Control of plasma cell generation and population dynamics
Plasma cells, the effector stage of the B cell compartment, secrete large amounts of antibody. These cells arise in two waves during T-‐dependent immune responses; an early wave (extrafollicular plasma cells) generate low-‐affinity antibodies that provide a first line of defence against invading pathogens. Later, plasma cells emerge from the germinal centre reaction and secrete high-‐affinity antibodies. These plasma cells have the capacity to migrate to the bone marrow, where they become established as long-‐lived, non-‐dividing plasma cells. Here, I show that plasma cells found in the bone marrow of young (5-‐week-‐old) mice had a turnover comparable to that seen in the spleen. Long-‐lived plasma cells accumulated over the ensuing weeks until they came to dominate the bone marrow plasma cell compartment by 30-‐weeks of age. This accumulation required MHC II, CD40 and a normal B cell receptor repertoire, implying that these cells are generated during T-‐dependent immune responses. Secondly, I determine the signalling pathways required to generate splenic extrafollicular plasma cell responses in the T-‐dependent response to sheep red blood cells (SRBC) and in bacterial infection with Salmonella. While T cell help, antigen recognition through the B cell receptor (BCR) and TLR signalling were required for maximal plasma cell responses to SRBC, in Salmonella infection TLR signalling was required for day 4 IgM plasma cell responses, whereas class-‐ switched responses at day 8 required T cell help. The extrafollicular responses generated in Salmonella persisted for around 35 days, far greater than the 2-‐3 days seen following SRBC immunisation. This was likely due to both antigen persistence causing the generation of new plasma cells, and the induction of cellular populations that produced the plasma cell survival factor APRIL. Thirdly, I document the failure of chronic immune responses to generate long-‐ lived bone marrow plasma cells. This was accomplished by measuring the generation and survival of bone marrow plasma cells in models of rheumatoid arthritis (K/BxN mice), long-‐term infection with Salmonella, and a direct comparison between acute and chronic delivery of the T-‐dependent protein antigen NP-‐KLH. In all cases, chronic immune responses generated few bone marrow plasma cells, ostensibly due to a failure to migrate to the organ. Finally, I show the depletion of bone marrow plasma cell populations caused by inflammatory episodes. This was observed in Salmonella infection, Schistosoma mansoni infection and immunisation with protein antigen plus adjuvants. This depletion mediated a reduction of antigen-‐specific bone marrow plasma cell populations and serum antibody previously established by the secondary response to NP-‐KLH.
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