B cell response regulation to influenza virus infection

Influenza virus infection induces the generation of virus-specific B lymphocytes that contribute to short and long-term immune protection. Extrafollicular foci are recognized as the source of rapid and short-lived antibody production, whereas germinal centers are thought of as the generators of B cell memory and long-lived antibody-secreting plasma cells. The mechanisms underlying the induction and regulation of these responses and their respective contributions to short and long-term local and systemic humoral immune responses are not completely understood. The objective of this dissertation was to address these important issues by establishing a murine in vivo system of infection.;Work outlined in Chapter 2 describes a murine model system with which the regulation of early B cell selection events was studied after influenza virus infection. Use of a monoclonal antibody against a particular Ig-idiotype (C12), known to be strongly expressed among early-responding B cells to influenza hemagglutinin (HA) in BALB/c mice and labeled HA of influenza A/Puerto Rico/ 8/34, in conjunction with multicolor flow cytometry, determined that follicular B cells expressing the same (C12) Ig-idiotype and fine specificity for HA contribute to both extrafollicular and germinal center responses. Collectively the data suggest a stochastic mechanism of B cell response regulation in which extrafollicular versus germinal center fate-decisions are based on B cell and T cell extrinsic, likely innate signals.;Chapter 3 describes the use of a new multicolor flow cytometric staining method to identify and quantify the rare HA-specific B cell populations that proliferate in vivo in response to infection or immunization, using BrdU-labeling techniques.;Chapter 4 pursues the unexpected observation that the mainly extrafollicular foci-inducing Cl2ld+ HA-specific cells provided life-long antibody secretion following infection. The study demonstrates that this life-long antibody secretion occurred in the absence of B cell memory formation and formation of long-lived plasma cells in bone marrow and spleen. Instead, these antibodies were contributed by secreting cells in the lung parenchyma that appeared to be maintained by continuous replenishment. Collectively, this study suggests a crucial role for extrafollicular foci responses in the development of local immune protection in the respiratory tract.