Like a cat toying with a mouse before inflicting the coup de gr ce,multiple sclerosis (MS) torments its human victims by alternatingrelapses and remissions in a disease that may progress off and on fordecades before terminal paralysis ends it.
This waxing and waning pattern is one of MS's salient diagnostichallmarks, but what brings on a relapse remains as mysterious as theroot cause of the demyelinating autoimmune disease itself.
Could these clinical setbacks be inflicted by a bacterial infection?
A paper in last week's issue of Nature titled "Induction of relapsingparalysis in experimental autoimmune encephalomyelitis bybacterial superantigen" suggests that they could.
Lacking an animal model that faithfully imitates MS, researchersresort to a laboratory-induced mimic, experimental autoimmuneencephalomyelitis (EAE). By inoculating mice with a myelin basicprotein (MBP) peptide similar to the antigenic protein attacked by anMS patient's own immune system, researchers can bring on EAE atwill. Now, the Nature paper's lead author, Stefan Brocke of StanfordUniversity, reports triggering EAE relapses and teasing out themolecular mechanism that unleashes them.
He took as a prime infectivity suspect the intestinal toxin released byStaphylococcus aureus, a common cause of food poisoning and septicshock. Staphylococcal enterotoxin B (SEB), injected into mice alreadyin remission from their initial attack of EAE, promptly producedtypical relapsing paralysis.
In five experiments, 37 of 67 animals, or 62 percent, suffered anincrease in EAE symptoms, such as tail weakness, paraparesis,paraplegia and death. Of 46 mice dosed with a saline placebo, onlyfive, or 11 percent, developed signs of relapse. EAE-remittent micenormally have a 10 to 20 percent rate of spontaneous recurrence.
Brocke, a physician, is a post-doc at Stanford's Laurence SteinmanNeurological Laboratory. Besides heading the neurology departmentat Stanford, Steinman is founder and chief scientist/immunology ofNeurocrine Biosciences Inc. of San Diego.
Staphylococcal enterotoxin B is a superantigen, Brocke told BioWorld.These activate T cells independently of ordinary antigenic specificity.They switch on a whole class of T cells that display a variable-regionbeta-chain 8 (Vb8) T cell receptor.
"We know that in our animal models the T cell receptor Vb8-positiveT cells are the ones that mediate the response against the outerdemyelinating antigen, MBP, which is a brain antigen," Brocke said.
"SEB can do two things," he added. "It can exacerbate EAE in an acutephase. Second, as we showed, it can induce far more relapses after ananimal recovers from the disease than occur spontaneously. This isour major finding."
That does not mean staph causes MS. Brocke made the point that EAEis an imperfect model of MS. "It's the best model we have, but howclose it comes to the human disease, no one knows."
He added: "We have shown in our animal model that SEB does notcause the initial EAE, only the relapse. Only when animals are eitherimmunized with an antigenic BMP or receive pathogenic T cells dowe see an effect in terms of disease." The best bet for an etiologicalpathogen of MS is the measles virus, most people would say."
Brocke and his associates at Stanford are now looking for agents toinhibit the EAE relapsing effect. He has designed "some competitivepeptides, which can block the effect of SEB on those Vb8 cells PPsofar, in vitro."
Significantly, the Nature paper reported, antibody against tumornecrosis factor (TNF) slowed the onset of EAE paralysis. TNF's likelyeffect in MS has not escaped the notice of researchers in the field.Notably, Mark Feldman of the Kennedy Institute of Rheumatology inLondon is investigating anti-TNF antibodies as putative therapy forrheumatoid arthritis, another human autoimmune disease, Steinmantold BioWorld. He added that trials of the anti-TNF molecule for MSare due to start soon in Europe.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.