McCloskey, Natalie; (1996) The avidity of human IgG subclasses. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The four human IgG subclasses display greater than 90% sequence homology and their production is antigen restricted, with IgG1 and IgG3 being preferentially elicited against protein antigens and IgG2 against carbohydrate antigens. Although the titre of a particular subclass is clearly important in overcoming infection, it is becoming apparent that the functional affinity (avidity) of such a response is also crucial. These studies were therefore initiated to investigate aspects of antibody avidity of the four human IgG subclasses. Utilising V region identical mouse-human IgG subclasses avidity differences were found by solid-phase avidity ELISA and biospecific interaction analysis (BIA). IgG4 was consistently of highest avidity and furthermore this reflected differences in dissociation rate constants. Following removal of the constant region such differences were abolished suggesting an involvement for the constant region in the control of human IgG subclass avidity. Serum IgG subclass avidity specific for pneumococcal polysaccharide serotypes 3, 6, 19 and 23 were measured by solid-phase avidity ELISA following pneumococcal vaccination. A complex pattern of avidity emerged with serotype 3 specific antibodies generally being of higher avidity. Significant differences were obtained comparing serum antibodies from children below 2 years of age with children more than 2 years of age. Such differences may contribute to the higher incidence of bacterial infection observed in children less than 2 years of age. Another aspect of IgG subclass avidity which has received little attention, is the control of affinity maturation. One possible area of regulation addressed in this study was the control of antibody affinity by cytokines. The effect of various cytokines on antigen specific total IgG avidity utilising solid-phase avidity assays developed throughout this thesis. Preliminary evidence presented in this thesis suggest that the cytokines IL-6, IL-10, TNF? and IFN? do not influence antibody avidity. The development of solid phase avidity ELISAs and BIA opens up an exciting area of biology and future investigations should answer many of the remaining questions concerning human IgG subclass avidity.

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