Much of the controversy surrounding PLS arises from the lack of sufficient knowledge about the etiology and pathology of the disease. This is compounded by the fact that there are few or no objective methods available for diagnosis and follow-up of affected individuals. In light of the results from the aforementioned clinical trials of antibiotic treatment and the lack of convincing evidence for active infection in PLS, other hypotheses, including a role for involvement of the immune system, have been suggested (Bolz and Weis, 2004
; Marques, 2008
). If present, immune abnormalities—possibly triggered by the original infection—may offer clues about the disease (Jarefors et al., 2007
; Segal and Logigian, 2005
). Considering the neurologic and psychiatric nature of post-Lyme symptoms, we sought to assess the presence of nervous system-specific antibodies in patients and control subjects. Approximately half of the examined PLS patients had heightened levels of antibodies to neural proteins, compared with 18.5% of post-Lyme healthy subjects and 15% of normal healthy controls. In fact, the heightened antibody response level in PLS was statistically similar to that in SLE, a multisystem autoimmune disease. Immunohistochemical analysis with representative PLS patient sera demonstrated binding of the antibodies to pyramidal neurons in the cerebral cortex and neurons of the DRG, highlighting their relevance in the context of central and peripheral nervous system disease.
It is important to note that our method of analysis only detected antibodies against prominently expressed proteins. Elevated antibodies to minor proteins or non-protein antigens might also exist in some cases that were reported to be negative. Therefore, examination of antibody binding to antigens in specific regions of the nervous system might reveal reactivity in more individuals. In addition, although this work focused on antibodies against neural proteins, antibodies to specific antigens in other tissues (e.g. muscle, thyroid, etc.) may also be found in some patients and could be relevant to PLS. At the same time, the absence of anti-neural antibodies in many patients might provide evidence for the heterogeneous nature of the population under study.
We can make some conjectures about the possible reasons for the observed increased antibody reactivity to self antigens in PLS. First, our experiments with affinity-purified antibodies generated in rabbits against B. burgdorferi
antigens clearly show that anti-borrelia antibodies can cross-react with several neural proteins. A number of earlier studies have also demonstrated the potential for cross-reactivity of the anti-borrelia immune response towards neural antigens (Alaedini and Latov, 2005
; Dai et al., 1993
; Garcia-Monco et al., 1995
; Maier et al., 2000
; Sigal and Tatum, 1988
). A portion of the detected anti-neural antibody reactivity in PLS patients is, therefore, likely to be the result of such cross-reactivity. However, the observed anti-neural antibody reactivity cannot be attributed solely to positive anti-borrelia serology, as increased anti-neural antibody reactivity was also seen in the borrelial seronegative PLS group. Second, considering the non-specific pattern of immunologic reactivity, the presence of these antibodies might signify an activated immunologic response to neural injury caused by the original borrelial infection or another disease. Tissue injury can, in fact, result in the release of autoantigens and lead to an increase in post-translational modification of proteins and production of novel self-epitopes that elicit a strong immune response (Doyle and Mamula, 2005
). Third, borrelial infection has been shown to be a potent polyclonal B cell activator, capable of inducing the non-specific proliferation and differentiation of antibody-secreting cells (Ma and Weis, 1993
; Yang et al., 1992
). The ability of borrelia to act as a B cell activator is likely to be enhanced the longer the infection is left untreated (Soulas et al., 2005
). Therefore, the observed non-specific increase in autoreactive antibodies in PLS may be due to the mitogenic effect of the borrelial antigens, including OspA and OspB, and point to a possible association between post-Lyme disease symptoms and the duration of the course of active infection prior to treatment. Finally, immune abnormalities stemming from genetic predisposition might also play a significant role in the form of B cell and effector cell dysregulation that leads to elevated levels of released autoantibodies (Hostmann et al., 2008
At this point, it is difficult to know what role, if any, the anti-neural antibodies might play in the pathogenesis of PLS. Several immune-mediated diseases of the nervous system, including multiple sclerosis, paraneoplastic nervous system disorders, autoimmune neuropathies, myasthenia gravis, and stiff-person syndrome, are associated with elevated levels of antibodies to neural antigens. A disease-causing role for such antibodies has been demonstrated in some of these disorders (Dalakas, 2008
). In general, antibodies might have a pathogenic effect in the body through direct binding to a molecule and interference with its function, by activation of complement and initiation of an inflammatory response, or by inducing tissue injury through binding to Fc receptors on macrophages, neutrophils, and NK cells (Diamond et al., 2009
). Considering the non-specific antibody response seen in the examined PLS cohort, however, a direct pathogenic role for the antibodies is doubtful. Nevertheless, even without a direct role, antibodies have the potential to be involved in disease mechanism through the activation of toll-like receptor pathways and secretion of various inflammatory molecules, which can affect the function of other cells responsible for neuropsychiatric defects (Crow, 2007
; Halperin, 2008
; Nawa and Takei, 2006
The aim of this study was to begin a process of examining potential immune abnormalities in PLS that would be relevant to the reported neurologic and cognitive symptoms of affected patients. Results of the antibody analysis demonstrate the presence of a heightened, but apparently non-specific, production of antibodies to neural antigens in PLS. We speculate that these antibodies may either 1) be indicative of past injury to the nervous system during the active phase of the Lyme disease infection, resulting in the immune system being exposed to and activated by novel self antigens, or 2) point to the enhanced B cell mitogenic effect of the borrelia pathogen in cases of delayed treatment and prolonged infection in genetically predisposed individuals. As such, this study points to the presence of a differential immune response in PLS in comparison to healthy individuals. Obviously, these findings are preliminary and must be extended in future studies using a larger number of subjects and additional cohorts, including healthy individuals with past Lyme arthritis and neurologic Lyme, as well as patients with similar complaints and no history of Lyme disease. At this juncture, it is logical to assume that further study of immune system response in PLS is likely to yield more clues about the etiopathogenesis of the disease and provide insights that may pave the way for developing safe and effective treatments.