Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease
Introduction
Borrelia burgdorferi (Bb), the causative agent of Lyme disease (LD), infects humans through Ixodes tick bites. Infection can involve several tissues, including skin, joints, heart and nervous system and can result in arthritis, carditis, and neurological symptoms [1]. Involvement of nervous system, known as neuroborreliosis, may manifest as encephalopathy, myelopathy, and peripheral neuropathy, which usually respond to antibiotic treatment [2]. Nevertheless, some patients with LD report only partial and transient improvements in cognitive impairment, fatigue and musculoskeletal pain with prescribed courses of antibiotics and develop a chronic condition referred to as post-treatment Lyme disease syndrome (PTLDS) [3]. It is currently under debate if a partial response to antimicrobials could be due to persistent infection, damage to the brain, or to some form of acquired immune dysfunction [4]. In detail, several studies have supported the hypothesis that some sort of immune dysregulation could occur. Both T and B cell autoimmunity have been detected in drug-resistant Lyme arthritis [5], [6] and several authors have reported on the potential of autoimmunity against neural antigens due to molecular mimicry, in LD: cross-reactivity has been experimentally shown between B. burgdorferi’s flagellin and a component of human peripheral nerve axon (heat shock protein 60) [7], between non-protein antigens of the pathogen and gangliosides [8], and between Borrelia OspA and antigens expressed in human brain, spinal cord and dorsal root ganglia [9]. Recently, two studies reported heightened, but apparently non-specific, production of antibodies against brain proteins in about 50% of patients with a history of LD and persistent symptoms [10], [11]. Here, we report the detection of anti-γ enolase antibodies in one patient with evidence of Borrelia burgdorferi infection and persistent symptoms of fatigue and cognitive impairment. Mammalian enolase acts as homodimeric or heterodimeric isoenzymes, combining three subunits: α, β, and γ enolase. Alpha-enolase is ubiquitous, β enolase is mainly expressed in muscles, while γ enolase in neurons and neuroendocrine tissues [12]. In absence of serum reactivity against the α subunit of the same enzyme, and assuming the enolase of B. burgdorferi as the trigger for the autoantibody, a bioinformatical analysis with an ad-hoc-developed software has been carried out to propose a cross-reactive conformational epitope between γ enolase and Borrelia burgdorferi enolase and to suggest a possible pathogenic mechanism for chronic symptoms in Lyme disease.
Section snippets
Patient
A man (aged 35 at diagnosis), with a long-lasting history of fatigue and cognitive issues, presented at the University Hospital of Trieste, where he was submitted to a complete clinical and instrumental evaluation. Infectious agents were searched for in the patient’s serum as shown in Table 1. DNA from peripheral blood was submitted to Borrelia detection as previously reported [13]. Anti-Borrelia burgdorferi antibodies were detected by Western blot using anti-Borrelia-Euroline-RN-AT (Euroimmun,
Patient
The patient is a 37-year-old man. Since 1999 he has been afflicted by severe fatigue, memory impairment and lack of concentration. At that time, he was 19 and he had never had any neurological symptom before. In the early years, the abovementioned symptoms presented with a cyclic trend of relapses and recoveries. In 2002, a flu-like illness precipitated his condition which has since become chronic. During the last 15 years, he has been experiencing other symptoms, such as muscular and joint
Discussion
There is currently debate on whether Lyme patients with long-term symptoms are suffering from persistent infection and/or from some sort of immune-mediated disorder. These symptoms most commonly include fatigue, cognitive deficits and musculoskeletal pain [3]. Persistent cognitive abnormalities have been associated to hypometabolism in several brain regions [25], [26]. In this study, we hypothesize that chronic symptoms are caused by an autoantibody - triggered by Borrelia infection through a
Conclusion
In this study, the presence of antibodies against γ enolase was found in a patient with a complex picture of neurological symptoms and with exposure to B. burgdorferi. We hypothesize that the infection by B. burgdorferi elicits an antibody to Borrelia enolase that cross-reacts - via molecular mimicry - with human γ enolase. A possible cross-reactive conformational epitope has been found and a possible mechanism for the causal role of this antibody in the genesis of cognitive manifestations has
Acknowledgments
We are grateful to Margarita Bitetti and Giada Da Ros for their support in this study.
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Borrelia burgdorferi and other Borrelia species
2023, Molecular Medical Microbiology, Third EditionNews and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments
2020, Medical HypothesesCitation Excerpt :The role of presumed (viral) infection remains elusive, and more accurate diagnostic test such as polymerase chain reaction (PCR) and Western Blot electrophoresis may be recommended. Special attention should be given to the post-treatment Lyme disease syndrome [29,30], which is considered not to be due to persistence of the pathogen Borrelia burgdorferi, but possibly to result from immune cross-reactivity causing anti-enolase antibodies which would and impair glycolysis [31]. There were no significant differences between the patients of the female and male groups regarding age, duration of disease and severity of fatigue, nor were there difference regarding these variables between patients who did or did not respond to treatment with sodium dichloroacetate (DCA).
Thyroid gland and brain: Enigma of Hashimoto's encephalopathy
2019, Best Practice and Research: Clinical Endocrinology and MetabolismCitation Excerpt :This allures to assume that cross-reactivity between certain microbial epitopes and human α-enolase can induce aNAE autoimmunity. Similar mechanism was hypothesized for a case of post-treatment Lyme disease chronic fatigue syndrome with autoantibodies towards γ-enolase, and shared sequences were located in human and Borrelia burgdorferi homologous enzymes [138]. The cross-reactivity of α-enolases from Streptococci and human cells is involved in pathogenesis of rheumatic fever [139] and perhaps several other infectious diseases [140].
Bacterial Amyloids: The Link between Bacterial Infections and Autoimmunity
2019, Trends in MicrobiologyCitation Excerpt :For example, Lyme patients, like SLE patients, test positive for anti-nuclear antibodies (ANAs) [16,17]. Molecular mimicry of γ-enolase by Borrelia enolase has been suggested to drive the autoimmune response and more chronic symptoms [18]. Mysteriously, most individuals positive for ANAs do not have an autoimmune disease.
Post-bacterial infection chronic fatigue syndrome is not a latent infection
2019, Medecine et Maladies InfectieusesCitation Excerpt :Picha et al. performed a study with B. burgdorferi-infected patients, and identified B. burgdorferi DNA up to six months after the administration of an effective antimicrobial treatment. However, this result does not indicate the presence of living bacteria, and all patients with a positive B. burgdorferi PCR did not present with subjective symptoms [24,25]. Autoimmune diseases are believed to be involved in patients diagnosed with PTLDS.