Elsevier

Medical Hypotheses

Volume 110, January 2018, Pages 1-8
Medical Hypotheses

Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease

https://doi.org/10.1016/j.mehy.2017.10.024Get rights and content

Abstract

Some patients with a history of Borrelia burgdorferi infection develop a chronic symptomatology characterized by cognitive deficits, fatigue, and pain, despite antibiotic treatment. The pathogenic mechanism that underlines this condition, referred to as post-treatment Lyme disease syndrome (PTLDS), is currently unknown. A debate exists about whether PTLDS is due to persistent infection or to post-infectious damages in the immune system and the nervous system. We present the case of a patient with evidence of exposure to Borrelia burgdorferi sl and a long history of debilitating fatigue, cognitive abnormalities and autonomic nervous system issues. The patient had a positive Western blot for anti-basal ganglia antibodies, and the autoantigen has been identified as γ enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase. Assuming Borrelia own surface exposed enolase as the source of this autoantibody, through a mechanism of molecular mimicry, and given the absence of sera reactivity to α enolase, a bioinformatical analysis was carried out to identify a possible cross-reactive conformational B cell epitope, shared by Borrelia enolase and γ enolase, but not by α enolase. Taken that evidence, we hypothesize that this autoantibody interferes with glycolysis in neuronal cells, as the physiological basis for chronic symptoms in at least some cases of PTLDS. Studies investigating on the anti-γ enolase and anti-Borrelia enolase antibodies in PTLDS are needed to confirm our hypotheses.

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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