In a study published in the October issue of The Journal of Clinical Investigation, psychiatrist Adam Kaplin, M.D., Ph.D., an assistant professor at The Johns Hopkins University School of Medicine, and neurologist Douglas Kerr, M.D., Ph.D., also an assistant professor at Hopkins, showed that the levels of the protein, IL-6, are dramatically elevated in the spinal fluid of transverse myelitis (TM) patients.
Although the majority of TM patients suffer a single attack, 15 percent to 30 percent of patients go on to develop full-blown MS. TM evolves rapidly and without warning and usually results in permanent impairment, including weakness of the legs and arms, bowel and bladder dysfunction, pain and paralysis.
IL-6 is a chemical messenger that cells of the immune system use to communicate with one another. One of the cell types injured by high levels of IL-6 includes oligodendrocytes, which help produce the protective myelin sheath coating around nerve cells. The findings offer one possible mechanism responsible for demyelinating disorders, such as TM and MS, and may aid in the development of effective therapies against these disorders, the researchers say.
"This is the first time a single culprit has been identified as causing a CNS autoimmune disease," said Kaplin.
The researchers began investigating the protein IL-6 when they became aware that TM patients suffered from memory impairment and depression. IL-6 has been implicated in mood and concentration disorders.
"This discovery is a success story that begins with listening carefully to what patients are telling us about their suffering and then collaborating across disciplines to open up new avenues of investigation," said Kaplin.
"TM is related to other autoimmune disorders of the nervous system, including Guillain-Barré syndrome, MS and acute disseminated encephalomyelitis. This study may give us a foothold in understanding all of these disorders and how they are linked together. The benefit is, therefore, not only to those who are paralyzed by TM, but to those who have disabilities due to a variety of autoimmune disorders. We are actively using these findings to aid in developing future diagnostic, prognostic and therapeutic advancements," said Kerr, director of the Johns Hopkins Transverse Myelitis Center, the only center devoted to TM in the world.
Researchers analyzed 42 inflammatory proteins in the cerebrospinal fluid of both TM and healthy patients. They found that IL-6 was consistently elevated in TM patients' spinal fluid. Further, the level of IL-6 directly correlated with the severity of paralysis.
Using cell culture and animal studies, the researchers confirmed that elevated IL-6 levels were directly injurious to the spinal cord. They showed that spinal fluid from TM patients induced death of spinal cord cells when cultured in a dish and that IL-6, when infused in adult rats, induced paralysis. Under the microscope, tissue from IL-6-infused rats showed demyelination and injury of axons, pathology that was nearly identical to that seen in human patients with TM.
Kerr and Kaplin also deduced that the reason IL-6 elevations injure only the spinal cord and not other regions of the nervous system was because distinct regions of the nervous system have different responses to IL-6. They concluded that these different types of responses might be a part of why different autoimmune disorders of the nervous system affect distinct regions and cause distinct symptoms.
"When we started, we knew nothing about the bad players in this drama in the spinal cord of CNS autoimmune diseases - it was a classic murder mystery and we set out together to find out 'who done it'," said Kaplin. "We've answered who could have done it, and how, and where."
Funding for this study was provided by the National Institutes of Health.
Other investigators involved in this study, conducted solely at Hopkins, were Deepa M. Deshpande, M.S.; Erick Scott, B.S.; Chitra Krishnan, M.S.; Jessica S. Carmen, B.S.; Irina Shats, M.S.; Tara Martinez, B.S.; Jennifer Drummond, B.S.; Sonny Dike, M.D.; Mickail Pletnikov, M.D., Ph.D.; Sanjay C. Keswani, M.B.; Timothy H. Moran, Ph.D.; Carlos A. Pardo, M.D., and Peter A. Calabresi, M.D.
Journal
Journal of Clinical Investigation