Rheumatoid arthritis is a complicated disease, as anyone who’s tried to do drug discovery work in the area can verify. It’s been recognized for a long time as an autoimmune disorder, but given the complexities of the human immune response, knowing that only takes you so far. Most of the therapies available are directed at turning down the immune/inflammation response in the joint tissues, and while these can be very helpful to patients (although not without side effects), the underlying cause of the disease has remained elusive. Which is something you can say about most autoimmune diseases, of course: what exactly sets off lupus, Hashimoto’s, Type I diabetes, multiple sclerosis and other such diseases is not an easy question to answer.
In many cases, it’s believed that some external antigen could be a cause, and that the immune response to these gets mixed and overlapped with one or more of a person’s own biomolecules. You can see this happening in things like Guillian-Barré syndrome, which almost always occurs after some sort of bacterial or viral infection (and yes, rarely after some vaccinations, most notably the 1976 swine flu shot). But even there, we don’t know the exact antigens involved and have no good ways to predict who might be more at risk and from which kinds of infections. Campylobacter jejuni bacteria or CMV viral infection (for example) are involved far too often to be due to chance, but we don’t know the mechanism by which these set off G-B in susceptible patients – remember, only one in a thousand patients (at most) with either of those infections show any sign of Guillian-Barré. There’s the personal variability of the immune system for you. Evolutionarily that’s a major feature, but it sure complicates medical practice!
Rheumatoid arthritis is unfortunately a lot more common thatn Guillian-Barré, with up to 1% of the adults in the world affected. We know that risk for developing it increases with age, and that women are at significantly higher risk than men (a pattern seen with many autoimmune diseases). There has been a great deal of effort put into the (very plausible) hypothesis that some environmental cause interacts with an individual’s genetic/immune background to set off the disease, and a number of interesting but hard-to-work-with correlations have shown up (for example, with peridontal disease as a risk factor, and clues pointing towards both the oral and intestinal mucosa). It’s been known for years that there are particular antibody classes that appear in the human blood stream several years before RA symptoms develop, but what are they reacting to? Several different types of bacteria have come under suspicion over the years, but none of them (to the best of my knowledge) can reproduce an RA phenotype in an animal model, or at least one that hasn’t been set up to be very susceptible to disease. But here’s a new paper that has some very interesting new data on the idea.
The authors used antibodies from the blood of RA patients (dual IgA/IgG types that have recently been described in patients at risk for the disease) to look for cross-reactivity with stains of bacteria found in the human body – especially from families of bacteria that seem to have an elevated profile in people at risk of developing RA. They found a strong hit with particular Subdoligranulum strains: “Isolate 7” in this genus reacted with monoclonal antibodies from those RA patients, and (in the forward-facing experiment), inoculating germ-free mice with these bacteria led to joint swelling, T-cell expansion, and antibody production very reminiscent of wild-type RA. What’s more, these changes were shown to be dependent on particular B-cell and T-cell pathways which also fit the disease hypothesis. So that’s quite a step forward.
What we don’t know is what the antigen is that’s associated with these bacteria. The hypothesis is still that there’s some particular thing (or maybe more than one) coming from them that kicks the immune response into gear, and you can bet that the authors of this paper are cranking away on an effort to find it. It could be a straight-up surface antigen that’s mimicing a human protein, or perhaps these bacteria are producing some sort of excreted factor that’s setting things off, and there could be several mechanisms for that as well. One of the main ideas in the field is that there’s a “two-hit” mechanism for rheumatoid, with the first being some kind of microbial trigger that’s able to go from mucosal immune response to systemic response, and the second being an unidentified process (perhaps associated with a person’s genetic background?) that allows things to go on to full-blown arthritis and attack on the synovial tissues. This would indeed be a candidate for the first hit, but a lot of work remains to be done: for example, how prevalent is this Subdoligranulum bacterial species in the general population, and in RA patients versus those with no signs of the disease? Are there other species with this same sort of profile? If there are people with the bacteria and without rheumatoid arthritis, are there any differences we can spot in them that might point to a mechanism? And so on – watching this develop will be interesting.
