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Title: Unravelling the solution structure of secretory immunoglobulin A
Author: Bonner, Alexandra
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2008
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Immunoglobulin A (IgA) is the most abundant and heterogenous human antibody class, being present in two major subclasses, IgAl and IgA2, and different oligomeric states. Secretory component (SC) binds to dimeric IgAl (dlgA) to form secretory IgA (SIgA). In this thesis, X-ray and neutron scattering, analytical ultracentrifugation and constrained modelling were used to determine their structures in solution. Free SC consists of five Ig-variable domains, with seven glycosylation sites. SC was found to adopt a compact, J-shaped structure in solution, with the glycosylation sites probably located on one face of SC. In this model, one side of SC and SC Dl, containing known IgA-binding motifs, is free to interact with dlgA. Dimeric IgAl (dlgAl) is formed by two IgAl monomers covalently bound by the joining (J) chain. The modelling of the solution structure of dlgAl shows that the arrangement of the two monomers are near-planar in an extended arrangement. The two Fc regions form a slightly bent end-to-end contact. All four Fab antigen-binding sites are independent of one another. The model shows that the two Fc regions are accessible to the Fc alpha receptor (FcaRI) and the polymeric immunoglobulin receptor (plgR). This dlgAl structure suggests a mechanism for dlgAl aggregation in IgA nephropathy through oligomerisation caused by removal or movement of the Fab regions by proteolysis or changes in the glycosylation of the hinge region. SIgA is formed by the transcytosis of dlgA across epithelial cells, where after binding plgR (membrane-bound SC) it is secreted into the mucosa. At the mucosal surfaces SIgA acts as the first line of defence against pathogens. The solution structure of SIgAl suggests that the arrangement of the IgAl monomers are not altered when SC is binds to dlgAl, therefore retaining their near-planar structure. The five domains of SC are in an extended conformation along the convex Fc-Fc edge of the dimer. The SIgAl solution structure shows how SC and dlgAl confer mutual protection to one another from proteolysis. The modelling of the solution structure of SIgA2 shows that, although the IgA2 monomers are in a similar arrangment to that in SIgAl, SIgA2 has a non-planar structure in solution. SC is located in a similar extended arranagment on the Fc-Fc convex edge to that in SIgAl, yet the Fab regions are positioned out of the Fc-Fc plane. These structural differences between the SIgA isotypes may increase their efficiency in mucosal immunity but confer varied susceptibilities to mucosal proteases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available