Lyme disease is the most common tick-borne bacterial infection in the Northern Hemisphere. The causative agent is a spirochete belonging to the Borrelia burgdorferi sensu lato complex, which is primarily transmitted by Ixodes species. The clinical spectrum of the disease is extremely broad: it can range from early localised skin symptoms (erythema migrans) to joint, neurological or cardiac manifestations. In recent years, an increasing number of studies have addressed the question of how the immune response triggered by the infection might be linked to allergic and inflammatory mediators, particularly histamine. Although the relationship between histamine and Lyme disease is not yet fully understood, several immunological and pathophysiological mechanisms suggest the possibility of such an interaction.
The role of histamine in the immune response
Histamine is a biogenic amine primarily released from mast cells and basophils. Its role is multifaceted: it participates in allergic reactions, the regulation of vascular permeability, and the modulation of the innate and adaptive immune responses. Via histamine receptors (H1–H4), it influences the function of various immune cells, including the direction of the T-cell response, cytokine production and inflammatory processes.
In recent years, a growing body of evidence suggests that histamine is not merely a mediator of allergic reactions, but also an important immunomodulator in infectious diseases. This may be of particular significance in conditions where the interaction between the pathogen and the immune system is complex and prolonged, such as in Lyme borreliosis.
Tick bites and the release of histamine
The first step in the pathogenesis of Lyme disease is the bite of an infected tick. Tick saliva contains numerous bioactive molecules designed to locally inhibit the immune response and facilitate blood feeding. Research has shown that tick saliva contains a so-called ‘histamine release factor’ (tHRF), which is capable of stimulating the release of histamine from basophils in the human host. This process increases local vascular permeability and blood flow, which facilitates the tick’s feeding and the transmission of the pathogen.
Interestingly, tHRF expression is elevated in ticks infected with Borrelia burgdorferi, suggesting that the pathogen itself may contribute to the establishment of a histamine-mediated environment in the early stages of infection. This mechanism may potentially facilitate the entry and local spread of the bacterium within the skin.
Borrelia and mast cell activation
Among the immune cells found in the skin, mast cells play a particularly important role in the early immune response. These cells react rapidly to microbial components and release mediators such as histamine, cytokines and proteases.
Experimental studies have shown that Borrelia burgdorferi is capable of directly activating mast cells. In vitro experiments demonstrated that the presence of the bacterium induced low-level degranulation and the release of inflammatory cytokines, such as TNF-α, from mast cells. This phenomenon suggests that the release of histamine in the early stages of infection may form part of the innate immune response.
Other studies have also shown that certain surface proteins of Borrelia – such as the OspC lipoprotein – can also trigger degranulation of mast cells. This process may contribute to the local inflammatory response, which may also play a role clinically, for example, in the development of erythema migrans.
IgE response and histamine release in Lyme infection
One of the immunological characteristics of Lyme disease is that, during infection, not only does a classic bacterial immune response develop, but in certain cases reactions resembling allergic mechanisms can also be observed. An early study showed that specific IgE antibodies are produced against Borrelia burgdorferi antigens in some Lyme disease patients.
The same study also observed that spirochaete antigens are capable of triggering histamine release from basophils. Although total serum IgE levels remained within the normal range in the majority of patients, a significant increase was observed in some cases. These results suggest that, under certain immunological conditions, Lyme infection can also trigger allergy-type reactions.
Histamine and the polarisation of the immune response
Histamine plays an important role in the regulation of the T-cell immune response. In the immunology of Lyme disease, the balance between Th1 and Th2 responses is particularly important. Effective early defence is generally associated with a Th1-dominant reaction, which promotes bacterial elimination.
According to some hypotheses, histamine signalling may influence this balance. For example, activation of H2 receptors may have an immunomodulatory effect and contribute to a reduction in the Th1 response. This has raised the possibility that H2 receptor antagonists – such as cimetidine – may play an immunomodulatory role in the early stages of Lyme disease, potentially promoting a more effective Th1 response.
It is important to emphasise, however, that these ideas are primarily based on theoretical or experimental evidence, and clinical evidence is currently limited.
Clinical implications and research directions
The link between histamine and Lyme disease may be clinically significant in several respects. On the one hand, in the early stages of infection, histamine may contribute to the inflammatory reaction around the tick bite and to the transmission of the pathogen. On the other hand, the activation of mast cells and basophils may play a role in shaping the immunological environment of the infection.
In recent years, an increasing number of studies have investigated the role of mast cells and innate immunity in the pathogenesis of Lyme borreliosis. Although there is currently no evidence that histamine is directly responsible for the chronic symptoms of the disease, mapping the immunomodulatory mechanisms may help to better understand the complex immunology of the infection.
One important avenue for future research may be to clarify whether targeted modulation of histamine signalling pathways – for example, through the use of antihistamines or receptor antagonists – can influence the course of the disease or the nature of the immune response.
Summary
Based on the available experimental and immunological data, histamine may be involved in the pathogenesis of Lyme disease at several points. The histamine-releasing factor found in tick saliva, mast cell activation induced by Borrelia burgdorferi, and the IgE response observed in some patients all suggest that histamine may play a role in the early immunological processes of the infection. However, there is currently insufficient clinical evidence to suggest that histamine is a central pathogenic factor in the late or chronic forms of the disease.
Further investigation into the link between histamine and Lyme disease may contribute to a better understanding of the disease’s immunological mechanisms and, in the long term, even to the development of new therapeutic approaches.
Sources:
https://pubmed.ncbi.nlm.nih.gov/2437736/
https://pubmed.ncbi.nlm.nih.gov/10024550/
https://pubmed.ncbi.nlm.nih.gov/21124826/
(C) Lyme Borreliosis Foundation
