It has been proposed that an increase in circulating levels of IL-6 may decrease the availability of serotonin and other neurotransmitters, and simultaneously activate the hypothalamic-pituitary-adrenal axis, resulting in increased oxidative stress in the brain. Is this merely a short-term stress-related effect, a cerebral version of Walter Cannon’s fight or flight hypothesis, or can the effects last longer? A longitudinal study of a cohort of 4,500 British adolescents followed from birth observed that higher levels of circulating IL-6 in childhood were significantly associated with an increased risk of developing depression and psychosis in young adulthood.6
There may be a host of other links between pro-inflammatory cytokines and mood. Anecdotal evidence obtained from earlier immunotherapy trials in oncology and hepatology suggest that when used as therapeutic agents, cytokines, including IL-2 and gamma-interferon, are capable of inducing depression.7
Brain on Fire
Aside from activated pro-inflammatory cytokine pathways, other critical immune mechanisms can trigger aberrant behaviors and influence mood. An intriguing story concerns the induction of autoimmunity targeting the brain’s glutamine receptors and how this aberrant immune response may play a critical role in the pathogenesis of some of the neuropsychiatric features of lupus. The glutamate receptor, N-methyl-D-aspartate (NMDA), is a complex structure responsible for regulating glutamate, the main excitatory neurotransmitter in the brain. Activation of these receptors plays a key role in learning and memory formation and may help regulate synaptic strength and neural plasticity. These receptors may also help control mood and behavior. When consumed, psychotropic drugs, such as phencyclidine (better known by its street appellation, angel dust), inhibit the function of these receptors and, with prolonged use, may cause severely altered thought disturbances, depression and personality changes—just ask any medical resident who worked in an emergency department a few decades ago at the height of this drug’s popularity. Some researchers speculate that a similar biochemical situation may be occurring in the minds of schizophrenics.8 Others have carried this idea forward in an effort to solve the vexing issue of what causes lupus cerebritis.
Elegant work conducted by our colleague, Betty Diamond, MD, professor of molecular medicine at Hofstra North Shore Long Island Jewish Hospital in New York, has demonstrated that antibodies targeting the NMDA receptor are cross-reactive with double-stranded DNA and are present in a large percentage of patients with lupus.9 She and her colleagues have shown that when these antibodies are circulating in the serum of mice, there is no tissue damage in the brain because they lack access to brain tissue. Antibody-mediated neuronal damage can occur only following an insult that abrogates the blood–brain barrier (BBB), nature’s border-crossing mechanism that shields the brain from the rest of the body. However, when the BBB is breached, for example, in times of extreme stress following the release of epinephrine or with infection and the release of lipopolysaccharide, antibody-mediated neuronal death occurs in the hippocampus, resulting in impaired memory function. This appears to be the case in some murine models of lupus cerebritis. But what actually happens in humans? Are autoantibodies targeting the NMDA receptor relevant to human lupus cerebritis or other neuroinflammatory disorders?
The beauty of rheumatology may lie in the fact that our specialty lacks boundaries. Rhumatologues sans frontières! … Autoimmune illnesses can pop up anywhere.
Throughout history, the concept of demon possession has captivated the public’s attention. Many religious leaders considered some individuals to be infiltrated by devilish creatures. Clinical manifestations included explosive episodes of rage, extreme aggression toward others and oneself, speech deterioration, sudden “shouts in unknown tongue” and “bouts of contorted postures into seemingly impossible shapes,” propagating vibrations and even “movements to surrounding pieces of furniture.” These were some of the terms used to describe the case of a 14-year-old boy in St. Louis, Mo., whose story was popularized decades later in the blockbuster movie, The Exorcist. It is now believed that he suffered from a rare pediatric form of NMDA-receptor autoimmunity-inducing encephalitis.10
