Immunodiagnostics of Lyme neuroborreliosis

Gorkom, T. van

Lyme borreliosis (LB) is caused by spirochetes that are part of the Borrelia burgdorferi sensu lato (s.l.) complex group. The most prevalent manifestation of LB is characterized by a red, migrating skin lesion, also known as erythema migrans. If left untreated, then B. burgdorferi s.l. can disseminate through the body and infect other body parts such as the joints, the nervous system (Lyme neuroborreliosis (LNB)), the heart and/or other parts of the skin, although for the majority of cases LB resolves without treatment. The diagnosis of LB is based on the presence of clinical symptoms and, for most Lyme manifestations, should be supported by laboratory tests. The most widely used laboratory test is based on the detection of Borrelia-specific antibodies. The utility of antibody detection to support the diagnosis of LB, however, is hampered by a low sensitivity of antibody detection early in the infection, and the persistence of antibodies after a cleared infection. The research...Show moreLyme borreliosis (LB) is caused by spirochetes that are part of the Borrelia burgdorferi sensu lato (s.l.) complex group. The most prevalent manifestation of LB is characterized by a red, migrating skin lesion, also known as erythema migrans. If left untreated, then B. burgdorferi s.l. can disseminate through the body and infect other body parts such as the joints, the nervous system (Lyme neuroborreliosis (LNB)), the heart and/or other parts of the skin, although for the majority of cases LB resolves without treatment. The diagnosis of LB is based on the presence of clinical symptoms and, for most Lyme manifestations, should be supported by laboratory tests. The most widely used laboratory test is based on the detection of Borrelia-specific antibodies. The utility of antibody detection to support the diagnosis of LB, however, is hampered by a low sensitivity of antibody detection early in the infection, and the persistence of antibodies after a cleared infection. The research conducted in this thesis focused on the humoral and the cellular immune response to investigate whether LB diagnostics can be improved. As clear case-definitions are available for active LNB, well-defined patients with LNB were used as a proxy for patients with active LB.
The research in this thesis has provided more insight into the added value and the pitfalls of laboratory tests for the diagnosis of LNB. It shows that the interferon-gamma enzyme-linked immunospot assay cannot be used for the diagnosis of LNB. Furthermore, it demonstrates the added value of elevated levels of the B-cell chemokine (C-X-C motif) ligand 13 in the cerebrospinal fluid for the diagnosis of LNB and that more research is necessary to investigate if an international reference standard can be established. Additionally, the research in this thesis underlines that a thorough validation of serological tests is important before its use in diagnostics and it illustrates that antibiotic treatment of an infection with B. burgdorferi s.l. is associated with discordant serological test results. The most important finding of the research conducted in this thesis; however, is the proposal of a diagnostic algorithm for LNB diagnostics. Such an algorithm should include tests that consider both the humoral as well as the cellular immune response as both may contribute to the diagnosis of LNB. By covering different aspects of the immune system, a concrete and feasible tool is provided that can better discriminate between an active and a previous infection with B. burgdorferi s.l., which and this will improve LNB diagnostics.
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Immunodiagnostics of Lyme neuroborreliosis

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