G04SecL04Tpc1: Difference between revisions

Line 21:

OspA has a structure composed of a single alpha helix and 21 anti-parallel beta strands. OspA also contains a B-cell epitope that binds with LA-2 Fab, an antigen combining fragment of the LA-2 monoclonal antibody, which is a major component in effective OspA vaccinations (Ding et al. 2000). Early vaccination for OspA is critical as OspA is only up-regulated during late stages of the disease; anti-OspA antibodies can only kill spirochetes in the tick gut, but is ineffective once it has migrated into host (Rupprecht et al. 2008). Through NMR chemical shift-perturbation and crystallographic identification, the LA-2 antibody is shown to make direct contact with the three loops in the C-terminal tip, which consists of approximately 39 amino acid residues (Ding et al. 2000). Specifically, the LA-2 Fab makes a concave groove over the three loops using all six of its light and heavy variable chain domains seen by NMR-perturbation analysis (Ding et al. 2000). The sequence variation of Loop 1 (~17 residues) has even shown to dominate LA-2 recognition of the OspA antigen; furthermore, <scene name='G04SecL04Tpc1/Ospa_complex/3'>position 208</scene> (Residue Alanine) is a major dynamic for current studies of antibody cross-reactivity between different strains of the Borrelia that transmit Lyme disease (Ding et al 2000).

Similar to the LA-2 epitope, the H6831 epitope is positioned opposite to the N-terminus near the end of the antigen. The buried surface area of OspB in the H6831 Fab complex is smaller than that of the OspA-LA2 complex. Loop 1 in the OspA-LA2 complex has the most interactions with the Fab, whereas Loop 1 in the OspB-H6831 complex has the fewest interactions with the Fab (Golde 1997)

==Possible Mechanism of Bactericidal Properties of Antibody Bound Complex==

Although the exact mechanism of the bacterial effect of OspB and Fab H6831 complex is not know there are several hypotheses on how bacteria lysis occurs. One such hypothesis is that bacteria lysis is the direct result of oxidative reaction of singlet oxygen and water to yield hydrogen peroxide, ozone, and hydroxide radicals (Becker et al. 2005). Experiments done by Jorge Nieva and Paul Wentworth Jr of The Scripps Research Institute describe this reaction further. They suggest that this antibody-catalyzed water oxidation pathway is a property of nearly all antibodies and is similar to phagocytosis and that this may prove to be an important defense of the immune system. However, in order for phagocytosis to occur the immune system must use a complement indirect cascade initiating a membrane attack complex (Connolly and Benach 2005). In the experiments by Nieva and Wentworth they provide evidence that this oxidative reaction is independent of this compliment system. They believe that singlet oxygen acts as the substrate and binds to binding sites within the outer surface protein folds (Nieva and Wentworth 2004). A singlet oxygen acts a nucleophile and attacks one water molecule to form the dihydrogentrioxide (H2O3) intermediate which then reacts to form hydrogen peroxide (H2O2) which when given an oxygen source proves to be bactericidal. Catalase prevents the reaction of hydrogen peroxide and ozone that produces hydroxide radicals which is the potential antibacterial agent (Nieva and Wentworth 2004). This oxidation reaction leads to damage in the cell wall and plasma membrance which leads to lysis of the cell which was observed through observation under an electron microscope (Nieva and Wentworth 2004). Because B. burgdorferi survives best in environments with limited oxygen and its genome does not encode for catalase it may be vulnerable to this oxidative reaction (Becker et al. 2005).

G04SecL04Tpc1: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 21: / Line 21: @@
 OspA has a structure composed of a single alpha helix and 21 anti-parallel beta strands.  OspA also contains a B-cell epitope that binds with LA-2 Fab, an antigen combining fragment of the LA-2 monoclonal antibody, which is a major component in effective OspA vaccinations (Ding et al. 2000). Early vaccination for OspA is critical as OspA is only up-regulated during late stages of the disease; anti-OspA antibodies can only kill spirochetes in the tick gut, but is ineffective once it has migrated into host (Rupprecht et al. 2008). Through NMR chemical shift-perturbation and crystallographic identification, the LA-2 antibody is shown to make direct contact with the three loops in the C-terminal tip, which consists of approximately 39 amino acid residues (Ding et al. 2000). Specifically, the LA-2 Fab makes a concave groove over the three loops using all six of its light and heavy variable chain domains seen by NMR-perturbation analysis (Ding et al. 2000). The sequence variation of Loop 1 (~17 residues) has even shown to dominate LA-2 recognition of the OspA antigen; furthermore, <scene name='G04SecL04Tpc1/Ospa_complex/3'>position 208</scene> (Residue Alanine) is a major dynamic for current studies of antibody cross-reactivity between different strains of the Borrelia that transmit Lyme disease (Ding et al 2000).
 Similar to the LA-2 epitope, the H6831 epitope is positioned opposite to the N-terminus near the end of the antigen. The buried surface area of OspB in the H6831 Fab complex is smaller than that of the OspA-LA2 complex. Loop 1 in the OspA-LA2 complex has the most interactions with the Fab, whereas Loop 1 in the OspB-H6831 complex has the fewest interactions with the Fab (Golde 1997)
+==Possible Mechanism of Bactericidal Properties of Antibody Bound Complex==
+Although the exact mechanism of the bacterial effect of OspB and Fab H6831 complex is not know there are several hypotheses on how bacteria lysis occurs. One such hypothesis is that bacteria lysis is the direct result of oxidative reaction of singlet oxygen and water to yield hydrogen peroxide, ozone, and hydroxide radicals (Becker et al. 2005). Experiments done by Jorge Nieva and Paul Wentworth Jr of The Scripps Research Institute describe this reaction further. They suggest that this antibody-catalyzed water oxidation pathway is a property of nearly all antibodies and is similar to phagocytosis and that this may prove to be an important defense of the immune system.  However, in order for phagocytosis to occur the immune system must use a complement indirect cascade initiating a membrane attack complex (Connolly and Benach 2005). In the experiments by Nieva and Wentworth they provide evidence that this oxidative reaction is independent of this compliment system. They believe that singlet oxygen acts as the substrate and binds to binding sites within the outer surface protein folds (Nieva and Wentworth 2004). A singlet oxygen acts a nucleophile and attacks one water molecule to form the dihydrogentrioxide (H<sub>2</sub>O<sub>3</sub>) intermediate which then reacts to form hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) which when given an oxygen source proves to be bactericidal. Catalase prevents the reaction of hydrogen peroxide and ozone that produces hydroxide radicals which is the potential antibacterial agent (Nieva and Wentworth 2004). This oxidation reaction leads to damage in the cell wall and plasma membrance which leads to lysis of the cell which was observed through observation under an electron microscope (Nieva and Wentworth 2004). Because B. burgdorferi survives best in environments with limited oxygen and its genome does not encode for catalase it may be vulnerable to this oxidative reaction (Becker et al. 2005).