Malaria remains a significant global health challenge, particularly in tropical regions, where high morbidity and mortality persist. The need for new therapeutic strategies remains urgent as increasing antimalarial drug resistance threatens treatment efficacy and highlights the need for innovative approaches that target not only the parasite but also host–pathogen interactions. While malaria immunology has traditionally focused on adaptive responses, including T-cell dysfunction, the role of innate immune checkpoints remains underexplored. Among these, CD47- a transmembrane protein best known for delivering a “don't-eat-me” signal to phagocytes has emerged as a potential therapeutic target. This concept is particularly relevant to malaria because Plasmodium infects red blood cells, whose survival and clearance are tightly regulated by CD47–SIRPα signalling.Emerging evidence suggests that CD47 contributes to the regulation of phagocytic clearance of infected red blood cells and may influence inflammatory responses associated with disease severity. Disruption of CD47–SIRPα signalling may enhance host phagocytic responses, promoting clearance of parasitized erythrocytes and potentially improving disease control. This review examines the immunopathological role of CD47 in malaria, evaluates its potential as a host-directed therapeutic target, and discusses the challenges and future directions for translating CD47-targeted strategies into clinical practice. CD47, therefore represents a promising but incompletely validated host-directed therapeutic target, with important translational gaps that must be addressed before clinical application.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder associated with dementia, progressive neuronal loss, extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau deposition. Currently, no curative therapies are available for this condition. Beyond these features, AD pathogenesis is associated with neuroinflammation, which is thought to be primarily driven by microglial cells, and has evolved as an important contributor to AD pathogenesis over the past decade. Although microglia cells play a central role in neuroinflammation, they are also a highly heterogeneous population existing in distinct transcriptional states that can be either beneficial or detrimental to disease progression. Importantly, microglial activation and the ensuing neuroinflammatory milieu do not operate independently of the systemic immune system. The longstanding view of the brain as an immune-privileged organ has been fundamentally revised, with increasing evidence demonstrating that the crosstalk between brain-resident and circulating peripheral immune cells plays a pivotal role in AD pathogenesis. Peripheral immune cells, recruited in the central nervous system in response to Aβ and tau pathology, actively modulate the neuroinflammatory environment. While CD4+ and CD8+ T cells have been extensively investigated in this context, the contribution of B cells to AD remains poorly understood. Here, we comprehensively review the phenotypic and functional alterations of B cells in AD, integrating evidence from experimental models and human studies, to evaluate whether B cells constitute an underappreciated component of the adaptive immune response in AD and whether they represent a compelling immunotherapeutic target. We also highlight key unresolved questions and propose future research directions to guide the field towards a deeper mechanistic understanding of B cell biology in AD.
BACKGROUND:Mucosal-associated invariant T (MAIT) cells are innate-like T cells that respond rapidly to microbial metabolites presented by MR1. Patients with aplastic anemia (AA) are prone to bacterial and fungal infections, but the MR1-related effector responses of MAIT cells in AA remain unclear. METHODS:Peripheral blood mononuclear cells from 27 patients with AA and 29 healthy individuals were stimulated with fixed Escherichia coli for 2, 3, 6, or 12 h, with or without MR1 blockade. CD8+ MAIT cell activation, cytokine production, degranulation, CD69 expression, and polyfunctional profiles were assessed by flow cytometry. RESULTS:CD8+ MAIT cells from patients with AA showed higher CD69 expression under unstimulated conditions, suggesting a basal activation state. After fixed E. coli stimulation, CD8+ MAIT cells from patients with AA displayed enhanced early effector responses compared with those from healthy individuals, characterized by increased TNF production, CD107a expression, and polyfunctional subset frequencies, particularly CD107a+TNF+ populations. These enhanced responses were most pronounced at 6 h after stimulation. MR1 blockade markedly reduced E. coli-induced cytokine production and CD107a expression in CD8+ MAIT cells, supporting an important contribution of MR1-dependent signaling to these responses. CONCLUSIONS:In patients with AA, CD8+ MAIT cells display markedly enhanced effector functions and polyfunctional responses upon E. coli stimulation. These findings indicate that riboflavin metabolism-related bacterial infection in patients with AA can induce functional disorders of CD8+ MAIT cells via the MR1-TCR pathway.
Autoreactive T and B cells recognizing tissue-associated self-antigens are tolerized in the periphery, where dendritic cells (DCs) initiate the inactivation of autoreactive T cells. Here, we generated a mouse model in which a neo-self-antigen is expressed in the epidermis and examined interactions between DCs and antigen-specific CD4 T cells, as well as between CD4 T cells and B cells under tolerant conditions. We found that one of the tumor necrosis factor receptor superfamily (TNFRSF) molecules, herpesvirus entry mediator (HVEM), in CD4 T cells performs two key functions: it promotes regulatory T cell (Treg) expansion in response to epidermal antigen and suppresses B cell activation by sending inhibitory signals. HVEM-deficient Tregs failed to respond to self-antigen-loaded migratory DCs from the skin, whereas HVEM-deficient CD4 T cells enhanced B cell activation, leading to increased IgG1+ B cells. These findings demonstrate that HVEM in CD4 T cells contributes to peripheral tolerance to tissue-associated self-antigens by promoting Treg expansion and restraining B cell responses.
