Fate Mapping Quantifies the Dynamics of B Cell Development and Activation throughout Life.

Follicular mature (FM) and germinal center (GC) B cells underpin humoral immunity, but the dynamics of their generation and maintenance are not clearly defined. Here, we exploited a fate-mapping system in mice that tracks B cells as they develop into peripheral subsets, together with a cell division fate reporter mouse and mathematical models. We find that FM cells are kinetically homogeneous, recirculate freely, are continually replenished from transitional populations, and self-renew rarely. In contrast, GC B cell lineages persist for weeks with rapid turnover and site-specific dynamics. Those in the spleen derive from transitional cells and are kinetically homogeneous, while those in lymph nodes derive from FM B cells and comprise both transient and persistent clones. These differences likely derive from the nature of antigen exposure at the different sites. Our integrative approach also reveals how the host environment drives cell-extrinsic, age-related changes in B cell homeostasis.

Pathogenic CD8+ T Cells Cause Increased Levels of VEGF-A in Experimental Malaria-Associated Acute Respiratory Distress Syndrome, but Therapeutic VEGFR Inhibition Is Not Effective.

Malaria is a severe disease and kills over 400,000 people each year. Malarial complications are the main cause of death and include cerebral malaria and malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite antimalarial treatment, lethality rates of MA-ARDS are still between 20 and 80%. Patients develop pulmonary edema with hemorrhages and leukocyte extravasation in the lungs. The vascular endothelial growth factor-A (VEGF-A) and the placental growth factor (PlGF) are vascular permeability factors and may be involved in the disruption of the alveolar-capillary membrane, leading to alveolar edema. We demonstrated increased pulmonary VEGF-A and PlGF levels in lungs of mice with experimental MA-ARDS. Depletion of pathogenic CD8+ T cells blocked pulmonary edema and abolished the increase of VEGF-A and PlGF. However, neutralization of VEGF receptor-2 (VEGFR-2) with the monoclonal antibody clone DC101 did not decrease pulmonary pathology. The broader spectrum receptor tyrosine kinase inhibitor sunitinib even increased lung pathology. These data suggest that the increase in alveolar VEGF-A and PlGF is not a cause but rather a consequence of the pulmonary pathology in experimental MA-ARDS and that therapeutic inhibition of VEGF receptors is not effective and even contra-indicated.