B cell homeostasis and activation following spinal cord injury or stimulation by TLR9 linked antigens

The immune system is subject to homeostatic and regulatory mechanisms that afford robust responses against pathogens, while simultaneously avoiding reactivity to self. The studies herein examine aspects of these mechanisms under two different conditions. The first examines how chronic spinal cord injury influences B cell development, homeostasis, and responses. Mice received complete crush injury or control laminectomy at either thoracic level 3, which disrupts autonomic control of the spleen, or at thoracic level 9, which conserves most splenic sympathetic activity. Bone marrow B cell production was transiently but profoundly depressed after injury. Further, mice receiving thoracic level 3 injury showed a significant reduction in their ability to mount primary immune responses. Importantly, injury did not affect affinity maturation per se, pre-existing B cell memory, or secondary humoral immune responses. Taken together, these findings show that chronic high thoracic SCI impairs the ability to mount optimal antibody responses to new antigenic challenges, but spares previously established humoral immunity. Further, they suggest that dysregulated sympathetic nervous system signaling to the spleen underlies the immune depression syndrome that accompanies spinal cord injury. The second set of studies describes a novel post-proliferative death response in B cells activated by BCR-delivered TLR9 ligands. Death involves the intrinsic mitochondrial apoptotic pathway, is mediated by p38, occurs following G1 cell cycle arrest, and is common to all pre-immune murine B cell subsets and naïve human B cells. BLyS binding to BR3 rescues cells from death and affords survival and differentiation to antibody secretion. Importantly, this pathway is not operative in B cells from SLE susceptible Lyn-/- mice. Together, these findings reveal an unappreciated system of crosstalk between BCR and TLR9 signaling pathways that limits responses to antigens containing TLR9 ligands, and may help explain why circumventing this response-limiting system can lead to sustained autoantibody production