Deadline for manuscript submissions: 30 September 2025.
Aging has been associated with an increase in the expression of MHC class I molecules (MHC-I, HLA-I in humans, and H-2 in mice) in the brain, a process linked to synaptic pruning and neurodegeneration. However, several studies have also suggested a role for MHC-I molecules in neuroregeneration. Chronic low-grade inflammation is a common feature of the aging brain and is related to cognitive decline. In Alzheimer's and Parkinson's diseases, increased expression of MHC-I molecules in the brain parenchyma (e.g., microglia, endothelial cells, neurons, etc.) has been associated with dysregulation of brain homeostasis and cognitive decline. Interestingly, certain HLA-I genes/alleles, such as HLA-A2, HLA-A23, HLA-A24, HLA-B7, and HLA-B8, are associated with neurodegeneration. In contrast, others, such as HLA-B40 and HLA-C03, confer protection, suggesting a common role for MHC-I molecules in fine-tuning the equilibrium between neurodegeneration and neuroregeneration.
In this special issue of Immune Discovery, we invite you to contribute original research articles, reviews, case reports, or expert perspectives and/or opinions on all aspects related to "MHC Class I Research in Aging and Brain Homeostasis (ABH)."
Relevant topics related to ABH might include:
As mankind breaks the boundaries of potential years to live, the process of aging imposes various cellular challenges, from less capacity of cell repair and damage to impaired protein formation, causing chronic low-level inflammation on tissues including the brain. Persistent chronic neuroinflammation can harm neurons, contributing to the development of neurodegeneration, a pathological process that affects cognitive function and is often reflected by dementia. This opinion article tries to recapitulate the influence that major histocompatibility class I (MHC-I) molecules have on brain homeostasis and how abnormalities in their expression can lead to cognitive deterioration. Studies carried out during recent years not only demonstrated that neurons and other central nervous system (CNS) cells express MHC-I molecules, but also that these molecules play essential roles in the establishment, function, and modeling of synapses in the CNS during the embryonic period, at birth and during adulthood, namely during inflammatory conditions. The accumulated body of evidence suggests that MHC-I molecules and the signaling pathways they regulate could provide clues on some of the molecular and cellular mechanisms regulating brain homeostasis and neuroregeneration in health and disease, thus becoming potential biomarkers of cognitive decline and targets for innovative immunotherapies.
This Perspective paper is motivated by a novel understanding of the human glymphatic system (GS) functional anatomy, its critical role in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative and autoimmune disorders, as well as by novel therapeutic possibilities critically relevant in enhancing the GS function and its healing. Non-invasive transcranial magnetic stimulation (TMS) technology and administration of cell-free extracellular vesicles (EVs) in clinical conditions may well constitute potentially synergistic, versatile, and effective next generation neurotherapeutic approaches to treat human GS dysfunctions. Brain stimulation approaches, such as TMS, act upon brain circuits, which have been strongly considered candidate endophenotypes and factual targets in neuromodulation interventions using multimodal neuroimaging. The dorsolateral prefrontal cortex (DLPFC) has been proposed as a potential target for neuromodulating the GS, a fluid-compartment mechanism involved in waste disposal that is not entirely elucidated in humans, yet considered of critical importance for the normal functioning of the brain and a key factor for its dysfunction in such neurodegenerative conditions as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Likewise, EVs have been proposed as potential GS therapeutic agents, given their capability to traverse the blood-brain barrier (BBB), reduce neuroinflammation, increase cellular communication and central nervous system (CNS) homeostasis, and promote healing. The combined effect of TMS-EEG (TMS-Electroencephalography), and EV approach is putatively complementary, and thus we envision their combined use as a promising, versatile, and potentially effective next generation neurotherapeutic strategy to treat human GS dysfunctions and to become a powerful asset in the treatment of neurodegenerative and autoimmune disorders. Furthermore, anatomically accurate neuroimaging-based navigation of TMS and the assessment of GS functionality via diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) enable precision-medicine personalized interventions in these disorders. On these grounds, we formulate a hypothesis-driven conceptual framework connecting neurocircuitry-based neuromodulation, EV-mediated neuroimmune effects, and DTI-ALPS assessable glymphatic function to identify directions for future experimental and translational clinical research.
