Hopkins researchers have discovered a single molecule that is a causeof an autoimmune disease in the central nervous system, calledtransverse myelitis (TM), that is related to multiple sclerosis.
In a study published in the October issue of The Journal of ClinicalInvestigation, psychiatrist Adam Kaplin, M.D., Ph.D., an assistantprofessor at The Johns Hopkins University School of Medicine, andneurologist Douglas Kerr, M.D., Ph.D., also an assistant professor atHopkins, showed that the levels of the protein, IL-6, are dramaticallyelevated in the spinal fluid of transverse myelitis (TM) patients.
Although the majority of TM patients suffer a single attack, 15percent to 30 percent of patients go on to develop full-blown MS. TMevolves rapidly and without warning and usually results in permanentimpairment, including weakness of the legs and arms, bowel and bladderdysfunction, pain and paralysis.
IL-6 is a chemical messenger that cells of the immune systemuse to communicate with one another. One of the cell types injured byhigh levels of IL-6 includes oligodendrocytes, which help produce theprotective myelin sheath coating around nerve cells. The findings offerone possible mechanism responsible for demyelinating disorders, such asTM and MS, and may aid in the development of effective therapiesagainst 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 theybecame aware that TM patients suffered from memory impairment anddepression. IL-6 has been implicated in mood and concentrationdisorders.
"This discovery is a success story that begins with listeningcarefully to what patients are telling us about their suffering andthen collaborating across disciplines to open up new avenues ofinvestigation," 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 afoothold in understanding all of these disorders and how they arelinked together. The benefit is, therefore, not only to those who areparalyzed by TM, but to those who have disabilities due to a variety ofautoimmune disorders. We are actively using these findings to aid indeveloping 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 thecerebrospinal fluid of both TM and healthy patients. They found thatIL-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 researchersconfirmed that elevated IL-6 levels were directly injurious to thespinal cord. They showed that spinal fluid from TM patients induceddeath of spinal cord cells when cultured in a dish and that IL-6, wheninfused in adult rats, induced paralysis. Under the microscope, tissuefrom IL-6-infused rats showed demyelination and injury of axons,pathology that was nearly identical to that seen in human patients withTM.
Kerr and Kaplin also deduced that the reason IL-6 elevationsinjure only the spinal cord and not other regions of the nervous systemwas because distinct regions of the nervous system have differentresponses to IL-6. They concluded that these different types ofresponses might be a part of why different autoimmune disorders of thenervous system affect distinct regions and cause distinct symptoms.
"When we started, we knew nothing about the bad players in thisdrama in the spinal cord of CNS autoimmune diseases - it was a classicmurder mystery and we set out together to find out 'who done it'," saidKaplin. "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 atHopkins, were Deepa M. Deshpande, M.S.; Erick Scott, B.S.; ChitraKrishnan, M.S.; Jessica S. Carmen, B.S.; Irina Shats, M.S.; TaraMartinez, B.S.; Jennifer Drummond, B.S.; Sonny Dike, M.D.; MickailPletnikov, 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.
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