Mast cells have traditionally been recognised as effector cells in allergic and inflammatory processes; however, research over the past few decades has shed fundamentally new light on their role. It can now be clearly stated that these cells are not merely passive participants in the immune response, but also active regulators of neuroimmune communication. This is of particular significance in the case of infections that also affect the nervous system, such as those caused by Borrelia burgdorferi (which causes Lyme disease) or Bartonella infections. There is growing evidence to suggest that mast cell activation is not solely the result of classic inflammatory stimuli, but may be directly linked to the functioning of the nervous system and its infection-induced dysregulation.
From an anatomical and functional perspective, the connection between mast cells and the nervous system is close and well documented. Mast cells are often located directly near nerve endings in both peripheral tissues and the border regions of the central nervous system, such as the meninges and perivascular regions. This location enables rapid and efficient communication between the two systems. It has been demonstrated that neurotransmitters and neuropeptides released by neurons, such as substance P or calcitonin gene-related peptide (CGRP), are capable of directly activating mast cells. At the same time, mediators released by mast cells – such as histamine, tryptase, cytokines and chemokines – act back on nerve cells, influencing their excitability and contributing to the development of pain and neuroinflammation. This bidirectional communication can be described as a so-called ‘mast cell–nerve unit’, which forms one of the basic units of neuroimmune regulation.
The activation of mast cells is therefore a far more complex process than that assumed by the classical immunological model. Although IgE-mediated allergic reactions remain important, it is now known that numerous non-classical stimuli can also trigger degranulation. These include neuropeptides, stress-related mediators, and various microbial components. It is particularly significant that stimuli of neuronal origin may be sufficient on their own to activate mast cells, even in the absence of a significant inflammatory environment. This means that a functional disturbance of the nervous system – for example, as a result of infection – can directly trigger mast cell activation.
In the case of Borrelia burgdorferi, several experimental data support this link. In vitro studies have shown that Borrelia spirochetes are capable of directly inducing mast cell degranulation and triggering the production of inflammatory cytokines, such as TNF-α. Interestingly, this effect does not occur exclusively via classical lipid-bound bacterial antigens, suggesting that alternative activation pathways also play a role. Furthermore, mast cells contribute to the early immune response to infection, whilst they may also participate in the maintenance of inflammation and the persistence of the pathogen. As Borrelia is capable of causing neurological complications, a complex neuroimmune mechanism is postulated. Damage to the nervous system caused by the infection may result in increased release of neuropeptides and neurotransmitters, which activate nearby mast cells. These mast cells release further inflammatory mediators, which further exacerbate neuroinflammation and nervous system dysfunction, thus creating a self-perpetuating, positive feedback loop.
In the case of Bartonella infections, there is less direct evidence regarding the role of mast cells; however, based on clinical and pathophysiological data, a similar mechanism can be hypothesised. Bartonella species are known to affect the nervous system, causing various neurological and neuropsychiatric symptoms. Chronic inflammatory and vascular abnormalities are also characteristic. These processes create an environment in which the activation and stress response of nerve cells are heightened, which may secondarily lead to mast cell activation. Although this model is currently largely hypothetical, it fits well with already known neuroimmune interactions.
In the central nervous system, mast cells play a particularly important role in regulating neuroinflammation. Upon activation, they release numerous mediators that influence blood–brain barrier permeability, promote the activation of microglia and astrocytes, and may contribute to neurodegenerative processes. In the event of infection, when the nervous system is already damaged or under stress, mast cell activation can significantly exacerbate the disease process.
Based on this, it is increasingly accepted that mast cell activation is not merely a consequence of inflammation, but in many cases one of its triggers or maintainers, particularly in a neuroimmune context. This realisation has important clinical implications. It may, for example, explain why persistent, chronic symptoms such as pain, cognitive impairment or autonomic nervous system dysfunction develop following certain infections. It also raises the possibility that infections and neurological abnormalities may underlie certain cases of mast cell activation syndrome (MCAS). From a therapeutic perspective, this may open up new approaches, such as mast cell-stabilising treatments, reducing neuroinflammation, or restoring nervous system regulation.
Overall, it can be concluded that the role of mast cells in neurological processes associated with infections is far more significant than previously thought. In the case of Borrelia burgdorferi, direct evidence of mast cell activation is already available, whilst in the case of Bartonella, a similar mechanism is highly likely based on current data. Due to the close connection between mast cells and the nervous system, these cells may play a key role in neuroimmune dysregulation, which may underlie numerous chronic symptoms.
Sources:
https://pubmed.ncbi.nlm.nih.gov/36902240/
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https://pmc.ncbi.nlm.nih.gov/articles/PMC96436/
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https://pmc.ncbi.nlm.nih.gov/articles/PMC6524694/
https://www.frontiersin.org/articles/10.3389/fncel.2019.00110/full
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