Immunological Reviews最新文献

Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long-term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal-offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota-derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue-specific immune education to offspring. We propose a “maternal-driven immune education” hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.

Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation, engulf and kill infecting organisms, and clear out apoptotic debris all the while making antigens available and accessible to the lymphoid organs for future use. Therefore, phagocytes provide the gateway and the first check in host protection and immune response. Disorders in killing and chemotaxis lead not only to infection susceptibility, but also to autoimmunity. We aim to describe chronic granulomatous disease and the leukocyte adhesion deficiencies as well as myeloperoxidase deficiency and G6PD deficiency as paradigms of critical pathways.

Inborn errors of immunity (IEI) comprise a diverse spectrum of 485 disorders as recognized by the International Union of Immunological Societies Committee on Inborn Error of Immunity in 2022. While IEI are monogenic by definition, they illuminate various pathways involved in the pathogenesis of polygenic immune dysregulation as in autoimmune or autoinflammatory syndromes, or in more common infectious diseases that may not have a significant genetic basis. Rapid improvement in genomic technologies has been the main driver of the accelerated rate of discovery of IEI and has led to the development of innovative treatment strategies. In this review, we will explore various facets of IEI, delving into the distinctions between PIDD and PIRD. We will examine how Mendelian inheritance patterns contribute to these disorders and discuss advancements in functional genomics that aid in characterizing new IEI. Additionally, we will explore how emerging genomic tools help to characterize new IEI as well as how they are paving the way for innovative treatment approaches for managing and potentially curing these complex immune conditions.

The Yellow Brick Road leads Dorothy through Oz to the Emerald City—a luminescent green metropolis where she hopes to meet the great and powerful Wizard. The Emerald City is the destination of Dorothy's journey, where desires become reality. Arguably, the “Emerald City” for most physician-scientists caring for patients with inborn errors of immunity (IEI) is to apply effective therapies that target the specific impaired cell type/pathway, while avoiding detrimental effects on the rest of the immune system and other tissues (Figure 1). That is, to use the right treatment, at the right time, for the right patient—precision medicine at its best. The journey to this Emerald City has always started with the patient's symptoms and history. However, the constellation of these clinical clues has significantly changed over time, making it more challenging to begin the odyssey down the yellow brick road. In 1952, Dr. Ogden Bruton started his journey with patients who had recurrent pneumonias. Along the road, he found that they lacked serum γ-globulins. He then discovered a causative single gene defect, inherited as a Mendelian trait with full penetrance. Finally, he arrived at the targeted destination of immunoglobulin replacement therapy.¹ Today, neither the starting point nor the road that follows are as straight and smooth.

As Bucciol et al. (1) describe in this issue, the wide availability and application of next-generation sequencing (NGS) methods, particularly whole exome/genome sequencing (WES/WGS), has significantly increased “the discovery rate” of additional IEI. The most recent International Union of Immunological Societies update (2022) included 55 novel monogenic gene defects, and one phenocopy due to autoantibodies discovered since January 2020, bringing the total number of IEI to 485.² In some cases, distinct pathogenic variants at the same locus cause different IEI phenotypes (allelic heterogeneity; one gene, many phenotypes). In other cases, pathogenic variants in different genes governing one common pathway cause the same IEI (locus heterogeneity; many genes, one phenotype).³ Furthermore, as Vinh (2) discusses, IEI can also exemplify non-Mendelian basis of disease. While the overwhelming majority of IEI have been identified and mechanistically deciphered as monogenic, there are increasing reports of oligogenic IEI syndromes,^4-8 wherein lesions in two or more distinct genes contribute to a clinical phenotype that has some features of the corresponding monogenic IEI disorders. Somatic mosaic mutations may lead to a milder or a more severe form of the disease, which may be influenced by the known pathogenicity of the mutation at the germline level.⁹ Alterations in gene expression such as