Goldblatt, David; (1991) Qualitative and quantitative aspects of human igg subclass responses with special reference to a common microorganism, moraxella (branhamella) catarrhalis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Although much is known of the physico-chemical characteristics of the IgG subclasses, their specific biological function remains poorly understood. The consequence of either absence or low levels of one or more subclasses is still unclear. In an effort to document the clinical manifestation of IgG subclass deficiency in a paediatric population, a clinical study of children presenting with IgG subclass deficiency was undertaken. 42% of the 232 children reviewed presented with frequent infections, 17% presented with allergy and 13% presented with a combination of infection and allergy. No clear trends emerged relating the deficiency of a particular subclass with any given clinical manifestation. Since healthy individuals may have low levels or a complete absence of certain IgG subclasses the functional study of IgG subclasses needs to go beyond their quantitative estimation. It is known that individuals with normal IgG subclass levels may nevertheless suffer from frequent infection due to an inability to respond in an isotype appropriate way to carbohydrate antigens. This phenomenon suggests that an appropriate qualitative assessment is needed to further elucidate IgG subclass function. To this end a study of Moraxella (Branhamella) catarrhalis was undertaken. This bacterium is a ubiquitous gram negative organism which is emerging as an important paediatric pathogen. While healthy children may acquire infection with this organism, in adults it infects predominantly those with compromised immunity or chronic lung disease. To investigate whether this difference might have an immunological basis, a study of the antigens of M. catarrhalis and the age related IgG subclass response to them was undertaken. The surface antigens were defined by the purification of outer membrane proteins (OMPs) followed by SDS-PAGE and immunoblotting. This revealed that the OMPs were targets of human antibody and, furthermore, this recognition differed between the various isotypes with IgG3 recognising an extended range of proteins. By modification of a newly developed enzyme-linked immunosorbent assay (ELISA) the binding affinities of the M.catarrhalis specific IgG subclasses were measured and IgG3 antibodies were found to be of higher affinity than IgGl and IgG2 antibodies, further emphasising the importance of this isotype. An ELISA procedure was also used in an analysis of the age related appearance of IgG subclasses specific for the organism and this revealed that IgG3 antibody was undetectable in children under the age of four yet present in healthy adults and older children. Age related delay in IgG subclass antigen specific responses has previously only been described for carbohydrate antigens and the IgG2 response. Extending these findings to IgG3 regulation and function emphasises the need to acquire antibody response data on both an organism and subclass specific basis.

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