User:Amal Hope Jasentuliyana/Sandbox 1
From Proteopedia
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| - | The only diagnostically sufficient clinical sign for Lyme disease in the presence of Erythema Migrans rash. The rash does not present on all cases, however, and when present, it is only there in the early stages of infection. Other symptoms of Lyme, such as fever, neurological signs, and joint inflammation, are non-specific to the disease. Because of this antigenic testing is an important component of Lyme diagnosis<ref>PMID:17538122</ref>. The invariable IR6 region of VLsE | + | The only diagnostically sufficient clinical sign for Lyme disease in the presence of Erythema Migrans rash. The rash does not present on all cases, however, and when present, it is only there in the early stages of infection. Other symptoms of Lyme, such as fever, neurological signs, and joint inflammation, are non-specific to the disease. Because of this antigenic testing is an important component of Lyme diagnosis<ref>PMID:17538122</ref>. The first tier test for Lyme is often the C6 ELISA, which uses an artificial analog of the invariable IR6 region of VLsE as its antigen<ref name="LiangJCM">Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT. 1999. Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi vlsE. ''J Clin Microbiol'' 37(12):3990-6.</ref>. IR6 has several qualities that make it a good antigen for a single-epitope immunologic test such as ELISA: (1) most patients with Lyme produce detectable levels of antibody to IR6, (2) the antigenic epitope is conserved so that one antigenic test sequence suffices regardless of the strain of ''B. burgdorferi'' being tested for, and (3) the antibody is not generally found in patients without a history of Lyme. These characteristics allow anti-C6 antibody to be a sensitive test for Lyme disease, with 74% of acute phase infections and over 90% of convalescent and late-phase infections yielding positive results<ref name="LiangJCM"/>. Anti-C6 antibody also results in good test specificity, with a 1.1% rate of false positives among patients with relapsing fever and autoimmune conditions (symptoms which can be mistaken for Lyme), patients with syphilis (caused by the sister genus to ''Borrelia''), and patients drawn at random from areas to which Lyme is not endemic<ref name="LiangJCM"/>. |
Revision as of 08:30, 15 August 2012
VlsE
Vmp-like sequence, Expressed
|
Introduction
Lyme disease is a systemic bacterial infection that can lead to chronic dehabilitating effects if left untreated. The symptoms are varied and affect multiple systems, sometimes making diagnosis difficult. Some initial symptoms are not unique to Lyme disease, and include fever, headache, lethargy, and soreness. The main identifying symptom is a characteristic bullseye rash that develops locally near the site of infection. If the infection is allowed to progress, more serious symptoms develop such as arthritis, swollen joints, and even neurological symptoms such as depression and psychosis.
The disease is caused by the bacterium, Borellia burgdorferi, the spirochete responsible for most Lyme disease in most of the Eastern region of North America. B. burgdorferi has a complex life cycle, transferring from different hosts. However, the main vector of disease transmission to humans is the deer tick, Ixodes scapularis, particularly the young nymph stage.
The main challenge to treatment of the disease is the bacteria's lengthy incubation time. After the time of entry, weeks may pass before symptoms begin to emerge, many of which are indistinguishable from more common maladies such as a cold or fatigue. During these initial weeks, Borellia burgdorferi is able to evade immune response for reasons which are not completely understood. It appears that this allows the bacteria to spread systemically and effect sites distal to the infection site, such as the joints.
VlsE and Immune Evasion
The evasive nature of the pathogen Borrelia burgdorferi is believed to be due in part to its unique surface antigen, , or "Vmp-like sequence, Expressed". VlsE is a lipoprotein that is abundantly found on the membrane of the bacteria. It belongs to a class of proteins known as variable surface antigens, meaning that they are antigens located on the outer surface of the membrane, but are also of a variable nature. This unique variability is what is responsible for the proliferative nature of the bacteria in the human body, through its ability to evade immune recognition.
VlsE may serve other unknown functions, but there is support for its role in immune evasion. If B. burgdorferi loses the encoding plasmid Lp28-1, which is responsible for the production of VlsE, the result is a significantly reduced degree of infection in the mouse model[1]. This property is a result of the antigen's complex structure, which is comprised of a proximal region which is presumably embedded in the bacteria's membrane, and an exposed distal region. The distal exposed region is the area of most interest, because it is comprised of small alternating variable and invariable regions. While the invariable regions maintain a constant amino acid sequence between generations of bacteria, the variable regions undergo a complex gene recombination mechanism which alters the variable regions between generations[2]. These rapid modifications in the variable regions may confer the bacteria with a kind of protection from immune recognition. The constantly changing variable regions on the exposed surface may act as a mask, preventing antibodies from making a reliable identification.
Antibody Recognition
Antibody recognition is difficult, because genetic recombination is constantly altering the residues in the exposed variable regions, making the antigen appear different and unidentifiable Therefore, if an antibody does match a region on VlsE and binds, its effectiveness will become null once the bacteria produces a daughter cell with different variable regions. There is, however, a discrete region that has been shown to elicit an antibody response. The invariable region 6, or IR6, is one of the 6 invariable regions contained within the variable domain of the antigen. Serum samples from rhesus monkeys analyzed through a peptide based ELISA assay showed a strong antibody response to IR6. The antigenticity of this particular region was confirmed because none of the other IR regions (IR1-IR5) elicited an antibody response [3].
There is also an indication that the formation of in vivo may be responsible for some sheilding of the invariable regions at the connection between the two monomers[2]. This may help to further explain why the invariable regions are so inaccessable to antibodies.
Structure
VlsE is composed of a variable domain flanked by two invariable domains. The invariable domain
Clinical Relevance
ELISA test
The only diagnostically sufficient clinical sign for Lyme disease in the presence of Erythema Migrans rash. The rash does not present on all cases, however, and when present, it is only there in the early stages of infection. Other symptoms of Lyme, such as fever, neurological signs, and joint inflammation, are non-specific to the disease. Because of this antigenic testing is an important component of Lyme diagnosis[4]. The first tier test for Lyme is often the C6 ELISA, which uses an artificial analog of the invariable IR6 region of VLsE as its antigen[5]. IR6 has several qualities that make it a good antigen for a single-epitope immunologic test such as ELISA: (1) most patients with Lyme produce detectable levels of antibody to IR6, (2) the antigenic epitope is conserved so that one antigenic test sequence suffices regardless of the strain of B. burgdorferi being tested for, and (3) the antibody is not generally found in patients without a history of Lyme. These characteristics allow anti-C6 antibody to be a sensitive test for Lyme disease, with 74% of acute phase infections and over 90% of convalescent and late-phase infections yielding positive results[5]. Anti-C6 antibody also results in good test specificity, with a 1.1% rate of false positives among patients with relapsing fever and autoimmune conditions (symptoms which can be mistaken for Lyme), patients with syphilis (caused by the sister genus to Borrelia), and patients drawn at random from areas to which Lyme is not endemic[5].
Picture from wiki entry on ELISA
References
- ↑ Labandiera-Rey, M., Baker, E., and Skare, J. T. (2001) J. Infect. Immun. 446-455.
- ↑ 2.0 2.1 Eicken, C., Sharma, V., Klabunde, T., Lawrenz, M. B., Hardham, J. M., Norris, S. J., and Sacchettini, J. C. (2002) J. Bio. Chemistry 227:24 21691-21696.
- ↑ Liang, F. T., Phillip, M. T. (1999) Infection and Immunity" 67:12 6702-6706.
- ↑ Gomes-Solecki MJ, Meirelles L, Glass J, Dattwyler RJ. Epitope length, genospecies dependency, and serum panel effect in the IR6 enzyme-linked immunosorbent assay for detection of antibodies to Borrelia burgdorferi. Clin Vaccine Immunol. 2007 Jul;14(7):875-9. Epub 2007 May 30. PMID:17538122 doi:10.1128/CVI.00122-07
- ↑ 5.0 5.1 5.2 Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT. 1999. Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi vlsE. J Clin Microbiol 37(12):3990-6.
