The causative spirochete of Lyme disease, Borrelia burgdorferi, is the most common human tick-borne pathogen in the Northern hemisphere. It is also probably the most complex bacteria known, as it has 132 genes and 21 plasmids, with 90% of this genetic material unrelated to any known bacteria.
These genes facilitate adaptation of the organism in different forms and in different hosts with multiple mechanisms to evade and weaken host defenses. By comparison, the spirochete Treponema pallidum pallidum (the organism that causes syphilis) is a comparatively simple organism, with only 22 genes and much less adaptive capability.
Lyme disease is currently viewed as being a mostly zoonotic tick-borne disease. The human mouth contains 400 different species of bacteria, as well as viruses and parasites. By contrast, ticks live in filth and feed on the blood of rodents and a variety of other animals, meaning that there are likely numerous other human pathogens besides B. burgdorferi potentially transmitted by tick bites. These other known and unknown pathogens may result in interactive coinfections. In addition, a number of opportunistic infections (mostly viral) are associated with B. burgdorferi infections.
The term “Lyme disease” only refers to an infection by B. burgdorferi (which has four different species that are pathogenic in humans and 300 different strains), or to a tick-borne infection that may include B. burgdorferi and/or other tick-borne pathogens and opportunistic infections. This complex interactive infection is sometimes called Lyme/tick-borne disease (LYD/TBD) or Lyme borreliosis complex.
Adding to the complexity and confusion is that there is no consensus regarding the definition of Lyme disease. Some define it with very narrow criteria, whereas others define it with broader clinical and laboratory criteria.
Some believe chronic persistent infection does not exist and speculate that persistent symptoms are associated with a self-perpetuating immune process that continues after the infection has cleared. However, no self-perpetuating immune process without persistent infection has ever been scientifically proven.
In contrast, those who consider a broader disease definition view the aberrant immune process as being associated with a persistent infectious process. Although multiple controversies surround Lyme disease, most agree that many of the symptoms associated with LYD/TBD are mediated by immune processes.
LYD/TBD is associated with multisystemic symptoms, including psychiatric symptoms. Currently, there are 240 peer-reviewed articles demonstrating the association between LYD/TBD and psychiatric symptoms.
The most common mental symptoms include fatigue; nonrestorative sleep; impairments of executive functioning, attention, memory, and processing speed; sensory hyperacusis; and low frustration tolerance, irritability, depression, and anxiety.
Psychiatric symptoms are more significant with Babesia and Bartonella coinfections. A combination of our current limitations in understanding this disease, misinformation regarding this disease, and the failure to diagnose and treat it in the early stages results in a significant burden of psychiatric illness associated with LYD/TBD.1
Immune Effects of Lyme Disease
Recent attention has focused on the association between LYD/TBD and immune-mediated psychiatric symptoms.2,3 Acute infections are usually associated with an early inflammatory reaction followed by adaptive immunity and a resolution of symptoms, but in Lyme disease this progression does not always occur. Instead, inflammation can persist without adaptive immunity, autoimmune symptoms may occur, and reinfections are common.
The complex genetic sophistication of B. burgdorferi allows it to adapt to multiple environments and disseminate and evade the host’s immune system.4 In a compromised environment, B. burgdorferi can survive by converting from a spirochetal form to granular and cystic forms. After entry, B. burgdorferi activates local inflammation yet evades host defenses and facilitates dissemination by potentially masquerading with host components such as plasmin and complement.5
B. burgdorferi is recognized by immune cells and attacked by complement and antibodies. B. burgdorferi responds by down-regulating its surface proteins and hiding in the extracellular matrix.6
Some of the psychiatric sequelae may be associated with direct effects, such as possible toxin release and cell penetration and lysis. Like other infections, most symptoms are instead associated with immune effects. These immune effects include persistent inflammation with cytokine effects, the release of proinflammatory lipoproteins from the outer coat of B. burgdorferi and autoimmunity.
There are most likely other immune effects from the other coinfections and opportunistic infections seen with tick-borne diseases. For example, coinfections with Anaplasma phagocytophilum results in impairment in the ability to mount strong early inflammatory Th1-responses as demonstrated by a reduction of interleukin (IL)-12.7
There is a time progression of immune processes and a resulting progression of immune-mediated symptoms seen with LYD/TBD. Initial stages may include an erythema migrans (“bull’s eye”) rash, a flu-like illness, cranial nerve and other early neurologic symptoms, and musculoskeletal symptoms. Next, fatigue and cognitive impairments may occur. Subsequently, depression and other psychiatric symptoms are common, and in some cases late-stage disease is associated with dementia.
Autoimmune effects may also parallel these changes and may increase with peaks in antineuronal antibody production. The disease progression is associated with a progressive sequence of immune effects. Fatigue and cognitive impairments are associated with the action of proinflammatory cytokines, depression is associated with inflammatory-induced changes in tryptophan catabolism, and dementia is associated with central nervous system (CNS) gliosis. All of these symptoms may be temporarily exacerbated in response to a Jarisch-Herxheimer immune reaction provoked by antibiotic treatment.3
B.burgdorferi may reach the CNS either through peripheral nerves or through the bloodstream. Although CNS penetration is well documented, it is still not clear how B. burgdorferi passes the blood–brain barrier. Two possible explanations include penetration between endothelial cells or transcellular passage.6 When early CNS penetration occurs, the more common early CNS symptoms include painful meningoradiculitis with inflammation of the nerve roots and lancinating radicular pain, lymphocytic meningitis, and various forms of cranial or peripheral neuritis.8
Early Immune Effects
The erythema migrans rash is associated with polymorphonuclear cells replaced by a few infiltrating macrophages that are then replaced by a lymphocytic infiltrate.9 Associated with these cellular changes are a humoral inflammatory reaction that includes tumor necrosis factor-alpha (TNF-alpha), IL-6, chemokines (CXCL1 and IL-8), NF-kappaB factors, metalloproteinases-1, -3, and -12, superoxide dismutase, and C3a and C4a complement increases.10,11
High levels of proinflammatory cytokines (TNF-alpha), transforming growth factor-beta1, and IL-6 early in the disease correlate with recovery, whereas low levels of proinflammatory cytokines correlate with chronicity.12
Symptoms of Infection
It is important to recognize that infection without CNS penetration can have immune effects in the brain. Infections provoke proinflammatory cytokines that can cross the blood–brain barrier and affect neural and mental functioning. Like many infections, LYD/TBD has been associated with the proinflammatory cascade, which initially manifests as “sickness syndrome” symptoms.
Interferon treatment is a useful model to understand the earlier and later effects of inflammation upon mental functioning. Early interferon treatment symptoms include fatigue and cognitive impairments, whereas later symptoms are more emotional and behavioral in nature and include depression, anxiety, mania, irritability, impulsiveness, hostility, apathy, and relapse of substance abuse.13
The symptoms associated with the proinflammatory cascade in LYD/TBD have been associated with the proinflammatory cytokines IL-6, IL-8, IL-12, IL-17, IL-18, interferon-gamma, neo-pterin, and the chemokines CXCL12 and CXCL13. In addition, the outer coat of B. burgdorferi consists of lipoproteins that are proinflammatory, including the VlsE lipoprotein. Pathophysiologic changes are associated with oxidative stress, excitotoxicity, changes in homocysteine metabolism, and altered tryptophan catabolism.
B. burgdorferi reproduces in a cyclic manner, similar to relapsing fever and malaria. This cyclic reproduction is also associated with a cyclic provocation of proinflammatory cytokines and a cyclic appearance of symptoms associated with inflammation, such as fatigue, apathy, and the multiple cognitive and mood impairments associated with Lyme encephalopathy.1,3
Elevations of proinflammatory cytokines are associated with suicide attempts, self-destructive behavior, aggressive behavior, and fatigue, and the severity of suicidal tendencies correlates with the level of IL-6 in the CSF.14 Similar to what is seen with interferon treatment, when inflammation persists with Lyme disease, mood and behavioral symptoms become apparent.
Persistent immune stimulation of the brain is associated with changes in tryptophan catabolism that include an increase of the enzyme indoleamine 2,3-dioxygenase. This enzyme reduces the conversion of tryptophan into serotonin, melatonin, and kynurenic acid (a neuroprotective N-methyl-D-aspartate [NMDA] antagonist) and instead converts tryptophan into kynurenine, which results in an increase of the production of quinolinic acid, an excitotoxin and NMDA agonist that can cause excitotoxicity and contribute to the cognitive, mood, and behavioral symptoms seen in many LYD/TBD patients.3,15
Quinolinic acid levels in the cerebral spinal fluid of Lyme disease patients is higher in patients with CNS infections and correlates with the severity of CNS symptoms, including depression.15,16 Violent behavior is sometimes seen associated with LYD/TBD; it appears to be immune mediated and is often bizarre, senseless, and unpredictable.17
The stress of chronic infections causes a vicious cycle of chronic stress and nonrestorative sleep that contributes to perpetuating the disease process and is associated with decreased regenerative functioning, compromised immunity, oxidative stress, decreased growth hormone production, and decreased resistance to infectious disease.1,18
Autoimmune mechanisms provoked by B. burgdorferi in chronic Lyme disease have been implicated in the pathogenesis of psychotic symptoms19 and neurologic symptoms of the central and peripheral nervous systems.20
In addition, B. burgdorferi outside the brain can release outer coat lipoproteins and flagella that may provoke antineuronal antibody production (molecular mimicry) that can disseminate to the brain; these multiple mechanisms can evoke autoimmune symptoms in the brain, including intrusive symptoms, obsessiveness, movement disorders, paranoia, and other symptoms.17,21–23
Late-Stage Immune CNS Effects
The three principal mechanisms leading to the injury of neuronal cells are: 1) the secretion of cytotoxic substances by leucocytes and glial cells; 2) direct cytotoxicity; and 3) autoimmune-triggered processes via molecular mimicry. An interaction between B. burgdorferi and the neural cells can cause dysfunction by adherence, invasion, and cytotoxicicity of neural cells. In addition, B. burgdorferi outer surface protein A induces apoptosis and astrogliosis. B. burgdorferi spirochetes interacting with Schwann and glial cells also appear to produce nitric oxide, and the spirochetes can induce cytokines such as IL-6 or TNF-alpha in glial cells, both of which are neurotoxic and might provoke autoimmune reactions.3
When there is inflammation within the CNS, the chemokine CXCL13, which is produced by monocytes and dendritic cells in response to the spirochetal encounter, is found in high concentrations in the CSF.6 Also, the inflammatory response elicited by B. burgdorferi in glial cells contributes to damage of oligodendrocytes that are vital for the functioning and survival of neurons.24
There are multiple known and unknown mechanisms through which B. burgdorferi can induce the neuronal dysfunction that leads to late-stage clinical symptoms.
Multiple studies and a meta-analysis of 86 studies have demonstrated dementia is accompanied by a significant inflammatory response. Because CNS B. burgdorferi infections are associated with CNS inflammation and systemic LYD/TBD are also associated with low-grade inflammatory processes, it supports clinical observations that rapidly progressive dementia can be associated with CNS infection and that slowly progressive dementia can be associated with systemic LYD/TBD.25
Autism spectrum disorders have been associated with a number of infections, including LYD/TBD. Both inflammatory and autoimmune processes that adversely affect developing fetal neural tissue appear to be involved in the pathophysiology. Effects upon the developing fetus from the mother’s immune system and infection of the infant that adversely alters developing neural tissue are both possible pathophysiologic processes.26–28
The blood–brain barrier is permeable during fetal development and can be compromised by infections and environmental exposures throughout life. The absence of a complete barrier allows immune components access to the brain. Individuals with autism show increased proinflammatory cytokines in the brain, as well as activation of microglia.27
Additionally, antibodies that target brain tissues have been described in both children with autism and their mothers, and antineuronal antibodies can be present in LYD/TBD patients. These immunologic phenomena may interfere with normal brain development and function, potentially contributing to developmental impairments and/or autistic spectrum symptoms.27,29 When autism spectrum disorder is associated with chronic B.burgdorferi infection, effective treatment with antibiotics can reduce the infection, thereby reducing the immune provocation and, in turn, reducing the symptoms.30
Most symptoms associated with Lyme disease and other tick-borne diseases are immune mediated. A progressive sequence of immune effects is associated with a progressive development of cognitive, psychiatric, neurologic, and somatic symptoms. These progressive immune effects include persistent inflammation with cytokine effects, the release of proinflammatory lipoproteins from the outer coat of B. burgdorferi, and autoimmunity.
Prolonged inflammation, particularly the type associated with chronic infection within the CNS, is associated with further cognitive impairments, more severe psychiatric symptoms, gliosis, and dementia. Autoimmune effects also can be present at the same time and can include antineuronal antibodies and B. burgdorferi lipoproteins that can disseminate from the periphery to inflame the brain.
These immune reactions can result in psychiatric symptoms such as obsessiveness, movement disorders, paranoia, and others. Autism spectrum disorders associated with Lyme disease and other tick-borne diseases appear mediated by a combination of inflammatory and autoimmune mechanisms from the mother’s and/or infant’s immune system. Understanding this pathophysiology will help physicians create new treatment options.
- Bransfield R. Neuropsychiatric Lyme disease: pathophysiology, assessment & treatment. Paper presented at: 2nd ILADS European Meeting. ; May 28, 2011. ; Augsburg, Germany. .
- Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Inflammation and central nervous system Lyme disease. Neurobiol Dis. 2010;37:534–541. doi:10.1016/j.nbd.2009.11.016 [CrossRef]
- Bransfield R. The Psychoimmunology of Lyme/tick-borne diseases and its association with neuropsychiatric symptoms. Open Neurol J. 2012; in press.
- Coburn J, Fischer JR, Leong JM. Solving a sticky problem: new genetic approaches to host cell adhesion by the Lyme disease spirochete. Mol Microbiol. 2005;57(5):1182–1195. doi:10.1111/j.1365-2958.2005.04759.x [CrossRef]
- Auwaerter PG, Aucott J, Dumler JS. Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment. Expert Rev Mol Med. 2004;19;6(2):1–22.
- Rupprecht TA, Koedel U, Fingerle V, Pfister HW. The pathogenesis of Lyme neuroborreliosis: from infection to inflammation. Mol Med. 2008;14(3–4):205–212.
- Jarefors S, Karlsson M, Forsberg P, et al. Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum. Clin Exp Immunol. 2006;143(2):322–328. doi:10.1111/j.1365-2249.2005.02993.x [CrossRef]
- Pfister HW, Rupprecht TA. Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients. Int J Med Microbiol. 2006;296(Suppl 40):11–16. doi:10.1016/j.ijmm.2005.12.003 [CrossRef]
- Chong-Cerrillo C, Shang ES, Blanco DR, Lovett MA, Miller JN. Immunohistochemical analysis of Lyme disease in the skin of naive and infection-immune rabbits following challenge. Infect Immun. 2001;69(6):4094–4102. doi:10.1128/IAI.69.6.4094-4102.2001 [CrossRef]
- Schramm F, Kern A, Barthel C, et al. Microarray analyses of inflammation response of human dermal fibroblasts to different strains of Borrelia burgdorferi Sensu stricto. PLoS One. 2012;7(6):e40046. doi:10.1371/journal.pone.0040046 [CrossRef]
- Shoemaker RC, Giclas PC, Crowder C, House D, Glovsky MM. Complement split products C3a and C4a are early markers of acute Lyme disease in tick bite patients in the United States. Int Arch Allergy Immunol. 2008;146(3):255–261. doi:10.1159/000116362 [CrossRef]
- Widhe M, Grusell M, Ekerfelt C, et al. Cytokines in Lyme borreliosis: lack of early tumour necrosis factor-alpha and transforming growth factor-beta1 responses are associated with chronic neuroborreliosis. Immunology. 2002;107(1):46–55. doi:10.1046/j.1365-2567.2002.01500.x [CrossRef]
- Constant A, Castera L, Dantzer R, et al. Mood alterations during interferon-alpha therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66(8):1050–1057. doi:10.4088/JCP.v66n0814 [CrossRef]
- Lindqvist D, Janelidze S, Hagell P, et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry. 2009;66:287–292. doi:10.1016/j.biopsych.2009.01.030 [CrossRef]
- Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis. Neurology. 1992;42(1):43–50. doi:10.1212/WNL.42.1.43 [CrossRef]
- Wichers MC, Koek GH, Robaeys G, et al. IDO and interferon-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005;10:538–544. doi:10.1038/sj.mp.4001600 [CrossRef]
- Bransfield R. Can infections and immune reactions to them cause violent behavior?Neurol Psychiatry Brain Res. 2012;18(3):42. doi:10.1016/j.npbr.2012.02.006 [CrossRef]
- Greenberg HE, Ney G, Scharf SM, Ravdin L, Hilton E. Sleep quality in Lyme disease. Sleep. 1995;18(10):912–916.
- Carter CJ. Schizophrenia: a pathogenetic autoimmune disease caused by viruses and pathogens and dependent on genes. J Pathog. 2011; doi:10.4061/2011/128318 [CrossRef]
- Schluesener HJ, Martin R, Sticht-Groh V. Autoimmunity in Lyme disease: molecular cloning of antigens recognized by antibodies in the cerebrospinal fluid. Autoimmunity. 1989;2(4):323–330. doi:10.3109/08916938908997158 [CrossRef]
- Alaedini A, Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J Neuroimmunol. 2005;159:192–195. doi:10.1016/j.jneuroim.2004.10.014 [CrossRef]
- Sigal LG, Tatum AH. Lyme disease patients’ serum contains IgM antibodies to Borrelia burgdorferi that cross-react with neuronal antigens. Neurology. 1988;38:1439–1442. doi:10.1212/WNL.38.9.1439 [CrossRef]
- Sigal LH. Cross-reactivity between Borrelia burgdorferi Flagellin and a human axonal 64.000 molecular weight protein. J Infect Dis. 1993;167:1372–1378. doi:10.1093/infdis/167.6.1372 [CrossRef]
- Ramesh G, Benge S, Pahar B, Philipp MT. A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflam. 2012;9(1):72. doi:10.1186/1742-2094-9-72 [CrossRef]
- Miklossy J. Alzheimer’s disease — a neurospirochetosis analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflam. 2011;8:90. doi:10.1186/1742-2094-8-90 [CrossRef]
- Bransfield RC, Wulfman JS, Harvey WT, Usman AI. The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders. Med Hypotheses. 2008;70:967–974. doi:10.1016/j.mehy.2007.09.006 [CrossRef]
- Bransfield RC. Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome. Pediatric Health. 2009;3:125–140. doi:10.2217/phe.09.5 [CrossRef]
- Nicholson G. Chronic bacterial and viral infections in neurodegenerative and neurobehavioral diseases. Lab Med. 2008;39:291–299. doi:10.1309/96M3BWYP42L11BFU [CrossRef]
- Goines P, Van de Water J. The immune system’s role in the biology of autism. Curr Opin Neurol. 2010; 23:111–117. doi:10.1097/WCO.0b013e3283373514 [CrossRef]
- Kuhn M, Grave S, Bransfield R, Harris S. Long term antibiotic therapy may be an effective treatment for children co-morbid with Lyme disease and autism spectrum disorder. Med Hypotheses. 2012;78(5):606–615. doi:10.1016/j.mehy.2012.01.037 [CrossRef]