Neural Pathways of Immune Regulation
Wednesday, February 1, 2006
Presented by the Brain Dysfunction and Neuroimmunology Discussion Group
The Neuroimmunology Discussion Group focuses on the interface between the immune system and the nervous system both in the brain and in the periphery, in normal and pathological conditions. This highly interdisciplinary group seeks to bring together immunologists and neuroscientists interested in exploring the intersection of these two fields in periodic meetings that will include discussions of basic, clinical and translational aspects of this emerging field.
Linda Watkins, University of Colorado at Boulder, "Listening & Talking to Neurons: Clinical Implications of Immune and Glial Regulation of Pain."
Virginia Sanders, Ohio State University College of Medicine & Public Health, "It Takes Nerve To Tell a B Cell What To Do."
"Clinical Implications of Immune and Glial Regulation of Pain."
This talk will weave together a story that's been developing over the past 15 years. It begins with the study of how the immune system "talks" to the brain to trigger survival-oriented sickness responses, including fever, sleep, generalized suppression of behavior, pain facilitation (sickness-induced hyperalgesia), and so forth. Recognition that fever, sleep and other sickness responses were created by the activation of glia and the release of glial proinflammatory cytokines predicted that sickness-induced hyperalgesia would be as well. Indeed it is. This raised the question of whether immune cells and glia only regulate pain during the sickness response, or whether there may be more than one way to tap into this ancient, survival circuit, so to drive pain in a pathological way. This appears to be true. Activated immune cells associated with peripheral nerves and activated glial cells within the spinal cord importantly contribute to the creation and maintenance of pain enhancement. Activated immune cells alter the function of peripheral nerves via the release of a variety of proinflammatory substances. Similarly, glial activation within the spinal cord enhances pain by increasing the release of "pain" transmitters from sensory afferents and increasing excitability of pain transmission neurons. This is again accomplished via the release of a variety of substances, with proinflammatory cytokines being key players. Intiguingly, inflammation and trauma in the body are not the only ways to activate spinal cord glia. Clinically relevant opioids, such as morphine and methadone, do so as well. Insidiously, glia become progressively more activated in response to chronic opioids, and contribute to decreasing analgesic efficacy by the release of proinflammatory cytokines. Taken together, these findings are leading to the development of novel strategies for controlling pathological pain conditions, and enhancing the analgesic efficacy of opioids, by targeting glial activation using anti-inflammatory cytokines and other therapeutics that disrupt glial proinflammatory signaling.
"It Takes Nerve To Tell a B Cell What To Do"
A B lymphocyte produces IgG1 to neutralize and clear foreign antigens. In vivo, the level of IgG1 produced in response to an antigen is suppressed when norepinephrine is depleted, but is restored when the beta-2-adrenergic receptor (Beta-2AR) on a B cell is stimulated, suggesting that norepinephrine participates in regulating the level of a normal antibody response to antigen. The mechanism responsible for mediating the increase in IgG1 involves: 1) A beta2AR-induced increase in CREB activity and expression of both the costimulatory molecule CD86 and the coactivator protein OCA-B; and 2) A CD86-induced increase in NF-kappaB activity and expression of the transcription factor Oct-2, which binds cooperatively with OCA-B to the 3'-IgH enhancer to increase the rate of IgG1 transcription. These findings suggest