International Reviews of Immunology最新文献

Aluminum salt-based adjuvants like alum, alhydrogel and Adju-Phos are by far the most favored clinically approved vaccine adjuvants. They have demonstrated excellent safety profile and currently used in vaccines against diphtheria, tetanus, pertussis, hepatitis B, anthrax etc. These vaccinations cause minimal side effects like local inflammation at the injection site. Aluminum salt-based adjuvants primarily stimulate CD4⁺ T cells and B cell mediated Th2 immune response leading to generate a robust antibody response. In this review article, we have compiled the role of physio-chemical role of the two commonly used aluminum salt-based adjuvants alhydrogel and Adju-Phos, and the effect of surface properties, buffer composition, and adjuvant dosage on the immune response. After being studied for almost a century, researchers have come up with various mechanism by which these aluminum adjuvants activate the immune system. Firstly, we have covered the initial works of Glenny and his "repository effect" which paved the work for his successors to explore the involvement of cytokines, chemokines, recruitment of innate immune cells, enhanced antigen uptake by antigen presenting cells, and formation of NLRP3 inflammasome complex in mediating the immune response. It has been reported that aluminum adjuvants activate multiple immunological pathways which synergistically activates the immune system. We later discuss the recent developments in nanotechnology-based preparations of next generation aluminum based adjuvants which has enabled precise size control and morphology of the traditional aluminum adjuvants thereby manipulating the immune response as per our desire.

Mycobacterium tuberculosis (M. tb) employs diverse virulence factors to evade immune defenses and persist intracellularly. The ESAT-6 secretion system-1 (ESX-1) type VII secretion system (T7SS) releases EsxA, EspA, and EspB, inducing phagosomal rupture and cytosolic access while triggering host defenses, including galectin recruitment and stress granule formation. To counteract host responses, M. tb utilizes phthiocerol dimycocerosates (PDIMs) to inhibit autophagy and LC3-associated phagocytosis (LAP) by suppressing NADPH oxidase (NOX2) recruitment and reactive oxygen species (ROS) production. Additionally, CspA blocks LC3 lipidation, impairing LAP activation and phagosome maturation. EsxG and EsxH interfere with ESCRT-mediated phagosomal repair, further enhancing intracellular survival. Cytosolic M. tb is ubiquitinated by host E3 ligases, marking it for selective autophagy (xenophagy), yet M. tb evades degradation by manipulating autophagic flux. Simultaneously, M. tb-derived DNA activates the cyclic GMP-AMP synthase-stimulator of interferon response cGAMP interactor 1 (CGAS-STING1) axis, leading to type I interferon (IFN) signaling and inflammasome activation, which drive IL-1B and IL-18 secretion, necrosis, and pyroptosis, facilitating bacterial dissemination. Additionally, exosomes released during infection disseminate bacterial components, modulating immune responses systemically. This review uniquely integrates current findings on the coordinated actions of ESX-1 T7SS and PDIMs in mediating phagosomal rupture and immune evasion, offering a unified framework for understanding M. tb's intracellular survival strategies. By bridging lipid- and protein-mediated virulence mechanisms and their impact on host autophagy, inflammasome activation, and phagosomal repair pathways, this work provides novel insights into therapeutic targets aimed at restoring host immune function.

Antibody-drug conjugates (ADCs) are produced by integrating the specificity of monoclonal antibodies with cytotoxic payloads. ADCs are vital biologics for breast cancer treatment where they not only exert direct cytotoxicity but also promote anti-tumor immune responses against breast cancers. In this review, the structure, mechanism of action, and the anti-tumor immune response properties of approved and emerging ADCs are presented and discussed. The FDA-approved ADCs include trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG-Trop2), and trastuzumab deruxtecan (T-DXd), as well as two emerging ADCs, i.e. datopotamab deruxtecan (Dato-DXd) and ladiratuzumab vedotin (LV). Preclinical and clinical studies demonstrate their efficacy in multiple breast cancer subtypes (e.g. HER2⁺ and triple negative breast cancers). These ADCs exert anti-tumor activity through cytotoxic effects and immune responses primarily by recruiting and activating cytotoxic T cells. Moreover, combining ADCs with immune checkpoint inhibitors (ICIs) shows enhanced therapeutic outcomes. ADCs resistance is caused by heterogeneous target antigens expression, modified ADC processing including endocytosis and lysosomal trafficking, as well as upregulated drug-efflux pumps that decrease payload concentration intracellularly. Strategies to mitigate ADCs resistance include multi-target ADCs, and stability-enhancing linkers that also reduce off-target toxicities. ADCs continue to play key roles in breast cancer treatment, while next-generation ADCs may address current ADCs' limitations and resistance mechanisms.

Membranous nephropathy (MN), an autoimmune cause of adult nephrotic syndrome, is driven by podocyte-targeting antibodies against PLA2R/THSD7A. Current models fail to fully capture human disease progression. This review evaluates three transformative approaches: (1) Heterologous antibody-induced models enabling acute injury replication; (2) Antigen-driven immunization modeling adaptive immunity; and (3) GBF-on-Chip platforms mimicking filtration barrier dynamics. Collectively, they reveal complement-dependent and direct podocytotoxic injury mechanisms. While antibody-induced models offer rapid injury induction and high reproducibility, their transient phenotype cannot model chronic progression or immune tolerance breakdown. Antigen-driven models recapitulate adaptive immunity but face prolonged timelines and epitope targeting bias diverging from human IgG4 dominance. GFB-on-Chip systems excel in mechanistic dissection of podocyte injury but lack immune microenvironment integration and physiologically accurate glomerular architecture. This review synthesizes strategies for MN model development through antibody-podocyte interaction studies, critically evaluates the strengths of existing platforms, and discusses emerging technologies for probing disease mechanisms and accelerating therapeutic discovery.

Host immunity helps the body to fight against COVID-19. Single-cell transcriptomics has provided the scope of investigating cellular and molecular underpinnings of host immune response against SARS-CoV-2 infection at high resolution. In this review, we have systematically described the virus-induced dysregulation of relative abundance as well as molecular behavior of each innate and adaptive immune cell type and cell state during COVID-19 infection and for different vaccinations, based on single-cell studies published in last three-four years. Identification and characterization of these disease-associated specific cell populations might help to design better, efficient, and targeted therapeutic avenues.

Macrophages are the primary targets of mycobacterial infection, which plays crucial roles both in nonspecific defence (innate immunity) as well as specific defence mechanisms (adaptive immunity) by secreting various cytokines, antimicrobial mediators and presenting antigens to T-cells. Sequencing of the mycobacterial genome revealed that 10% of its coding ability is devoted to the Pro-Glu motif-containing (PE) and Pro-Pro-Glu motif-containing (PPE) family proteins. While the function of most of the genes belonging to the PE-PPE family initially remained unannotated, recent studies have shown that many proteins of this family play critical roles in bacterial growth and cell functions, and manipulation of host immune responses, indicating their potential roles in mycobacterial virulence. In this review, we have focussed on describing the immunological importance of particularly the PE group of proteins in the context of 'virulence' determinants and outcome of tuberculosis disease. Additionally, we have discussed about the roles of these proteins on host-pathogen-interaction and how some of these genes can be targeted which may help us in designing effective anti-TB therapeutics.

Innate lymphoid cells (ILCs) have emerged as pivotal players in the field of immunology, expanding our understanding of innate immunity beyond conventional paradigms. This comprehensive review delves into the multifaceted world of ILCs, beginning with their serendipitous discovery and traversing their ontogeny and heterogeneity. We explore the distinct subsets of ILCs unraveling their intriguing plasticity, which adds a layer of complexity to their functional repertoire. As we journey through the functional activities of ILCs, we address their role in immune responses against various infections, categorizing their interactions with helminthic parasites, bacterial pathogens, fungal infections, and viral invaders. Notably, this review offers a detailed examination of ILCs in the context of specific infections, such as Mycobacterium tuberculosis, Citrobacter rodentium, Clostridium difficile, Salmonella typhimurium, Helicobacter pylori, Listeria monocytogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Influenza virus, Cytomegalovirus, Herpes simplex virus, and severe acute respiratory syndrome coronavirus 2. This selection aimed for a comprehensive exploration of ILCs in various infectious contexts, opting for microorganisms based on extensive research findings rather than considerations of virulence or emergence. Furthermore, we raise intriguing questions about the potential immune functional resemblances between ILCs and epithelial cells, shedding light on their interconnectedness within the mucosal microenvironment. The review culminates in a critical assessment of the therapeutic prospects of targeting ILCs during infection, emphasizing their promise as novel immunotherapeutic targets. Nevertheless, due to their recent discovery and evolving understanding, effectively manipulating ILCs is challenging. Ensuring specificity and safety while evaluating long-term effects in clinical settings will be crucial.

The livers' ability to regenerate after injury has attracted the investigation of possible therapeutic targets for liver disease. Cells of the immune system are considered fundamental for the initiation, propagation, and termination of liver regeneration as they produce essential signaling molecules, such as cytokines, chemokines, and growth factors. Previous evidence mainly focused on macrophage involvement in liver regeneration, namely Kupffer cells which secrete mitogenic cytokines. However, recent evidence has implicated other immune cell subsets in liver regeneration including platelets, the complement system, dendritic cells, granulocytes, and innate and adaptive lymphocytes. The concurrent function of different immune cell subsets highlights functional redundancies between immune cells and the temporospatial dynamics of liver regeneration. In this review, we discuss our understanding of the role of immune cells in liver regeneration, recent advances and cellular targets identified for clinical therapy over the past decade.