Welcome to the Lyme Disease Guide
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Lyme disease is caused by the spread of bacterial infection involving the Borrelia burgdorferi sensu lato genus. Lyme disease pathology and symptoms of Lyme disease condition correspond to the progressive involvement of multiple organs and systems in the body. Evidence of bacterial infection has been found in the skin, heart, peripheral and central nervous systems, and the joints. In some cases the presence of bacteria in organs such as the heart has only been found after autopsy and may have played a role in the cause of a patient’s death due to long-term damage going undetected. The symptoms of Lyme disease are largely due to the immune system’s response to the spirochaetes’ presence in a particular organ or tissue, in addition to disruption of the hypothalamic-pituitary adrenal axis, and alterations in cell proliferation and death in brain tissue.
Following a bite from an infected tick of the Ixodes genus the saliva of the tick is transmitted with accompanying spirochaetes into the skin during feeding. This saliva has components which disrupt the normal immune response to a bite and which afford protection to the infectious spirochaetes allowing them to establish themselves in the local area. These spirochaetes then multiply and begin to spread outwards in the skin resulting in the characteristic bull’s eye rash, erythema migrans. The redness of this rash is due to the immune system’s provocation to mount an inflammatory response to the invading organism. Unfortunately, even as this inflammation occurs the neutrophils which should accompany it fail to materialise. Neutrophils are the immune system components which would aid elimination of the bacteria from the skin; thus, the spirochaetes continue to survive and thrive.
The reason for this failure of the neutrophils to converge on the infected area is the use by the spirochaetes of the protein plasmin found in the tick saliva to effectively hide from the immune system. Despite B. burgdorferi s.l. antibody production the plasmin confounds the immune system’s efforts which is further obstructed by the spirochaetes ability to reduce the expression of surface proteins that would be targeted by such antibodies. This avoidance of detection involves alterations in the VIsE surface protein which effectively inactivates certain immune system components such as complement. Additionally, the bacteria may take up a position in the body’s extracellular matrix that makes it difficult to reach by the cells of the immune system.
Early Disseminated Lyme Disease Pathology
Over the days and weeks after a bite from an infected tick, the spirochaetes slowly enter the bloodstream from where they can gain access to almost every tissue in the body through the circulation. Infection can then spread quickly through the system and cause symptoms at places far away from the initial tick bite. The erythema migrans rash may now arise in other locations on the body as well as the original location as the spirochaetes cause other localised inflammation. Once again, the body’s normal response leading to the elimination of the spirochaetes through the action of neutrophils is inhibited by the pathogen’s use of the protease plasmin from the ticks’ saliva. The Borrelia bacteria are also adept at other tactics to avoid being targeted by the immune system and have been said to ‘hide’ from the immune system.
These tactics employed by the Lyme disease bacteria have potential ramifications for the development of autoimmune complications. Exposure to the spirochaetes creates a chronic inflammatory response which may begin to damage ordinary bodily tissues due to molecular mimicry employed by the bacteria to avoid detection. In their imitation of normal body cells the bacteria can confuse the immune system into attacking ordinary body tissues which goes some way to explaining the chronic symptoms of Lyme disease experienced by some patients even after eradication of the infection by antibiotics. Where the immune system has produced antibodies against its own cells it will continue to attack these cells even in the absence of the Borrelia bacteria, leading to persistent symptoms including joint pain. Effectively, Lyme disease may induce an autoimmune condition similar to rheumatoid arthritis which persists even after the causative agent, the Borrelia bacteria, is removed.
Borrelia burgdorferi s.l. infection creates multiple symptoms due to it multisytem effects. In a large number of those infected, the symptoms only go as far as an acute flu-like illness which is effectively fought by the body and which leads to no other persistent effects from the tick bite. Stage II, early disseminated Lyme disease, involves the cardiovascular system and/or the central nervous system, leading to myocarditis, meningoencephalitis, and polyradiculitis. The levels of inflammation during this stage are much higher in these tissues than anywhere else in the early acute stage and can lead to significant tissue damage if the infection continues unchecked. Progression into Stage III Lyme disease involves more bodily systems, including the joints, and exerts more serious effects such as dementia and transverse myelitis.
Central Nervous System Lyme Disease Pathology
The spread of the Lyme disease bacteria into the central nervous system varies in incidence and speed between individuals but when it does happen the spirochaetes may fundamentally alter brain function. It appears that astrocytes in the brain are involved in the pathogenesis of Lyme disease as these are glial cells providing support for endothelial cells that constitute the blood-brain barrier that protects the brain from damage by closely guarding entrance to brain circulation. The astrocytes are also important in maintaining nutrient supply to brain tissue, and in the repair process, and scarring, following trauma to the spinal cord or brain itself. The Borrelia bacteria induce astrogliosis in the astrocytes, a process where the cells rapidly reproduce and then die (proliferation followed by apoptosis). The effectiveness of the blood-brain barrier, the supply of nutrients to neural tissue, and the balance of ions in the brain can all be compromised through such events.
The secretory activities of brain cells are also adversely affected which is thought to contribute to some of the psychological and cognitive manifestations of Lyme disease. The spirochaetes can induce astrocytes and microglia to produce toxic substances such as quinolinic acid and specific cytokines interleukin-6 and Tumor necrosis factor-alpha, which damage nerve cells and can lead to the symptoms of fatigue and malaise in Lyme disease patients along with cognitive deficits such as memory impairment and poor concentration. Alterations in neurotransmitter function are also implicated in the development of some Lyme disease symptoms such as stress, anxiety, and sleep disturbance. There is some evidence showing that Borrelia bacteria induce the chronic elevated secretion of stress hormones such as cortisol which then reduce the effects of neurotransmitters and cause neurohormone disruption. Glucocorticoids and catecholamines are those neruohormones thought to be involved in this process and, with stem cell research recently revealing the benefits of anti-depressants such as sertraline (Zoloft) to be due to their effects on glucocorticoids, it appears likely that dysregulation of these pathways is a key factor in some neurological symptoms of Lyme disease. Reduced levels of tryptophan, a serotonin-precursor, have also been observed in those with infectious diseases affecting the central nervous system, such as Lyme disease. Low levels of serotonin in the brain are connected to symptoms similar to those found in neuropsychiatric disorders that arise in patients with Lyme Borreliosis.
Skin Conditions, Arthritis, and Treatment Implications
There are similarities between Lyme disease pathology and conditions such as Systemic Lupus erythematosus (SLE) and Lupus profundus which can complicate diagnosis of both conditions. Lyme disease may resemble mild cerebritis with lymphocytes and plasma cells in the leptomeninges as found in SLE, along with a similarity between lymphoplasmacytic panniculitis in Lyme disease and lupus profundis due to the interraction between plasma cells and blood vessels. The chronic inflammation that occurs in Lyme disease also leads to vascular thickening in many cases along with scleroderma-like collagen expansion, and this can create a similar type of degeneration in the synovia as found in the vessels of lupus spleens.
Cutaneous disorders are also a feature of chronic Lyme disease infection, with acrodermatitis chronic atrophicans (ACA) a major feature in elderly European populations where the disease is endemic. Sclerodermoid-like reactions, lichen sclerosis et atrophicus, eosinophilic fasciitis-like lesions of the extremities, and subcuticular fibrous nodules have all been associated with the presence of spirochaetes. The specific nature of these cutaneous conditions and their incidence appears to vary according to the species of infectious Borrelia bacteria, with ACA less common in North American Lyme disease patients.
Long-term chronic manifestations of Lyme disease are increasingly thought to be due to induced autoimmune conditions rather than acute pro-inflammatory action by the infection, although experimental support for this theory is lacking in most cases with the exception of a small group of patients with persistent arthritis symptoms following Lyme disease infection. These patients were found to have immune reactivity to outer surface protein A (OspA) of Borrelia burgdorferi, and the human leukocyte function-associated antigen-1 (hLFA-1) indicating a possible initiating bacterial antigen and a cross-reactive autoantigen which would explain the development of Lyme disease-related treatment-resistant arthritis. Research published in April 2011 has however found that the enzyme 5-lipoxygenase (5-LO), which catalyzes the conversion of arachidonic acid into the leukotrienes and was previously suspected of involvement in the development of arthritis is in fact not a causative agent and is unlikely to be a useful therapeutic target. Deficiency of the enzyme does however appear to lead to earlier manifestations of the condition and an inability to resolve the arthritis in the longer-term.
The variety of pro-inflammatory and immunomodulatory-immunosuppressive features of are still only beginning to be understood and have significant consequences for the success of any treatments. Whilst antibiotic treatment appears appropriate for acute and early stage Lyme disease, later manifestations may require immunosuppresive treatment to combat autoimmune-related Lyme disease pathology.