Singleton, Richard Thomas; (2004) B cell responses to respiratory viral infections. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease during infancy and early childhood. Previous studies have focused mainly on serum antibody responses and have largely neglected the mucosal (local) sites. The nasal- associated lymphoid tissue (NALT) is a mucosal lymphoid tissue located at the entrance to the naso-pharynx and is significant as it is the first site of contact with inhaled antigen suggesting it may play an important role in the immune response to respiratory pathogens. Our aim was to characterise the local humoral response to RSV in the mouse model using cellular and immunological techniques. Infection of mice with RSV induces an IgA dominated response in the nasal tissues that is extremely short-lived. In addition, very low frequencies of virus-specific antibody forming cells (AFC) were detected in the systemic tissues during the acute phase of infection and only the bone marrow possessed RSV-specific AFC long after infection, but at levels just above background. This is in direct contrast with the well-documented response to influenza virus infection where the AFC responses in the bone marrow are far more robust with frequencies four-fold in excess of those observed with RSV following only a single influenza virus infection. Significantly, the number of RSV- specific AFCs in the bone marrow, but not the D-NALT, can be boosted by subsequent infections with RSV and can attain a level comparable to that seen after a single exposure to influenza virus but only after three consecutive exposures to RSV. In addition, live RSV was still detected within the lungs of mice after secondary and tertiary exposures to RSV demonstrating the potential importance of antibody production at the site of infection. When compared with influenza virus infection, our observations on the antibody response to RSV during infection highlight some interesting differences. The lack of a robust, boostable, RSV-specific antibody response in the D-NALT may be a key factor in explaining how RSV can re-infect via the nasal route with such apparent ease. This, coupled with the observation that there is only a gradual build up of RSV-specific AFC in the bone marrow over successive infections, may potentially explain why reinfection is so commonplace, requiring multiple infections before even moderate protection is afforded.

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