As amyotrophic lateral sclerosis ravages motor neurons, causing paralysis, the immune system does not sit idly by. It sends out its troops to battle the internal threat—but some of those same soldiers may also turn against the neurons they were sent to protect. In the past few years, most attention has focused on the role of innate immunity in ALS: microglia, the nervous system’s resident immune representatives, can both assist and harm motor neurons depending on the circumstances (see ARF News story). Now, scientists have noticed that the adaptive side of the immune system, too, gets into the act in ALS and other neurodegenerative diseases. But the adaptive immune system may also fall victim to the disease, as a handful of papers show diminished immune responses in animal models as well as in people with ALS. “It is becoming a hot-button issue,” said Howard Gendelman of the University of Nebraska Medical Center in Omaha. “It is a new paradigm to look at these diseases.”
The most recent bit of evidence tying adaptive immunity to ALS comes from the laboratory of Michal Schwartz at the Weizmann Institute of Science in Rehovot, Israel (Seksenyan et al., 2009). T cells are born in the bone marrow and migrate to the thymus, where they undergo a maturation that involves rearranging their gene for the antigen receptor and discarding the DNA that is no longer necessary. Those waste bits remain in cells circulating in the bloodstream and serve as markers for mature T cells. The Israeli scientists reported that there were fewer such remnants in the blood of people with ALS, suggesting that fewer T cells were reaching maturity. The blood cells of people with ALS also showed reduced activity in key immune genes. In three people with ALS who underwent MRI or X-ray, Schwartz and colleagues found that the thymus was essentially gone; the chunk of tissue in its place lacked the organ’s characteristic layered texture. “The ALS patient shows an immune system like an 80-year-old,” Schwartz said.
The most common animal model for ALS is based on the fact that in one fifth of familial ALS cases, the person possesses a mutant form of superoxide dismutase 1 (SOD1). ALS model mice overexpressing human mutant SOD1 also show evidence of reduced immune function. Even before the animals exhibited motor neuron symptoms, Schwartz and colleagues found thymic abnormalities including fewer T cell progenitors. In this and a previous study by another group, researchers have shown that the spleen of mSOD1 mice is reduced in size and lymphocyte numbers, as well (Banerjee et al., 2008 ).
Two-Faced T Cells
Schwartz has been promoting the positive role of adaptive immunity in nervous system maintenance and repair since the late 1990s, when she and colleagues showed that macrophages and T cells are involved in injury repair in the CNS (Rapalino et al., 1998 ; Moalem et al., 1999). “The community thought that we were crazy,” she said. The conventional wisdom was that the brain and spinal cord were separated from immune cells by the blood-brain barrier, and that any immune cells infiltrating the central nervous system must be evidence of a pathologically leaking barrier.
A trio of recent publications from three different labs supports Schwartz’s ideas in the case of ALS. A few years back, Schwartz said, she suggested to Stanley Appel of the Methodist Hospital System in Houston, Texas, that he make ALS mice devoid of T cells. When he and colleagues crossed mSOD1 mice with a strain lacking functional T cells, the progeny sickened faster. Bone marrow transplants that produced T cells reversed the effect (see ARF News story on Beers et al., 2008).
Similarly, researchers led by Isaac Chiu in the Harvard Medical School lab of Michael Carroll in Boston, Massachusetts, crossed mSOD1 mice with animals deficient in T cell receptors. The progeny showed accelerated ALS disease (Chiu et al., 2008). In another report, Gendelman and colleagues also found evidence that T cells fight ALS, showing that providing activated T cells to mSOD1 animals delayed the onset of symptoms and slowed disease progression (Banerjee et al., 2008 ).
This role for the immune system in ALS is one of amplification, Appel said, and is distinct from pathological autoimmunity in diseases such as multiple sclerosis or lupus. Schwartz has proposed that long before noticeable symptoms of ALS appear, the immune system is busily protecting the neurons (Schwartz and Ziv, 2008): T cells flow to damaged or ailing areas to manage the healing process, dampen inflammation, or prevent cell death. But at some point, the disease overwhelms the immune system. “The onset will be when you pass the threshold between what the immune system can provide and what the central nervous system needs,” she said. Similarly, the immune system battles tumor cells, but when it can no longer withstand them, cancer develops. The same could be true for other neurodegenerative diseases, Schwartz suggested. In the case of Alzheimer disease, the symptoms may appear as the aging immune system can no longer hold the pathology in check.
Schwartz’s full theory remains controversial: “As far as I know, there is no compelling evidence to support such a system,” said Serge Przedborski of Columbia University in New York City. He would also like to see independent confirmation of the thymus deficits Schwartz reported. If people with ALS have weakened immune systems, Przedborski said, they should show high rates of infection, but he is unaware of such a correlation. That does not mean that the immune system is not involved at all. “It is good [that Schwartz] pushes us to think about it,” he said.
The protective adaptive immunity is not the whole story, Appel said. As with innate immunity, the same system that protects motor neurons may turn on them. T cells are a heterogeneous group that can produce a variety of outcomes. “Depending on probably a little bit of black magic, a little bit of things that we don’t understand, they can maybe go one way or another,” Przedborski said. Appel put it this way: Just as damaged neurons may cry out, ‘Repair me,’ neurons that are too far gone may instead send signals saying ‘Take me out.’ In that case, the immune system’s white knights could morph into dark riders. As evidence for the dual nature of immunity, Appel pointed to a clinical trial he led in the 1980s, testing the powerful immunosuppressant cyclosporine in people with ALS (Appel et al., 1988 ). “If in fact the immune cells are only good guys and you suppress the immune system, you would expect that everyone would do a whole lot worse—and they did not,” he said. In a more recent trial, the anti-inflammatory drug minocycline did appear to accelerate disease in ALS patients, supporting the hypothesis that the immune response does some good (Gordon et al., 2007).
T Cells Targets
If the suffering of the immune system is a secondary factor in ALS pathology, then immune-boosting treatments could help. “[Schwartz and I] have been saying for a long time that the immune system is playing an important role here,” Appel said. “Both of us feel strongly that this may be a relevant way to go.”
One immunomodulator scientists have tried is glatiramer acetate, marketed as Copaxone for people with multiple sclerosis. The compound is a synthetic random copolymer based on the amino acid content of myelin basic protein, which is likely to be released in damaged neural tissue. It is supposed to act as a sort of vaccine, inducing a beneficial immune response to the damaged nervous system. Schwartz’s early studies in ALS mice with weak mSOD1 expression showed some promise for glatiramer acetate treatment (Angelov et al., 2003), although animals with higher mSOD1 levels received less benefit in that and another study with a different strain (Habisch et al., 2007). The initial experiments also used complete Freund’s adjuvant, which is not suitable for people. The vaccine failed to pan out in later experiments (Haenggeli et al., 2007). The drug appears to be safe in humans (Gordon et al., 2006), but failed in a clinical trial for ALS run by Teva Pharmaceutical Industries, headquartered in Petah Tivka, Israel (see Teva press release). Inspired in part by data from the Weizmann Institute, this trial led to a lawsuit brought by it co-licensing partner, New York-based ProNeuron Biotechnology (see news story, blog account.)
“Now I understand why it did not work,” Schwartz said, suggesting that a vaccine cannot prime an immune system that is no longer there. Other conditions might still be amenable to glatiramer acetate treatment. For example, the compound reduced plaque load and cognitive decline in AD model mice (see ARF News story on Butovsky et al., 2006). Schwartz said she is currently planning a glatiramer acetate trial for Alzheimer’s at the Cedars-Sinai Medical Center in Los Angeles, California.
An alternative would be to mimic some of the mouse studies and provide fresh new T cells—or even a new thymus—to people with ALS. Such cells might come from fetal tissue or from the patient’s own cells, expanded and primed for action in the lab and then returned to the body. This method is not as simple in people as in lab mice, cautioned Przedborski, who finds expensive, invasive transplants less appealing than a simple vaccine. Additionally, doctors would have to be careful to promote only the positive immune response, noted Oleg Butovsky of Brigham and Women’s Hospital in Boston, Massachusetts. The ideal solution, Butovsky suggested, would be to combine transplanted T cells with a vaccine strategy. “You need to educate these T cells,” he said, so they will travel to the right spot and be neuroprotective.
Taking on T Cells
Research on adaptive immunity in ALS is in its early stages. One open question is which specific antigens activate T cells and recruit them to dying neurons. They might be normal peptides leaking out of damaged neurons, Przedborski suggested. The immune system normally deletes any T cells specific for self antigens, but these peptides might not normally be present in the blood stream and thus exempt from this selection process. Or, Appel suggested, the antigens might be fragments of the rogue proteins that aggregate in neurodegenerative disease: SOD1 in ALS, Aβ in Alzheimer’s, α-synuclein in Parkinson disease. “What is not clear is whether there are rogue proteins in sporadic cases” of ALS, he noted. “If it is not the SOD1 itself that is misfolded, there could be other rogue proteins that are active.”
Another quandary is how neurodegenerative disease dampens the immune response. “We have no idea at this point,” Przedborski said. ALS model mice express mSOD1 in every cell in their body, but motor neurons seem to be exquisitely sensitive to the effects; Przedborski suggested that T cells could be, too. Oxidative stress, common in neurodegenerative disease, could infiltrate the T cell army from within.
“We have more questions than answers at this point,” Butovsky said. Chiu, from Carroll’s lab, is curious about which of the multitude of known T cell flavors are involved in different stages of disease. Appel wonders if varied immune responses might be responsible for the huge range of speed in disease progression among people with ALS. Schwartz is sure of one thing, however: “I think it is time to educate the neurologists about the immune system.”—Amber Dance.
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