IgG subclass and heavy chain domains contribute to binding and protection by mAbs to the poly γ-D-glutamic acid capsular antigen of Bacillus anthracis.
IgG subclass and heavy chain domains contribute to binding and protection by mAbs to the poly γ-D-glutamic acid capsular antigen of Bacillus anthracis.
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DOI：
10.1371/journal.ppat.1003306
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Kozel TR
中科院分区：
文献类型：
--
作者：
Hovenden M;Hubbard MA;Aucoin DP;Thorkildson P;Reed DE;Welch WH;Lyons CR;Lovchik JA;Kozel TR
Bacterial capsules are common targets for antibody-mediated immunity. The capsule of Bacillus anthracis is unusual among capsules because it is composed of a polymer of poly-γ-d-glutamic acid (γdPGA). We previously generated murine IgG3 monoclonal antibodies (mAbs) to γdPGA that were protective in a murine model of pulmonary anthrax. IgG3 antibodies are characteristic of the murine response to polysaccharide antigens. The goal of the present study was to produce subclass switch variants of the γdPGA mAbs (IgG3→IgG1→IgG2b→IgG2a) and assess the contribution of subclass to antibody affinity and protection. Subclass switch antibodies had identical variable regions but differed in their heavy chains. The results showed that a switch from the protective IgG3 to IgG1, IgG2b or IgG2a was accompanied by i) a loss of protective activity ii) a change in mAb binding to the capsular matrix, and iii) a loss of affinity. These results identify a role for the heavy chain constant region in mAb binding. Hybrid mAbs were constructed in which the CH1, CH2 or CH3 heavy chain constant domains from a non-protective, low binding IgG2b mAb were swapped into the protective IgG3 mAb. The IgG3 mAb that contained the CH1 domain from IgG2b showed no loss of affinity or protection. In contrast, swapping the CH2 or CH3 domains from IgG2b into IgG3 produced a reduction in affinity and a loss of protection. These studies identify a role for the constant region of IgG heavy chains in affinity and protection against an encapsulated bacterial pathogen. The ability of an antibody to recognize and bind to its target is classically viewed as a function of the variable region of the molecule; this region distinguishes an antibody with one specificity from an antibody with a different specificity. We examined binding of antibodies to an outer coat of the biothreat Bacillus anthracis that is essential for bacterial virulence. We identified regions of the antibody constant region which contribute to antibody binding and the ability of the antibody to protect the host. These constant regions are distinct from the variable regions that directly mediate antibody binding. The results of the study have implications for i) understanding how antibodies function in protection against anthrax and possibly other diseases, ii) understanding how the host responds to a key bacterial virulence factor, iii) selection of antibodies that might be used to treat anthrax, and iv) design of vaccines to protect against anthrax.
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影响因子：
3.2
作者：
BEALL, FA;TAYLOR, MJ;THORNE, CB
通讯作者：
THORNE, CB
影响因子：
4.8
作者：
Joyce, J;Cook, J;Caulfield, M
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