Neuroimmunology is the discipline that studies the complex and dynamic communication between the nervous system and the immune system1. It was once believed that the brain was a solitary fortress, insulated from the turmoil of the body’s immune response by the blood-brain barrier. But this ancient dogma has been overthrown. We now know that the brain and immune cells are always in dynamic communication, interacting not just when illness or injury occurs, but throughout a person’s life, even in good health. Neuroimmunology explores how the nervous system and the immune system influence each other’s development, balance, and responses, and how their miscommunications can initiate neurological dysfunction.
The brain-immune axis
The so-called “brain-immune axis”—bidirectional communication pathways—permit the brain and immune system to influence each other at every turn. This network is accessed through various routes. Through soluble messengers like cytokines, chemokines, and hormones, vital information about infection, stress, or trauma can be effectively communicated across the blood-brain barrier. Neural circuits, including the autonomic nerves and the vagus, serve as lightning-fast communication lines, carrying immune messages from the periphery of the body to the command centers of the brain2. Immune cells from the periphery, such as T cells and monocytes, can also cross into the brain, particularly when there is inflammation but even under some healthy conditions3. The blood-brain barrier itself, previously considered a passive barrier, is now known to be an active checkpoint, comprising endothelial cells, pericytes, astrocytes, and microglia that control what enters and leaves, and when4.
Key cellular players in the neuroimmune landscape
A of specialized cells choreographs the brain’s immune responses.
- Microglia, the brain’s immune sentinels, are capable of pro-inflammatory or anti-inflammatory functions, influencing damage as well as repair5.
- Astrocytes, the star-shaped supporting cells, preserve the blood-brain barrier and regulate immune functions6.
- Oligodendrocytes insulate neurons with myelin, playing a major role in demyelinating diseases7.
- Peripheral immune cells—T cells, B cells, macrophages, tend to exist outside the brain but can invade or patrol certain brain areas and the meninges even in health8. The presence of T cells in healthy brain areas, potentially migrating from the gut, suggests a much broader immune surveillance system than once conceived9.
- The identification of meningeal lymphatic vessels indicates that a direct pathway exists for immune cells and waste to flow between the brain and peripheral lymph nodes10.
Neuroinflammation as a double-edged sword
Neuroinflammation refers to the brain’s immune reaction to injury, infection, or disease11. In its acute form, it may be beneficial, aiding in the elimination of pathogens and tissue repair12. But when this reaction becomes chronic or dysregulated, it becomes pathological, driving neurodegeneration and chronic dysfunction13. This is a complex array of signaling molecules, from pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, to anti-inflammatory drugs such as IL-10 and TGF-β. Microglia and astrocytes are the key players, but peripheral immune cells can get involved too14, 15.
Inflammasomes such as NLRP3 are major areas of research as the prime culprits of neuroinflammation in Alzheimer’s and Parkinson’s diseases, with novel therapies aimed at these mechanisms16, 17. Researchers also are exploring “smoldering” neuroinflammation—background, low-level inflammation that fuels relentless disability in conditions like multiple sclerosis, independent of acute attacks18. There’s increasing interest in dissecting how various types of neural cells perpetuate and react to inflammation, and how this influences disease outcomes.
Major neuroimmune disorders and recent advances
Multiple Sclerosis is the paradigm of neuroimmune disease, characterized by autoimmune invasion against myelin in the central nervous system19. Progress in immunomodulatory treatments has revolutionized the field, with novel medications directed against B cells, T cells, and other targets. Increasing attention is now directed towards neuroprotection and the use of biomarkers like neurofilament light chain20. These help to track smoldering inflammation and neuronal injury, aiming to prevent relapses along with reducing long-term disability.
Autoimmune encephalitis, in which antibodies are directed against neuronal surface antigens, is now more readily diagnosed, with the discovery of additional autoantibodies and more specific immunotherapies21. Neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disease (MOGAD) can now be differentiated from multiple sclerosis, and precise antibody tests (anti-AQP4, anti-MOG) allow for correct diagnosis and extremely effective specific treatments22, 23.
In neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), immune cell dysfunction and neuroinflammation are increasingly viewed as primary drivers, not merely outcomes, of neuronal injury and progression24, 25. Psychiatric disorders, depression, anxiety, and schizophrenia are also now being reconsidered from a neuroimmune perspective, with growing evidence implicating systemic and brain inflammation in their etiology26-29. The gut-brain-immune axis is especially relevant here, as is the investigation into long-term viral infection neuroimmune effects, including post-COVID neurological syndromes30, 31.
The gut-brain-immune axis: a central player in health and disease
The gut is more than a digestive organ. It is a command center that is full of microbes that produce metabolites and neurotransmitters, control immune responses, and communicate with the brain. The gut-brain-immune axis refers to the two-way communication between the gut microbiota, the gut lining, the enteric nervous system, the immune system, and the brain. Short-chain fatty acids and other metabolites are made by gut microbes, gut barrier integrity is controlled, and both immune and brain function are modulated.
This axis is strongly associated with neurological and psychiatric disorders, such as autism spectrum disorder, Parkinson’s, Alzheimer’s, depression, and anxiety32. Manipulation of the gut microbiome with probiotics, prebiotics, diet, or fecal transplants, is being considered as a new therapeutic approach to brain diseases33. The recent discovery that T cells originating from the gut can migrate into the healthy brain emphasizes the direct immune route within this axis, adding yet another aspect of brain-immune interaction9.
Emerging therapeutic strategies and technologies
The future of neuroimmunology is being influenced by emerging therapeutic strategies and technologies. Highly specific biologics and small molecules are in development to selectively target aberrant immune pathways while maintaining necessary immune functions. Cell-based therapies, including mesenchymal stem cells, are being studied for their immunomodulatory and neuroprotective properties34.
Earlier diagnosis and tailored treatment are becoming increasingly feasible thanks to the ongoing search for reliable biomarkers found in spinal fluid, blood, or via advanced imaging35. Artificial intelligence and big data are easing the complexity of neuroimmune relationships, revealing new drug targets, and speeding discovery36. Most promising, perhaps, is the major shift toward neuroprotection—approaches designed to actively protect neurons and glial cells from immune-mediated injury and chronic inflammation—with the hope of slowing or stopping the progress of neurodegenerative diseases37.
Conclusion
Neuroimmunology is now at the center of our knowledge of how brain and body communicate during health and disease. The brain-immune axis is no longer a theoretical entity, but a solid hypothesis for exploring the origin of neurological, psychiatric, and systemic diseases. In uncovering the sophistication of such interactions, opportunities for novel, tailored diagnostics and treatments expand exponentially. The next few years hold out great promise, new hope for the people, and new knowledge for science.