminate the ADE phenomenon, and proposes to avoid ADE in vaccine development from the perspective of antigens and adjuvants.