Immunological Reviews最新文献

Immunoglobulin E (IgE) is the most recently discovered and evolved mammalian antibody type, best known for interacting with mast cells (MCs) as immune effectors. IgE-mediated antigen sensing by MC provides protection from parasites, venomous animals, bacteria, and other insults to barrier tissues exposed to the environment. IgE and MCs act as inflammation amplifiers and immune response adjuvants. Thus, IgE production and memory formation are greatly constrained and require specific licensing. Failure of regulation gives rise to allergic disease, one of the top causes of chronic illness. Increasing evidence suggests allergy development often starts early in life, including prenatally, with maternal influence being central in shaping the offspring's immune system. Although IgE often exists before birth, an endogenous source of IgE-producing B cells has not been identified. This review discusses the mechanisms of maternal IgE transfer into the offspring, its interactions with offspring MCs and antigen-presenting cells, and the consequences for allergic inflammation and allergen sensitization development. We discuss the multifaceted effects of pre-existing IgG, IgE, and their glycosylation on maternal IgE transfer and functionality in the progeny. Understanding the IgE-mediated mechanisms predisposing for early life allergy development may allow their targeting with existing therapeutics and guide the development of new ones.

Thymic mimetic cells are hybrids of medullary thymic epithelial cells and diverse peripheral cell types. They are important for the imposition of self-tolerance and perform other functions similar to those of their peripheral counterparts. Following early histological observations of “misplaced” stromal cells in thymi from multiple species, mimetic cells were first molecularly investigated in mice. Recent studies have characterized mimetic cells in humans and zebrafish with high-resolution. Many mimetic cell types are conserved across species, although specialized subtypes as well as variable frequencies and levels of specialization are also apparent. Features of the human mimetic cell repertoire, such as the expanded nature of muscle mimetic cells with potential implications in myasthenia gravis and the similarity of tuft mimetic cells and thymic carcinomas, hint at their relevance in human disease. Here we review what is known about mimetic cells across diverse organisms. We discuss potential pressures shaping the composition of the mimetic cell repertoire within and across species, and highlight potential therapeutic applications in human disease.

Eosinophilia is a hallmark of allergic disorders, including asthma, allergic rhinitis, and atopic dermatitis. The onset and maintenance of allergic inflammation in atopic adults involves the activation of selective hemopoietic processes and the migration of mature and immature eosinophils to allergic tissue, where these cells release mediators of inflammation that participate in the regulation of inflammation. Eosinophils function in close cooperation with basophils and mast cells in allergic tissue, where crosstalk between these central effector cells regulates the inflammatory process. This chapter will review the cellular events leading to the accumulation of eosinophils and their progenitors in the airways in allergic asthma, with a particular focus on models of allergen-induced allergic inflammation. Inhaled allergen challenges in allergic asthmatics have advanced understanding of the pathogenesis of allergen exposure leading to early and late asthmatic responses and the associated airway hyperresponsiveness and type 2 airway inflammation. This chapter will also discuss the mechanisms of commonly used asthma therapies on allergen-induced eosinophilia and compare the effects of novel therapies targeting specific immune pathways for a better understanding of how to regulate airway eosinophil levels in patients with asthma.

Upon activation, B cells undergo either the germinal center (GC) or extrafollicular (EF) response. While GC are known to generate high-affinity memory B cells and long-lived plasma cells, the role of the EF response is less well understood. Initially, it was thought to be limited to that of a source of fast but lower-quality antibodies until the GC can form. However, recent evidence strongly supports the EF response as an important component of the humoral response to infection. EF responses are now also recognized as a source of pathogenic B cells in autoimmune diseases. The EF response itself is dynamic and regulated by pathways that are only recently being uncovered. We have identified that the cytokine IL-12 acts as a molecular switch, enhancing the EF response and suppressing GC through multiple mechanisms. These include direct effects on both B cells themselves and the coordinated differentiation of helper CD4 T cells. Here, we explore this pathway in relation to other recent advancements in our understanding of the EF response's role and highlight areas for future research. A better understanding of how the EF response forms and is regulated is essential for advancing treatments for many disease states.

T cells physically interrogate their targets using tiny membrane protrusions called microvilli, forming junctions ~400 nm in diameter and ~ 15 nm deep, referred to as “close contacts”. These contacts, which are stabilized by the binding of the small adhesion protein CD2 to its ligand, CD58 and locally exclude large proteins such as the phosphatase CD45, are the sites of antigen recognition by the T-cell receptor (TCR) and very early signaling by T cells. With our collaborators, we have characterized the molecular structures of several of the key proteins mediating these early events: i.e., CD2 and its ligands, CD45, the αβ- and γδ-TCRs, and the accessory proteins CD28, CTLA-4, and PD-1. Here, we review our structural work and the insights it offers into the early events underpinning T-cell responsiveness that take place in the confined space of the close contact. We reflect on the crucial roles that the structural organization and dimensions of these proteins are likely to have in determining the sequence of events leading to antigen recognition at close contacts and consider the general implications of the structural work for explanations of how immune receptor signaling is initiated.