Abstract
Background Animal models and more recently studies in humans have implicated the “extrafollicular” (EF) B cell response—rather than the germinal center (GC) response—as being prominent and possibly pathogenic in lupus. This response can also generate so-called “age- associated B cells” (ABC, known also as “DN2” in humans) under some conditions, a type of inflammatory B cell the frequency of which is elevated in some lupus patients and animal models of lupus. However, the basic biology that underlies why some immune responses are directed toward the EF mode and others to the GC mode is not well-understood. Nor are the identities and functions of ABC well-defined, particularly in lupus. ABC have been termed memory B cells, implying a quiescent or resting state, which seems incompatible with an ongoing inflammatory disease like lupus and raising the question of how these cells could contribute to pathogenesis
To understand the programming of B cell responses, we studied the response to Salmonella infection, which suppressed GCs while promoting strong EF responses. We discovered a particular cytokine network that suppressed the differentiation of GC B cells and T follicular helper cells, while at the same time enhancing the generation of EF plasmablasts and inflammatory T cells. I will present data on how this network functions as a molecular switch. To understand the role of ABC we studied them in both the immune response to Ehrlichia muris and in the MRL/lpr murine model of lupus, with contrasting results. I will present these data emphasizing that ABC in lupus are a dynamic and heterogeneous population that undergoes clonal expansion and contributes directly to pathogenesis.
Lay abstract I will present data showing how certain types of immune responses that promote lupus are controlled by the immune system. This in turn gives basic insight into lupus pathogenesis and may eventually help in categorizing types of lupus patients and designing and selecting appropriate therapies.
Acknowledgement Funded by R01 AI043603 (M. Shlomchik) and R21 AI141938 (K. Nickerson)
