Why is the standard Lab test for Lyme not conclusive?
Both in conventional and complementary medicine, detecting the Borrelia bacterium and certain co-infections is extremely challenging. The two most commonly used tests in conventional care are enzyme-linked immunosorbent assays (ELISA or EIA) and immunoblots (IB). ELISA is often used as an initial test, followed by IB if the result is positive. These tests measure the immune (antibody) response of the patient to the infection, rather than the infection itself. Borrelia is a unique organism that can significantly mislead the immune system, preventing a normal immune reaction. This often results in many false-negative outcomes, a lack of recognition, and inadequate treatment.
Why Is It So Difficult to Detect the Bacteria?
Tick saliva is rich in pharmacologically active substances that can quickly spread throughout the body. Of the 120 proteins found in tick saliva, only a few are well-understood in terms of their function and mechanisms. These substances have potent effects on the host's three primary defense mechanisms (1):
Inhibition of the Blood Clotting System
Ticks aim to drink blood without clotting agents and immune molecules that could interfere with their feeding. Therefore, tick saliva contains components that prevent blood from clotting.Suppression of Immune Mediators
Key immune system signals, such as 'alarmins' and other mediators responsible for swelling, redness, and heat at the infection site, are suppressed. Anti-inflammatory substances are also stimulated early on.Inhibition of the Immune Response
Both the innate immune system and the complement system are suppressed. The alternative pathway—one of the three primary functions of the complement system—is a critical first line of defense against invading pathogens and plays a role in tick resistance.
By suppressing the immune system, tick saliva inadvertently benefits the bacteria. Before the tick injects its suppressive substances (along with other pathogens) into the host, it first takes a sip of blood. This allows Borrelia to scan the host’s blood even before leaving the tick. Once inside the body, Borrelia can adapt remarkably well to new environmental conditions, such as changes in temperature, acidity, and other factors (2).
Borrelia's Advanced Evasion Mechanisms
The bacterium has multiple forms: a spiral shape (spirochete), a cyst form, and a biofilm-like structure. These adaptations make it difficult for both the immune system and diagnostic tests to detect the bacterium.
Borrelia has three outer layers, with the outer cell wall, like other bacterial species, consisting of a slimy layer of surface proteins (Outer Surface Proteins/Osp). This 'mucous skin' protects against the immune system’s T-cells. In typical gram-negative bacteria, these surface proteins are encoded by only 3 genes. However, in Borrelia, 150 genes are involved. Through horizontal gene transfer, the bacterium can continuously alter these surface antigens, camouflage itself by mimicking the host’s proteins, and thus deceive the immune system.
Borrelia can hide in tissues such as joints, the nervous system, and the brain, making it difficult to detect in blood samples.
Borrelia and the Immune System
The first line of defense the immune system deploys to protect the host against pathogens is the complement system. This tightly regulated cascade of enzymatic proteins is responsible for marking and phagocytizing pathogens. Both Borrelia and tick saliva can inhibit the complement system, keeping CRP levels low.
At the site of infection, the innate immune system responds to pathogens by producing various antimicrobial proteins and peptides. The Borrelia bacterium has demonstrated resistance to antimicrobial proteins like lactoferrin, azurocidin, and proteinase 3, as well as limited sensitivity to lysosomes. Borrelia's resistance to lactoferrin, an iron-binding transport protein, is partially due to the bacterium’s unique ability to survive without iron, unlike most other bacteria (3).
Cells of the innate immune system—including dendritic cells, neutrophils, and macrophages—quickly arrive at the infection site due to their proximity in the skin. They have the ability to phagocytize the bacterium, initiate inflammatory responses, and act as antigen-presenting cells. These antigen-presenting cells can recognize and respond to Borrelia’s surface antigens through Toll-like receptor 2 (TLR2). This triggers the production of cytokines, particularly pro-inflammatory ones like TNFα, IL-6, and IL-12, aimed at destroying the bacterium. To prevent unintended tissue damage, the cells later produce the anti-inflammatory cytokine IL-10 to “extinguish” the inflammation. Borrelia, however, stimulates an early increase in IL-10, suppressing phagocytosis and the secretion of pro-inflammatory cytokines.
Dendritic cells migrate to the lymph nodes, where they present Borrelia antigens to the adaptive immune system. The T-cells in the lymph nodes are present as naïve T-cells that have not yet encountered a pathogen. Only after contact with an antigen do they become active and differentiate. Antigen presentation is a crucial function of the innate immune system. Without clear instructions, the adaptive immune system cannot mount a specific response or produce the appropriate antibodies.
The Role of the Adaptive Immune System
While not exclusively, the adaptive immune system combats intracellular pathogens through a strong Th1 response, characterized by increased IFN-γ production, which further stimulates macrophage phagocytosis. Th1 cells are activated in response to viruses, intracellular bacteria like Borrelia, and many unicellular intestinal parasites. Research shows that Borrelia significantly diminishes Th1 activation. It achieves this by continuously altering its protein coating (antigens), making it difficult for naïve T-cells to identify the invader.
The Th2 response is essential for defending the host against extracellular pathogens and mitigating tissue damage. Th2 activation leads to the production of IL-4, IL-5, and IL-13. Th2 cells promote growth, healing, and wound repair by stimulating mast cells to release histamine. Together with B-cells (humoral immunity), Th2 cells act anti-inflammatory unless chronically activated. This part of the immune system can distinguish between self and foreign entities, such as extracellular bacteria, parasites, certain viruses, allergens, and even blood cells of a different blood type. When exposed to foreign antigens, B-cells are activated and differentiate into B-memory cells and B-plasma cells.
B-plasma cells produce specific antibodies belonging to the immunoglobulin family. These antibodies "tag" antigens (e.g., Borrelia), making it easier for Th1 cells to locate and destroy them. Cellular immune deficiencies caused by stress, corticosteroid therapies, chemotherapies, mycotoxins, etc., can lower the number of B-cells (and thus antibodies).
Challenges in Antibody Production Against Borrelia
In the first few weeks after infection, the body is unable to produce antibodies. Additionally, 5–10% of people in the Netherlands have antibodies in their blood due to past Borrelia infections, with or without symptoms. Moreover, conventional tests detect only free antibodies, not those already bound to Borrelia antigens. As a result, tests can yield false-negative results, giving Borrelia free rein in the body.
For many diseases, the presence of antibodies in the blood provides protection against reinfection with the same bacterium or virus. Unfortunately, this is not the case with Borrelia. Each new encounter with an infected tick can cause illness again.
Conclusion
The path to an adequate Borrelia antibody response (as tested by conventional healthcare) is long and complex. It is influenced by numerous factors, including tick saliva, the bacterium's unique "camouflage properties," the host’s ability to create a balanced Th1/Th2 response, genetic predisposition, co-infections, and more. Borrelia is exceptionally well-adapted to evade and manipulate the immune system, which is a key reason why Lyme disease can be so persistent and complex. Understanding these interactions between Borrelia and the immune system provides essential insights for developing more effective diagnostic methods.
The diagnosis of Lyme disease should be based on a holistic approach that prioritizes clinical symptoms, disease progression, medical history, and exposure risk. Diagnostic tests should play a supportive role, contributing to the confirmation of the diagnosis rather than excluding it. A narrow focus on test results can lead to missed diagnoses and a lack of timely and adequate treatment. A broad, personalized approach is essential to address the complex nature of this disease effectively.
Šimo L, Kazimirova M, Richardson J, Bonnet SI. The Essential Role of Tick Salivary Glands and Saliva in Tick Feeding and Pathogen Transmission. Front Cell Infect Microbiol. 2017 Jun 22;7: 281. doi: 10.3389/fcimb.2017.00281. PMID: 28690983; PMCID: PMC5479950
Storl Wolf-Dieter (2012); ‘De ziekte van Lyme’ 9789020206630
Anderson C, Brissette CA. The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes. Pathogens. 2021; 10(3):281.