The human immune system often has a troubled relationship with the brain; the brain is an “immune privileged” area, where only one type of immune cell, called microglia, reside. Invading bacteria, viruses, and toxins can enter the brain by breaching the blood-brain barrier, the tightly packed layer of cells in blood vessel walls that governs the transfer of substances from blood to the brain. When this occurs, immune cells then rush into the brain to fight the invaders off. 
Sometimes, however, immune cells mistake normal brain tissues as invaders and attack them. This occurs in multiple sclerosis, for instance, in which immune cells go overboard and attack the essential myelin insulation surrounding axons in the brain and central nervous system. The immune system also launches an attack against the amyloid proteins that build up in the brains of patients with Alzheimer’s disease; this attack is so aggressive that it provokes inflammation that damages neurons. A similar process may occur in Parkinson’s disease (see Movement Disorders).

The most significant advances in neuroimmunology in 2006 identified how certain immune cells become transformed to attack myelin in multiple sclerosis. Other research investigated how the immune system might serve to prevent or even reverse the degeneration of Alzheimer’s disease.

Multiple Sclerosis

In multiple sclerosis, the gaps that develop in the myelin covering of nerve cell axons after repeated immune system attacks disrupt neural signaling. This disruption produces an array of symptoms. Until recently, scientists assumed that such myelin attacks were waged by faulty immune helper T cells (called TH1 cells), which ordinarily alert the immune system to the presence of bacteria or viruses within a cell. However, researchers discovered in 2005 that another helper T cell, TH17, plays a crucial role in initiating an autoimmune attack on myelin. The TH17 cells are produced when immature T cells are exposed to the combination of two other molecules, according to a Nature study by researchers at Harvard Medical School in Boston, led by Estelle Bettelli.¹ One of these molecules is a signaling protein known as transforming growth factor-beta (TGF-beta). The other is an inflammation-promoting immune molecule called interleukin-6 (IL-6), which is released by T cells. Mice deficient in IL-6 had no TH17 cells and did not develop a mouse version of multiple sclerosis.

Moreover, Yoichiro Iwakura and Harumichi Ishigame found that a molecule called interleukin-23 (IL-23), a growth factor, transforms immature T cells into TH17 cells.² Their work, published in the Journal of Clinical Investigation, revealed that by blocking IL-23, they could significantly suppress the development of animal versions of multiple sclerosis and another autoimmune disease called inflammatory bowel disease. Taken together, these two studies suggest that therapies that block the transformation of immune T cells into TH17 cells might be effectively used in at least some autoimmune disease, including multiple sclerosis.

1. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, and Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector T^H17 and regulatory T cells. Nature 2006 441(7090):235–238.

2. Iwakura Y and Ishigame H. The IL-23/IL-17 axis in inflammation. Journal of Clinical Investigation 2006 116(5):1218–1222.

3. Weinshenker BG, Wingerchuk DM, Vukusic S, Pittock SJ, and Lennon VA. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Annals of Neurology 2006 59(3):566–569.

4. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, and Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. Journal of Experimental Medicine 2005 202(4):473–477.

5. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, and Ransohoff RM. Control of microglia neurotoxicity by the fractalkine receptor. Nature Neuroscience 2006 9(7):917–924.

6. Butkovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, and Schwartz M. Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proceedings of the National Academy of Sciences USA 2006 103(31):11784–11789.

7. Tobinick E, Gross H, Weinberger A, and Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: A six-month pilot study. Online publication in Medscape General Medicine 2006: http://www.medscape.com/
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8. Lee H, Zhu X, Nunomur A, Perry G, and Smith MA. Amyloid beta: The alternate hypothesis. Current Alzheimer Research 2006 3(1):75–80.

9. Belmadani A, Tran PB, Ren D, and Miller RJ. Chemokines regulate the migration of neural progenitors to sites of inflammation. Journal of Neuroscience 2006 26(12):3182–3191.

10. Trang T, Beggs S, and Salter MW. Purinoceptors in microglia and neuropathic pain. European Journal of Physiology 2006 452(5):645–652.

11. Sung YJ, Chiu DT, and Ambron RT. Activation and retrograde transport of protein kinase G in rat nociceptive neurons after nerve injury and inflammation. Neuroscience 2006 141(2):697–709.

12. Syken J, GrandPre T, Kanold PO, and Shatz CJ. PirB restricts ocular-dominance plasticity in visual cortex. Science 2006 313(5794):1795–1800.

13. Pace TWW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, and Heim CM. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. American Journal of Psychiatry 2006 163(9):1630–1633.