Friendly fire wounds and kills not only on military battlefields but also in the cells of mammalian immune defenses.
In humans, this collateral damage goes by the name of autoimmune diseases. These self-inflicted afflictions are numerous and varied. A dozen of the best-known maladies attack specific organs of the body, from Addison’s disease (damaging the adrenal cells) to insulin-dependent diabetes mellitus (destroying the pancreatic islet cells) to spontaneous infertility (disabling the sperm).
Another half dozen of the autoimmune diseases are systemic rather than organic. They savage cells and tissues widely throughout the body. Of these, the most familiar are three: multiple sclerosis (MS), which punishes the brain or its white matter; rheumatoid arthritis (RA), which abrades the joints’ connective tissues; and systemic lupus erythematosus (SLE or lupus), which strikes at DNA, nuclear proteins and red blood cells. None of these is acutely life threatening, just life blighting. MS counts an estimated 330,000 patients in the U.S. alone, and 1 million worldwide. RA numbers more than 2.5 million American victims. There are half a million SLE sufferers in the U.S.
Autoimmunity is a dark and largely trackless immunological landscape, with more theories than facts to explicate its devious mechanisms. An article in today’s Nature, dated April 11, 2002, casts new light, and introduces new players, on this wilderness of few hard facts. Its title: “Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors.” Its lead author is research immunologist Elizabeth Leadbetter at Boston University’s microbiology department. The paper’s senior author is Ann Marshak-Rothstein, who heads the university’s immunology training program.
“Our major finding is a link between autoimmune disease and innate immunity,” Leadbetter told BioWorld Today. “People usually think of that frontline immunity as separate your body’s defense against bacteria and viruses. And then in autoimmunity your body is attacking itself. So they normally think of two separate immune system arms. In our paper,” she continued, “we’ve linked the two by implicating one of the innate immune receptors to autoimmune disease. People haven’t thought about that connection before.
“So it has a number of implications as to how victims develop autoimmune diseases. One of their unique aspects is when your immune system makes an attack against itself, it doesn’t launch a response against every possible protein in your body. There are certain subsets that are particularly targeted in certain diseases. So this may take a step toward explaining why there is that correlation between infections and flare-ups in lupus, say, that doctors see but never can trace specifically.
“It explains also,” Leadbetter went on, “why some of the autoimmune diseases that people develop such as lupus and rheumatoid arthritis are commonly treated with chloroquine. This paper may elucidate why and how chloroquine works against autoimmune diseases. Physicians have been prescribing it for years but they really didn’t know how it worked.”
Chloroquine Paying The Toll
In fact, chloroquine is a prescription drug, exclusively given as a highly effective antimalarial. Of late, the malarial parasite, Plasmodium falciparum, has fought back with drug resistance that bids fare to retire chloroquine. To understand its apparent success in treating systemic autoimmune diseases, Leadbetter starts by presenting the Toll-like receptors.
“There’s a whole family of Toll-like receptors, about 10 in all,” she observed. “With few exceptions, these receptors have been shown to bind to antigenic bacterial components, and people have started identifying what the ligands the targets of these receptors are. Toll was originally described in Drosophila, which has only one Toll receptor,” Leadbetter recounted. “Its homologues were identified in murine and human cells.
“In the normal human body,” Leadbetter continued, “Toll-like receptors are responsible for binding to bacterial components. They’re expressed particularly in dendritic cells, which internalize and dispose of antigenic debris, but in our case also B cells, which make antibodies, which stimulate the immune system to mount a response to bacterial infection. Of Toll’s 10 receptors,” she explained, “the ninth one Toll-like receptor 9 specifically recognizes oligonucleotide sequences from bacterial DNA. We reported that what chloroquine does is inhibit signaling through Toll-like receptor 9. This molecule, uniquely, is not located on the B-cell surface. The actual site of that Toll-like receptor 9 is intracellular inside the cell in a vesicle or endosome. The B-cell receptor on its surface will engage an antigen, and bring it to this particular endosome. Inside it, the antigen gets degraded by acids. In order for that acid environment to exist, little pumps in that vesicle squirt in hydrogen ions to make the vesicle more acidic than the inside of the cell. It then degrades the antigen, or anything else that’s in the vesicle. That particular step is necessary for Toll-like receptor 9 to signal.
“Chloroquine has a number of effects in the cell,” Leadbetter pointed out, “but the particular function we’re interested in is blocking endosome acidification. Chloroquine actually blocks that acidification. Nobody knows the mechanism by which chloroquine treats autoimmune diseases, how it actually works. This is the first bit of evidence that suggests we might understand why that antimalarial drug is so therapeutically successful in the autoimmunity environment.”
“Based on that chloroquine evidence,” Leadbetter said, “and that it’s also affecting Toll-like receptor 9, we’re suggesting that blocking this receptor 9 more specifically would create a very effective therapeutic strategy, potentially for treating lupus and other autoimmune diseases like rheumatoid arthritis. We have in mind a particular inhibitor that very efficiently blocks Toll-like receptor 9. It’s a DNA [cytosine phosphate guanine] oligonucleotide.
Oligonucleotides: Useful In Autoimmune Disease?
“We’re setting up a collaboration with a company, Coley Pharmaceuticals Group Inc., of Wellesley, Mass.,” Leadbetter disclosed. “They’re going to make the drugs and we’re going to test them in the mouse model. If the inhibitor works in mice, we’ll look in humans. Coley is interested in studying these CpG oligonucleotides in vaccines and cancer therapy. Our results suggest,” she concluded, “that they may also be useful in autoimmune disease.”
The university has patents pending on “Method and composition for treating immune-complex-associated disorders.” Its inventors are Leadbetter, Ian Rifkin (another co-author) and Marshak-Rothstein.