Immunological Reviews最新文献

Systemic sclerosis (SSc) is a severe autoimmune disease characterized by vasculopathy, fibrosis, and dysregulated immunity, with hallmark autoantibodies targeting nuclear antigens such as centromere protein (ACA) and topoisomerase I (ATA). These autoantibodies are highly prevalent and disease-specific, rarely coexisting, thus serving as crucial biomarkers for SSc diagnosis. Despite their diagnostic value, their roles in SSc pathogenesis remain unclear. This review summarizes current literature on ACA and ATA in SSc, comparing them to autoantibodies in other rheumatic diseases to elucidate their potential pathogenic roles. Similarities are drawn with anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis, particularly regarding disease specificity and minimal pathogenic impact of antigen binding. In addition, differences between ANA and ACPA in therapeutic responses and Fab glycosylation patterns are reviewed. While ACA and ATA are valuable for disease stratification and monitoring activity, understanding their origins and the associated B cell responses is critical for advancing therapeutic strategies for SSc.

The study of antibodies in jawed vertebrates (gnathostomes) provides every immunologist with a bird's eye view of how human immunoglobulins (Igs) came into existence and subsequently evolved into their present forms. It is a fascinating Darwinian history of conservation on the one hand and flexibility on the other, exemplified by the Ig heavy chain (H) isotypes IgM and IgD/W, respectively. The cartilaginous fish (e.g., sharks) Igs provide a glimpse of "how everything got off the ground," while the amphibians (e.g., the model Xenopus) reveal how the adaptive immune system made an about face with the emergence of Ig isotype switching and IgG-like structure/function. The evolution of mucosal Igs is a captivating account of malleability, convergence, and conservation, and a call to arms for future study! In between there are spellbinding chronicles of antibody evolution in each class of vertebrates and rather incredible stories of how antibodies can adapt to occupy niches, for example, single-domain variable regions, cold-adapted Igs, convergent mechanisms to dampen antibody function, provision of mucosal defense, and many more. The purpose here is not to provide an encyclopedic examination of antibody evolution, but rather to hit the high points and entice readers to appreciate how things "came to be."

Nanobodies are the products of an intriguing invention in the evolution of immunoglobulins. This invention can be traced back approximately 45 million years to the common ancestor of extant dromedaries, camels, llamas, and alpacas. Next to conventional heterotetrameric H2L2 antibodies, these camelids produce homodimeric nanobody-based heavy chain antibodies, composed of shortened heavy chains that a lack the CH1 domain. Nanobodies against human target antigens are derived from immunized animals and/or synthetic nanobody libraries. As a robust, highly soluble, single immunoglobulin domain, a nanobody can easily be fused to another protein, for example to another nanobody and/or the hinge and constant domains of other immunoglobulins. Nanobody-derived heavy chain antibodies hold promise as a new form of immunotherapeutics.

Antibodies have multiple biological activities. They can both recognize and act on specific antigens. They can protect against and cause serious diseases, enhance and inhibit antibody responses, enable survival, and threaten life. Which among their many, often antagonistic properties explains that antibodies were selected half a billion years ago and transmitted to mammals across millions of generations? In other words, what is the function of antibodies? Here I examine how their structure endows antibodies with unique cognitive and effector properties that contribute to their multiple biological activities. I show that rather than specific properties, antibodies have large functional repertoires. They have a cognitive repertoire and an effector repertoire that are selected from larger available repertoires, themselves drawn at random from even larger virtual repertoires. These virtual repertoires provide the adaptive immune system with immense, constantly renewed, reservoirs of cognitive and effector functions that can be actualized at any time according to the context. I propose that such a flexibility, which enables living individuals to adapt to a rapidly changing environment, and even deal with an unknown future, may provide a better selective advantage than any particular function.

Natural killer (NK) cells are innate immune effectors whose functions rely on receptors binding cytokines, recognizing self-molecules, or detecting danger signals expressed by virus-infected or tumor cells. The potent cytotoxic potential makes NK cells promising candidates for cancer immunotherapy. To enhance their activity strategies include cytokine administration, blocking of immune checkpoints, and designing of antibody-based NK cell engagers (NKCEs). NKCEs represent a cutting-edge approach to cancer therapy: they strengthen the NK-to-target cell interactions and optimize tumor killing, possibly overcoming the immunosuppressive tumor microenvironment. NK cells belong to the innate lymphoid cells (ILCs) and are categorized into different subsets also including cells with a memory-like phenotype: this complexity needs to be explored in the context of cancer immunotherapy, particularly when designing NKCEs. Two strategies to enhance NK cell activity in cancer patients can be adopted: activating patients' own NK cells versus the adoptive transfer of ex vivo activated NK cells. Furthermore, the capability of NKCEs to activate γδ T cells could have a significant synergistic effect in immunotherapy.

Antibodies are able to up- or downregulate antibody responses to the antigen they bind. Two major mechanisms can be distinguished. Suppression is most likely caused by epitope masking and can be induced by all isotypes tested (IgG1, IgG2a, IgG2b, IgG3, IgM, and IgE). Enhancement is often caused by the redistribution of antigen in a favorable way, either for presentation to B cells via follicular dendritic cells (IgM and IgG3) or to CD4⁺ T cells via dendritic cells (IgE, IgG1, IgG2a, and IgG2b). IgM and IgG3 complexes activate complement and are transported from the marginal zone to follicles by marginal zone B cells expressing complement receptors. IgE-antigen complexes are captured by CD23⁺ B cells in the blood and transported to follicles, delivered to CD8α⁺ conventional dendritic cells, and presented to CD4⁺ T cells. Enhancement of antibody responses by IgG1, IgG2a, and IgG2b in complex with proteins requires activating FcγRs. These immune complexes are captured by dendritic cells and presented to CD4⁺ T cells, subsequently helping cognate B cells. Endogenous feedback regulation influences the response to booster doses of vaccines and passive administration of anti-RhD antibodies is used to prevent alloimmunization of RhD-negative women carrying RhD-positive fetuses.

Heavy-chain antibodies (HCAbs) are a unique type of antibodies devoid of light chains, and comprised of two heavy chains-only that recognize their cognate antigen by virtue of a single variable domain also referred to as VHH, single domain antibody (sdAb), or nanobody (Nb). These functional HCAbs, serendipitous discovered about three decades ago, are exclusively found in camelids, comprising dromedaries, camels, llamas, and vicugnas. Nanobodies have become an essential tool in biomedical research and medicine, both in diagnostics and therapeutics due to their beneficial properties: small size, high stability, strong antigen-binding affinity, low immunogenicity, low production cost, and straightforward engineering into more potent affinity reagents. The occurrence of HCAbs in camelids remains intriguing. It is believed to be an evolutionary adaptation, equipping camelids with a robust adaptive immune defense suitable to respond to the pressure from a pathogenic invasion necessitating a more profound antigen recognition and neutralization. This evolutionary innovation led to a simplified HCAb structure, possibly supported by genetic mutations and drift, allowing adaptive mutation and diversification in the heavy chain variable gene and constant gene regions. Beyond understanding their origins, the application of nanobodies has significantly advanced over the past 30 years. Alongside expanding laboratory research, there has been a rapid increase in patent application for nanobodies. The introduction of commercial nanobody drugs such as Cablivi, Nanozora, Envafolimab, and Carvykti has boosted confidence among in their potential. This review explores the evolutionary history of HCAbs, their ontogeny, and applications in biotechnology and pharmaceuticals, focusing on approved and ongoing medical research pipelines.

Antibodies generated after vaccination or natural pathogen exposure are essential mediators of protection against many infections. Most studies with viruses have focused on antibody neutralization, in which protection is conferred by the fragment antigen binding region (Fab) through targeting of different steps in the viral lifecycle including attachment, internalization, fusion, and egress. Beyond neutralization, the fragment crystallizable (Fc) region of antibodies can integrate innate and adaptive immune responses by engaging complement components and distinct Fc gamma receptors (FcγR) on different host immune cells. In this review, we discuss recent advances in our understanding of antibody neutralization and Fc effector functions, and the assays used to measure them. Additionally, we describe the contexts in which these mechanisms are associated with protection against viruses and highlight how Fc-FcγR interactions can improve the potency of antibody-based therapies.

In this review, we will highlight infants' immune responses to food, emphasizing the unique aspects of early-life immunity and the critical role of breast milk as a food dedicated to infants. Infants are susceptible to inflammatory responses rather than immune tolerance at the mucosal and skin barriers, necessitating strategies to promote oral tolerance that consider this susceptibility. Breast milk provides nutrients for growth and cell metabolism, including immune cells. The content of breast milk, influenced by maternal genetics and environmental exposures, prepares the infant's immune system for the outside world, including solid foods. To do this, breast milk promotes immune system development through antigen-specific and non-antigen-specific immune education by exposing the newborn to food and respiratory allergens and acting on three key targets for food allergy prevention: the gut microbiota, epithelial cells, and immune cells. Building knowledge of how the maternal exposome and human milk composition influence offspring's healthy immune development will lead to recommendations that meet the specific needs of the developing immune system and increase the chances of promoting an appropriate immune response to food in the long term.

DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights the involvement of DNA sensors in metabolic and cardiovascular diseases. Elevated levels of modified, damaged, or ectopically localized self-DNA and non-self-DNA have been observed in patients and animal models with obesity, diabetes, fatty liver disease, and cardiovascular disease. The accumulation of cytosolic DNA aberrantly activates DNA signaling pathways, driving the pathological progression of these disorders. This review highlights the roles of specific DNA sensors, such as cyclic AMP-GMP synthase and stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), interferon gamma-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA-PK), and DEAD-box helicase 41 (DDX41) in various metabolic disorders. We explore how DNA signaling pathways in both immune and non-immune cells contribute to the development of these diseases. Furthermore, we discuss the intricate interplay between metabolic stress and immune responses, offering insights into potential therapeutic targets for managing metabolic and cardiovascular disorders. Understanding the mechanisms of DNA sensor signaling in these contexts provides a foundation for developing novel interventions aimed at mitigating the impact of these pervasive health issues.