Johns Hopkins researchers have discovered a single
molecule that is a cause of an autoimmune disease in the
central nervous system, called transverse myelitis, that is
related to multiple sclerosis.
In a study published in the October issue of The
Journal of Clinical Investigation, psychiatrist Adam
Kaplin and neurologist Douglas Kerr, both assistant
professors at the Johns Hopkins
School of Medicine, showed that the levels of the
protein, IL-6, are dramatically elevated in the spinal
fluid of transverse myelitis 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," Kaplin
said.
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," Kaplin said.
"TM is related to other autoimmune disorders of the
nervous system, including Guillain-Barre 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 is 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,'" Kaplin said. "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 the
research, conducted solely at Johns Hopkins, were Deepa M.
Deshpande, Erick Scott, Chitra Krishnan, Jessica S. Carmen,
Irina Shats, Tara Martinez, Jennifer Drummond, Sonny Dike,
Mickail Pletnikov, Sanjay C. Keswani, Timothy H. Moran,
Carlos A. Pardo and Peter A. Calabresi.