User:Marvin O'Neal/VlsE: Difference between revisions

VlsE is a surface lipoprotein of Borrelia burgdorferi, the causative agent of [http://en.wikipedia.org/wiki/Lyme_disease Lyme Disease].  It undergoes [http://en.wikipedia.org/wiki/Antigenic_variation antigenic variation] seemingly important in evasion of the host’s immune system.  In addition, the protein is used for Lyme disease diagnosis.  It is composed of four similar subunits each possessing two invariable domains and one variable domain.<ref name="A">PMID:10569796</ref>  The variable domain contains six variable regions (VR₁-VR₆), and six invariable regions (IR₁-IR₆).  Research suggests that the protein may exist as a dimer where each monomeric C & N termini neighbor each other forming the membrane proximal portion of the protein, and the variable regions form the membrane distal portion. <ref name="B">PMID:11923306</ref> <ref name="C">PMID:11716485</ref>    The invariable regions are largely embedded in the protein and remain relatively unchanged within the host and across strains.  The variable regions encompass 37% of the VlsE’s exposed surface area despite comprising only 25% of the protein. <ref name="A" /> <ref name="B" />  However, 50% of the VR surface area is exposed while IR₆, the immunodominant portion, exposes just 13.7% of its surface area.  This leaves only <scene name='Studio:G5SecL01/Ir_6_4_residues/1'>four amino residues</scene> of the antigenic IR₆ unprotected; lysine-276, glutamine-279, lysine-291, and lysine-294.  Thus, it is almost entirely embedded in the protein and <scene name='Studio:G5SecL01/Ir6_embedded/1'>sheilded by the variable regions </scene>. <ref name="B" /> <br>

The variable regions undergo a recombination event stimulated by the host’s cytokines and absence of those cytokines results in a decreased bacterial burden. <ref name="D">PMID:11544329</ref>  This leads to variation with an estimated 10³⁰ possible combinations, far exceeding the number of antibodies found in the human immune system.  While the VR does exhibit antigenicity, this recombination makes it unlikely that a sufficient amount of a single VR variation will be present in large enough supply to lead to an immunodominant variable region. <ref name="E">PMID:10553085</ref>  IR₆, however, exhibits immunodominance while IR₁-IR₅ are primarily nonantigenic in humans.  Thus, shielding of the immunodominant IR₆ by VR regions not subject to antibody response allows for IR₆ to elicit an immune response while remaining inaccessible to antibody binding.  Research suggests that the 26 amino residues of <scene name='Studio:G5SecL01/Ir6_with_epitope/1'>IR6</scene> may function as a single epitope with a central alpha helical core. <ref name="B" /> <ref name="D" /> <ref name="F">PMID:10722641</ref>   

VlsE is essential to the persistence and virulence of Lyme disease and is upregulated under humoral immune pressure. <ref name="G">PMID:17714442</ref> <ref name="H">PMID:15385475</ref>  While the exact mechanism for immune evasion remains unknown several theories have been put forth.  One popular theory is that VlsE masks other surface antigens by coating the surface of the bacteria, thereby sterically blocking the antigens from antibody binding.  This is similar to other pathogens with variable regions, such as the [http://en.wikipedia.org/wiki/Trypanosoma_brucei protozoa] responsible for African sleeping sickness and also the [http://en.wikipedia.org/wiki/Neisseria_gonorrhoeae bacterium] that causes gonorrhea.  However, recent studies have cast doubt on this theory.  An alternate theory provides that VlsE directly stimulates B cell antibody production independent of T-cells.  The robust response elicited is thought to override antibody production against other antigens. <ref name="G" />   

Throughout the course of the disease IR₆ produces a strong antibody response that can be identified from early to late phases, and which lasts for months to years following treatment.  Applications in diagnostic testing have been identified as a result of this strong immune response and IR₆’s relative invariability across strains. <ref name="I">PMID:10565920</ref> <ref name="F" />  A C₆ ELISA test has been developed which uses a 26-mer synthetic peptide with the IR₆ sequence.  Results show 99% specificity and 100% precision with high sensitivity.  In fact, OspA vaccination does not influence C6 specificity; therefore, C₆ ELISA tests are valuable diagnostic tools. <ref name="I" />  The CDC currently recommends a [http://www.cdc.gov/lyme/healthcare/clinician_twotier.html two-step test] incorporating first a polyvalent, whole-cell sonicate (WCS) immunofluorescent assay.  If results are positive, this is followed by IgG and IgM WCS Western blots to eliminate false positives. <ref name="J">PMID:21865190</ref>  Therefore, this one-step ELISA test presents an accurate and economical alternative to the current two-step model. <ref name="I" /> <br>