A common way to investigate what role particular biological markers play is to breed (in the loosest sense of the word – ie genetically engineer) an animal that doesn’t have those biomarkers. Mice are the usual suckers. Mice can be ‘bred’ to have no T cells (T cells are otherwise known as T lymphocytes, white blood cells that are produced primarily in the thymus – hence the ‘T’ – reminds me of an oncologist I met in between sets at a conference dinner who, in potentially poor taste, described himself as a lymphomaniac). Mice without T cells find it harder to get around a maze and perform other spatial working memory tasks than ‘normal’ mice do[1,2]. These mice are not dodgy at spatial tasks because they have been sick most of their life. We know this because mice that have their immune system obliterated by irradiation lose their ability to do the maze but regain it when they have a bone marrow transplant2. We also know that mice that have been engineered to have an excess of T cells are water maze experts. So, T cells make mice smarter.
Thinking makes T cells. That is, performing cognitive tasks increases the stocks of T cells, particularly those that express interleukin 4 (IL-4) an anti-inflammatory cytokine. Mice that are bred to be IL-4 deficient are are no good at water mazes, and normal mice transplanted with IL-4 deficient bone marrow see their formally good water maze times plummet. In contrast, when IL-4 deficient mice get a blast of T cells, their water maze times drastically improve. So, IL-4 makes mice smarter.
What about humans? How do we perform in a water maze? Clearly ethics committees the world over will be reluctant to let us engineer T-cell or IL-4 deficient humans and make them swim through Venice (although Peter Singer would have a thing or two to say about that discrepancy but let’s not open THAT can of worms just now). Well there are correlational data – diminished T cell activity correlates with cognitive impairment in HIV infection, chemotherapy, schizophrenia and with ageing[1,5] and we know that physical exercise and restricting calorie intake improve cognitive performance and increase T-cell counts.
Is a similar relationship observed in people with chronic pain? Intuitively we would predict yes. With regard to T-cell expression in the bits that matter, I can’t see a whole of evidence either way. Clearly, there is an increase in T-cell expression in the periphery, dorsal root ganglion and spinal cord in animal models of neuropathic pain, but I don’t think we know about the brain, specifically the meninges, which is where it seems to matter in the mice studies. IL-4 however is a different story – we know IL-4 is reduced in people with chronic pain in a range of conditions eg and we are pretty sure people with chronic pain perform worse on spatial working memory tasks than people without chronic pain eg. The problem with any study of cognitive performance in people with pain is that their pain requires a good chunk of CNS processing resources. On that point, we were discussing this at BiM team lunch and noticed how easy it is to say that the pain disrupts performance, which is not, in my view, correct because the pain is the endpoint. I would say that the brain processes that produce pain would be disrupting cognitive performance. Anyway, that is by-the-by just now. Patients with chronic pain certainly report that they have problems thinking and performing spatial tasks (they don’t call them ‘spatial tasks’ of course!) I think it is reasonable to predict that IL-4 and cognitive performance would be related in people as they are related in mice, and that if IL-4 is underdone in chronic pain then it may contribute to disrupted cognitive performance. As I said in the last post, I am no expert on this stuff. So, if anyone out there is a bonafide expert on this, we would all LOVE to hear your thoughts on this prediction.
About Lorimer Moseley
Lorimer is NHMRC Senior Research Fellow with twenty years clinical experience working with people in pain. After spending some time as a Nuffield Medical Research Fellow at Oxford University he returned to Australia in 2009 to take up an NHMRC Senior Research Fellowship at Neuroscience Research Australia (NeuRA). In 2011, he was appointed Professor of Clinical Neurosciences & the Inaugural Chair in Physiotherapy at the University of South Australia, Adelaide. He runs the Body in Mind research groups. He is the only Clinical Scientist to have knocked over a water tank tower in Outback Australia.
 Kipnis, J. (2004). T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions Proceedings of the National Academy of Sciences, 101 (21), 8180-8185 DOI: 10.1073/pnas.0402268101
 Brynskikh, A., Warren, T., Zhu, J., & Kipnis, J. (2008). Adaptive immunity affects learning behavior in mice Brain, Behavior, and Immunity, 22 (6), 861-869 DOI: 10.1016/j.bbi.2007.12.008
 Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, & Schwartz M (2006). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature neuroscience, 9 (2), 268-75 PMID: 16415867
 Derecki, N., Cardani, A., Yang, C., Quinnies, K., Crihfield, A., Lynch, K., & Kipnis, J. (2010). Regulation of learning and memory by meningeal immunity: a key role for IL-4 Journal of Experimental Medicine, 207 (5), 1067-1080 DOI: 10.1084/jem.20091419
 Kipnis J, Derecki NC, Yang C, & Scrable H (2008). Immunity and cognition: what do age-related dementia, HIV-dementia and ‘chemo-brain’ have in common? Trends in immunology, 29 (10), 455-63 PMID: 18789764
 Yirmiya R, & Goshen I (2011). Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain, behavior, and immunity, 25 (2), 181-213 PMID: 20970492
 Marchand, F., Perretti, M., & McMahon, S. (2005). Role of the Immune system in chronic pain Nature Reviews Neuroscience, 6 (7), 521-532 DOI: 10.1038/nrn1700
 Uçeyler N, Valenza R, Stock M, Schedel R, Sprotte G, & Sommer C (2006). Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis and rheumatism, 54 (8), 2656-64 PMID: 16871547
 Dick BD, & Rashiq S (2007). Disruption of attention and working memory traces in individuals with chronic pain. Anesthesia and analgesia, 104 (5) PMID: 17456678