By David N. Leff
¿Systemic¿ is the operative word in the autoimmune disease, systemic lupus erythematosus (SLE or lupus).
What that means is that the self-destroying phalanx of autoimmune antibodies doesn¿t specialize in the bodily tissues they ravage. The litany of systemic ailments suffered by SLE patients runs from disorders of joints (arthritis) to kidneys, heart, lungs, blood cells and beyond. In the outback beyond these familiar organs and tissues lies terrae incognitae ¿ the largely unexplored terrain of the central nervous system, comprising brain and spinal cord.
Here too, SLE afflicts its victims ¿ mostly women of childbearing years ¿ with neuropsychological problems that may include paranoia, schizophrenia and stroke, as well as the less severe cognitive disorders arising from neuronal wastage by the autoantibodies
¿The nature of these cognitive disorders,¿ observed rheumatologist and immunologist Betty Diamond at the Albert Einstein College of Medicine in the Bronx, N.Y., ¿include some memory problems and some new learning challenges. These can be identified by neuropsychological testing, and patients with lupus perceive themselves as having difficulties with thinking and remembering. You certainly wouldn¿t notice these little things,¿ she said, ¿if you met an affected SLE patient at a dinner party.¿
Beyond the knowledge that friendly firing antibodies are implicated in SLE, scientists have had no idea how lupus destroys the nervous system. Now Diamond and her colleagues have discovered that these antibodies attach to subunits of the central nervous system¿s glutamate receptor. Those antibodies, it is thought, destroy neurons by binding to these receptors and triggering apoptosis ¿ programmed cell death ¿ of the nerves in question.
Diamond is senior author of a paper in Nature Medicine for November 2001, titled: ¿A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus.¿ Her husband, neurologist Bruce Volpe, is the article¿s corresponding author.
¿The novel aspect of our report,¿ Diamond told BioWorld Today, ¿is that these antibodies bind neurons and cause their cell death. That¿s an explanation for non-inflammatory central nervous system [CNS] disease in lupus, because there are also inflammatory problems in the CNS of lupus patients ¿ such as stroke and vasculitis, or blood vessel inflammation. But,¿ Diamond added, ¿there also seem to be patients in whom we cannot identify any inflammatory disease in their brain, but it appears to be this neuronal loss in the hippocampus underlying cognitive impairment. So, with this data we now propose a model for how that could occur.¿
She noted, ¿Most prevalence statistics estimate that there are maybe half a million to a million people with lupus in the U.S., but some say it¿s underreported. In small studies, neuropsychological tests have found cognitive abnormalities in 60 [percent] to 80 percent of lupus patients.
¿Glutamate,¿ Diamond explained, ¿is a potent neurotransmitter in the brain, [and] is known to cause an excitotoxic cell death. So too much triggering through the glutamate receptor causes apoptosis by an influx of calcium into the cell. And we think that the autoantibody is behaving like an agonist. It¿s mimicking glutamate in this way.¿
Human Trials In A Year Or Two
She and her co-authors knew that such antibodies directed against double-stranded nuclear DNA cross-react with a 5-amino-acid pentapeptide. ¿When we took this consensus [average] sequence from a phage-display screen to a protein database, we pulled out the NR2a and 2b subunits that had the sequence right in them.
¿Then we just injected the antibody directly into mouse brain,¿ Diamond recounted, ¿and showed that it caused neuron death. It did this not by activating complement, but by engaging cells through binding to the NR2 receptor, and were able to block it with MK801, an NR2 antagonist agent. Then we affinity-purified the antibodies from the serum of four lupus patients plus one who had had many years of this cognitive decline. These antibodies appeared not just in their serum, but also in their spinal fluid.
¿There¿s a blood-brain barrier there,¿ she went on, ¿that prevents proteins from crossing from serum into the brain. So we showed that the antibody actually got to neuronal tissue in the CNS. We don¿t know whether B cells ¿ which generate antibodies ¿ actually cross the barrier, thus, these antibodies are made in the brain, or if there is some breakdown in the blood-brain barrier so it may be antibodies or B cells that are getting through.¿
In the hippocampus of their mice injected with antibody, they found a high density of the NR glutamate receptors on neurons. However, ¿We didn¿t look for any cognitive or other neuronal behavior changes,¿ Diamond observed. ¿We sacrificed the mice a day or so after injecting them. Mice aren¿t real smart,¿ she added. ¿We¿re actually interested in doing that cognitive testing in rats, because rats are very smart.¿
She and Volpe are now making long-range plans to transfer their rodent findings to the human SLE condition.
¿There are glutamate receptor antagonists that have been used in cancer therapy clinical trials,¿ she pointed out, ¿so one could try to use an antagonist that prevents this excitotoxic cell death. The other approach, obviously, is that we formulate a soluble peptide to block the antibody from binding to the receptor.
¿We¿re trying to set up a clinical study here as part of our sabbatical at the National Institute of Arthritis & Musculoskeletal & Skin Diseases ¿ which is where lupus is at,¿ Diamond observed.
¿We¿re currently planning these human trials to see if the antibody associates with the cognitive problem, and if we can see changes in either neural imaging techniques or cognitive testing over a defined time period. Then we could do an interventional study. And know that we could see something happen in a year¿s time .
¿We have to demonstrate that we can develop a measure for seeing a decline in cognition or a neuroimaging abnormality that progresses, and show that we halt the rate of progression by that intervention.
¿I hope very much to see these trials start in a year, but that¿s probably a little optimistic,¿ Diamond said. ¿A couple of years is more realistic. I think that this approach may have broad applications to neurological diseases. And there¿s no reason to think,¿ Diamond concluded, ¿that lupus is the only disease where antibodies can underlie cognitive problems. So I think it¿s a frontier.¿