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The symptoms of Lyme Borreliosis are often categorized into three groups depending on the system affected, however it is important to note that Lyme Disease is a highly heterogeneous disease and symptoms can be nonspecific (4,5). The most common group of symptoms is Lyme Arthritis, which primarily affects the knees but also other large joints such as the ankles, wrists, and elbows (5). Lyme Neuroborreliosis is the second most common group of symptoms, affecting the nervous system, leading to such manifestations as Bannworth's syndrome, encephalitis, meningitis, radiculomyelitis, transverse myelitis, bilateral facial palsy, stroke-like disorders, and cranial nerve defects (5). Lastly, Lyme Carditis, affecting the heart, is the rarest of the manifestations targeted in Lyme Disease (5). Symptoms of Lyme Carditis most commonly include atrioventricular blockages (6,7).
In addition to systemic classification of Lyme Disease symptoms, three stages have been developed which cluster symptoms by time, chronicity, and severity. However, Lyme Disease may not necessarily proceed in stages (5). In the first stage or early infection (days to weeks), the most prominent symptom occurring in 35-60% of people (8) is erethra migrans. Erethra migrans is also know as the bulls-eye skin rash found on the skin following infection by B. Burgdorferi and is characterized by a red patch which often has a cleared central region (5). The circle often expands as the spirochete moves through the skin (5). Additional symptoms during Early Infection include fever, myalgia, headache (9), and fatigue (1,7,10). The next stage of Lyme Disease occurs between a few weeks to six months and is called Early Dissemination (1). Characteristic symptoms of stage two includes fatigue, symptoms of neuroborreliosis, pain involving the musculoskeletal system, and occasionally, cardiac problems (7). The final stage is classified as Late Persistent Infection and occurs longer than six months (7). In this stage Lyme Arthritis is prominent, especially in large joints, while secondary symptoms may include fatigue, fever, (7,11) and neurological problems such as spastic quadriparesis and paraparesia (1).
The heterogeneity of Lyme Disease makes it difficult to diagnose, however first signs of erethra migrans, ear lobe lymphoytoma, and Bannworth's syndrome are primary symptoms (5). In addition to exogenous signs, the patient's serum is a primary target in determining the presence of the pathogen. Laboratory methods which are commonly used examine IgM and IgG antibodies within the serum with immunoflourescent tests, identify borrelial DNA with Polymerization Chain Reaction tests, and examine T cell levels with T cell proliferation tests (1,5). However, if a patient presents with less specific symptoms the serum tests show less efficacy in predicting the pathogens presence (1).
Lyme Disease is not only the most common vectorborne disease in the U.S. (12), but also occurs widely in other temperate regions such as Europe, Russia, Japan, and China (13). In the U.S. alone, it is estimated that 10,000 cases are reported (13). Lyme Diseases' epidemiology follows a distinct geographic pattern as most cases in the U.S. are on coastal northeastern areas, mid-Atlantic regions, and North-central states (14). These geographic patterns correlate with the environments which support the ixode ticks' lifestyle such as humid, forest or forest edge habitats, environments which support white-tailed deer, and areas that contain abundant leaf litter (14). Consequently, risk factors include residence or seasonal residence in these typified regions (14). The highest incidence of Lyme Disease occurs in children under the age of 15 (11).
Transmission of B. Burgdorferi from Vector to Host
B. Burgdorferi is first found in the midgut of the tick (4) after the tick has obtained the pathogen from the primary host, which is most commonly the white tail deer or a small rodent (7). Once in the midgut, B. Burgdorferi expresses the outer surface protein (Osp) A which allows binding to the midgut epithelium (1,3,7,12). This Osp protects the spirochete from midgut proteases and the hosts complement system while the tick is feeding (15). The pathogen does not undergo changes until the tick has attached to the host and fed for 3-4 days (3). Once this has occurred, B. Burgdorgeri is then stimulated by the blood meal and proliferates, eventually changing its Osp to OspC, enabling its migration to the salivary glands of the tick (3). After the tick has been attached for 48 hours and OspC has been expressed, successful transmission may occur and the spirochete enters the host through the tick's feeding lesion (3,13). Once in the system, B. Burgdorferi uses chemotaxis and two flagella to swim through viscous materials such as connective tissue (15) and eventually spreads through the lymphatics and blood to invade the skin, heart, nervous system, and musculoskeletal system (15). Additionally, B. Burgdorferi increases its expression of adhesion molecules on endothelial cells, enabling it to move through extracellular matrices (7). Finally, the spirochete swiftly moves through tissues by using integrins to bind to platelets and endothelial cells (3).
B. Burgdorferi's Evasion of the Immune System
After entering the host, B. Burgdorferi has several mechanisms of evading potential immune responses. The mechanisms by which the spirochete carries out evasion include immunosuppression, genetic variation, physical seclusion, interaction with host molecules, and producing secretions leading to what Stricker et. al call the spirochetes' "stealth pathology" (8).
First, B. Burgdorferi engages in immunosuppressive action on the host. The spirochete takes advantage of secondary immunosuppression produced by the tick, as the ticks saliva leads to numbing, blood-thinning, and other factors which decrease immune response (8). B. Burgdorferi is then able to discretely pass through the skin and induces its primary immunosuppression by inhibiting host complement, decreasing MHC markers on Langerhan skin cells (7), triggering cytokines IL-10 (8), resisting phagocytosis by macrophages (11), and initiating monocyte and lymphocyte tolerization (8).
Once established in the host, B. Burgdorferi is able to undergo genetic variation which prolongs survival. One mechanism the spirochete uses involves rearranging its DNA on surface molecules to evade host detection (15). Furthermore, B. Burgdorferi can switch genes to a dormant state by utilizing neutrophil calprotectin so the pathogen can remain in the tissue without replication and detection by the immune system or by antibiotics (8).
The pathogen continues its evasion from the host's immune system by entering intracellular sites and binding to proteogylcan, collagen, plasminogen, integrin, and fibronectin (8). The entrance of the pathogen into intracellular sites is particularly found in synovial joints where dextrin sulfate and heparin are used as binding sites (11). By engaging in this type of cloaking, it is hidden from cells such as macrophages, neuronal cells, fibroblasts, and endothelial cells (8).
The "stealth pathology" and adhesion to cells is furthered by interactions with host molecules, as the pathogen uses these contacts as a mechanism of evasion. Upon contact with synovial fibroblasts, the cells down regulate intercellular cell adhesion molecules, allowing for the entry of the spirochete into the intercellular sites (7). B. Burgdorferi can also interact with platelet integrin receptor Î±IIÎ²3 in order to bind to cells especially in areas of vascular injury (4, 11) and uses its own surface proteins to help adhere to these sites (15). B. Burgdorferi is able to further penetrate tissue by utilizing utilizing plasmin proteolytic enzyme to break down extracellular matrices and quickly spread through the host while evading fibrin (3). Finally, the spirochete is able to evade the immune system involvement by binding to host complement control proteins such as factor H (3).
The final step B. Burgdoferi takes to evade detection is carried out by secreting factors. The spirochete can secrete actin and adhesion which aids in adhesion and entering into host cells (8). Secondly, B. Burgdorferi can switch from its dormant state by secreting pheromones AI-2 which leads to the autoresuscitation of the organism (8). B. Burgdorferi may also secrete aggreganase which damages cartilage and leads to subsequent inflammation and joint injury (8).
Involvement of the Immune System in Lyme Disease
Upon the spirochetes entry into the host and its detection, an innate immune response is elicited followed later by an adaptive immune response. Although fewer implications have been made for the activation of the innate immune system, Toll-like receptors are said to play an essential role in initiating this response (1, 10) by recognizing the pathogen and activating effector cells of the innate immune system (16). Additionally, the system activates classical and alternative pathways (3) of complement which play a crucial role in early detection and immune response well before antibodies become involved (17). The innate immune system is further involved when macrophages recognize lipoproteins and glycoproteins on the outer surface of the spirochete (3). Macrophage phagocyctosis of the pathogen leads to the triggering of cytokines such as IL-1Î² and TNFÎ±, while chemokine IL-8 (3, 10) is also used to generate a cellular response. Additionally, chemokines such as MIP-1Î± and MIP-1Î² are suggested to be involved, as higher levels of these factors are found in neuroborreliosis and seem to be key in the inflammation response (10). Researchers have found that the activation of these inflammatory responses is disproportionate to the minimal amount of bacteria present in cases of Lyme Disease (10). This inordinate reaction is central in understanding the pathogenesis of Lyme Disease as B. Burgdorferi does not inherently cause tissue damage (7) but acts to trigger excessive immune responses leading to symptoms (10).
After sufficient activation of the innate immune system, chemokines, complement, and cytokine activity leads to the involvement of the adaptive immune system. Stimulation of the adaptive immune system induces T cell and B cell stimulation and proliferation. A prominent feature in the activation of T and B cells is their specificity towards B. Burgdorferi. T cells such as CD4+ Th1 acquire a specific response to the spirochete which ultimately serves to prime T cell dependent B cell activation and the involvement of macrophages (7). ADDITIONAL MACROPHAGE activity is CRUCIAL IN UNDERSTANDING LyME Arthritis, AS MOLECULES DRIVEN BY MACROPHAGE action ARE FOUND IN SYNOVIAL FLUID OF THE jOINTS (7,10). Further T cell involvement occurs as antigen-SPECific CD8+ T cells stimulate IFN-Î³ proliferation (17), a molecule which is critical for communication between T cells and macrophages (6). T cell recognition of the antigen occurs when an antigen presenting cell digests peptides of the spirochete on class II MHC, leading to the involvement of antigen presenting cells and OspA specific T cells that are key to the disease process (17). Moreover, T cells role in Lyme Disease is paramount, as persistent activation of these cells seems to be critical in chronic Lyme Disease, particularly in Lyme Arthritis (7).
Further initiation of the adaptive immune system occurs as T cell and chemokine activation leads to additional response to the spirochete by recruiting B cell response. Although B cells are suggested to have antigen specificity and show activation, little information is known about specific roles B cells may play in Lyme Disease (7). Research has show that in chronic phases of the disease, B cells response is significant, although it has been shown that this B cell activation does not confer protection against reinfection (7).
Chronic Lyme Disease: Immune System Involvement, Autoimmunity, and Genetics
Immune system involvement discussed so far has reflected the typical sequence of events occurring in non-chronic Lyme Disease. However, involvement in chronic Lyme Disease differs and can ultimately produce autoimmunity (1) and subsequently chronic morbidity. The immune system processes are altered in chronic Lyme Disease either by specific genetic characteristics or by faulty selection of T cells in the thymus. Genetic involvement in Lyme Disease is only found in chronic cases where autoimmunity seems to occur (17). Genetic linkage studies have found associations between chronicity and susceptible MHC class II molecules DR2 and DR4 (18,19) and the DRB 0401 and 0101 alleles (17). Possible MHC class II alterations seem to be critical in the immune process as structural changes can alter the ability of peptide binding and presentation of the antigen (17). Additionally, MHC class II plays a crucial role in regulating T cell receptor specificity in the thymus, which may lead to T cell recognition of foreign and self molecules (17). While these overreactive T cells may not cause initial inflammation, Osp reactive cells may initiate inflammation and self-reactive T cells may maintain local inflammation creating autoimmunity (17). Additionally, these self-reactive T cells are found to be present after bacterial elimination as they will continue to bind with a structurally similar self-peptide called hLFA-1Î± (17). Researchers have found that OspA self-reactive T cells not only recognize the hLFA-1Î± self peptide but also OspA and that these reactive T cells concentrate in joints in those with chronic or treatment resistant Lyme Disease (17). These T cells appear to have undergone incompetent selection processes in the thymus which may be result of susceptible MHC class II alleles, ultimately leading to autoimmunity and chronic disease features.
Most patients with Lyme Disease have an excellent outcome (1,7) with many recovering within a few weeks or months with proper antibiotics (1, 5, 9). Successful treatment eliminates bacteria and any detectable remnants of DNA in the patient (17).
When a patient first presents with signs of Lyme Disease such as erythema migrans, a single dose of doxycycline must be administered within 72 hours of tick attachment to prevent Lyme Disease (5). If Lyme Borreliosis symptoms are present thereafter or the patient's symptoms were later detected, treatment can follow either by system or by stage. For those who are treated by system, drugs target Lyme Arthritis, Lyme Neuroborreliosis, and Lyme Carditis. For Lyme Arthritis patients, treatment is the longest at 28 days (1) and usually includes oral antibiotics such as doxycycline (7), amoxicillin, or probenecid and intravenous antibiotics such as ceftriaxone (7, 15) if the arthritis is accompanied by neuroborreliosis. Treatment of Lyme Neuroborreliosis includes oral antimicrobials such as doxcycline, but outcomes may vary with those experiencing meningitis having the most positive outcomes and those with damage to facial nerves or nerve roots never recovering (9). Finally, Lyme Carditis is treated with intravenous ceftriaxone or penincilin G and glucorticoids or corticosteroids for those not responding to the intravenous antibiotics (6). If the patient has an atrioventricular blockage, 38% of patients will also require a temporary pacemaker (5).
Treatment of Lyme Disease by stages differs slightly from treatment by system. Stage I symptoms are typically treated with doxycycline, cefuroximaxetil, and amoxicillin for 2 weeks (1). If the patient is diagnosed with Stage II Lyme Disease, penicillin G, cefotaxime, ceftriaxome, and doxycycline are administered for 2 weeks (1). Finally, Stage III is commonly treated with intravenous ceftriaxone (1). If a patient is not cured by antibiotics, fatigue, problems with concentration, and chronic pain will persist indicating a diagnosis of chronic Lyme Disease (1).
Preventative and Potential Treatments
Much of the research on Lyme Disease has been allocated to preventative measures which may be taken to decrease the number of Lyme Disease cases. Programs which educate individuals on preventing tick attachment such as wearing protective clothing, using repellents, and checking for ticks are currently in progress, yet show little effect on reducing cases of Lyme Disease (14). Alternative efforts have been made to prevent incidence of Lyme Disease by creating vaccines. Much of current drug research and potential treatments are focused on vaccination. The most established vaccine which has undergone clinical trials is recombinant OspA vaccine. The main target of this vaccine is preventing infection by targeting B. Burgdorferi in the midgut of the tick (5). The vaccine works to elicit antibodies in the midgut which destroys the spirochete (20). Researchers are unsure of the mechanism in which this occurs, but suggest that enhanced phagocytosis of the spirochete may play a role (20). Clinical trials have shown the success of the vaccine, however the vaccine does not protect against human granulocytic ehrlichiosis and babesiosis which are often transmitted during the tick feeding (20).
Additionally, researchers are working on several classes of vaccines which lead to inactivation or destruction of the spirochete. These treatments are aimed at targeting not only the antigen, but also the host and the vector. One class of vaccines called the anti-adhesion vaccine targets extracellular matrix molecules that the spirochete uses as a source of attachment (20). In addition, research has explored DNA vaccines which are designed to direct antigen processing and presentation. Lastly, research on vaccines which inhibit tick attachment called anti-tick vaccines have targeted salivary gland antigens to result in the rejection of the tick upon contact (20). Many of these vaccines are still experimental, but are expected to come into use in the near future as an effort to combat the high incidence of Lyme Disease.