Lupus has long been a mysterious disease. It’s been recognized since at least the Middle Ages, generally by its distinctive “butterfly rash” that can appear on the face. But it has a long and often bewildering list of other symptoms, giving it something of a legendary status among diagonsticians. The disease can manifest with inflammation around the lungs or heart (pleurisy or pericarditis), arthritis, mouth ulcers, CNS symptoms, false positive tests for syphilis, blood disorders (anemia, leukopenia, or low platelets, confusingly), photosensitivity, renal function problems, and more. You can see how it can lead a physician on quite a chase, and there are multiple diagnostic heuristics that are in use to finally say that lupus is (probably) what you’re dealing with. I myself have seen people affected by it, and it took quite a while to arrive at the final call, because so many other symptoms kept suggesting something else.
This crazy range of presentation comes about because lupus is a systemic autoimmune disease. That much has been clear for decades now, and that realization has led to better tests for the disease. Anti-nuclear antibodies (the ANA test) are one example – if you are negative on an ANA, you basically don’t have lupus. But if you’re positive, you could still have something else, because that’s a common positive in a number of autoimmune diseases. Antibodies to double-stranded DNA are also quite diagnostic – well under 1% of the population without lupus have these, but about 70% of lupus sufferers do.
You’re probably thinking that yeah, developing antibodies to your own DNA (or your own cell nuclei) does indeed sound like trouble, and it is. But it also suggests some possible details about the etiology – specifically, it points to problems with the innate immune system. I’ve talked about that on and off over the last couple of years in a coronavirus pandemic context, and I’ve also mentioned them in immuno-oncology. The toll-like receptors (TLRs) are a big feature of innate immunity, and they are continuously watching and reacting to general signs of infection, such as suspicious DNA or RNA fragments floating by that might be from pathogens rather than the human body itself. In particular, TLR7 has been implicated as having a role – in this recent paper, for example, an overactive TLR7 system was shown in some patients to set off B-cell responses that could account for many lupus symptoms. Now there’s a new paper that makes this story even stronger. These authors find several gain-of-function mutations in TLR7 itself among different lupus patients, which fits into the same explanation neatly. TLR7, as far as we can tell, senses both guanosine and single-stranded RNA as signs of viral infection, and these gain-of-function mutants show increased response to guanosine and guanosine monophosphate. That in turn sets off a whole list of changes in B-cell and T-cell reponses, and (it seems) the autoimmune phenotype itself.
This clarity is good news, because it gives everyone a more solid idea to try to work on – i.e, find a way to damp down aberrent TLR7 function again. Here’s a group in Japan that has already been working on an anti-TLR7 antibody, for example. There are probably several places where you could interfere to get that to work, but the tricky part will be doing that without setting off something unwanted in yet another part of innate immunity. The only way to be sure of that is with extensive human testing, but this seems like a clear starting point for therapeutic ideas. There’s already a TLR7 agonist for topical therapy of warts and skin lesions, but you’d want to find the opposite of that (indeed, such a topical agonist is very bad news in rodent models of lupus, as you would expect).
All this could be good news for lupus patients, and they certainly need some. Existing treatments have some real benefit, but certainly not enough. But there’s a coronavirus angle that might be good for them as well. It was recently established that one of the genetic risk factors for severe Covid infection is in fact an inactivated TLR7 receptor – its viral-infection-sensing function seems to be quite important against coronaviruses. So you could speculate that lupus patients with overactive TLR7s are going to pick up on such infections before the rest of us will, although the downstream changes in B-cell and T-cell function might complicate that story. And that also illustrates how you’re going to have to move carefully in turning down TLR7 function – too much, and you will help lupus symptoms but make the patients more open to severe viral infection. Moderation in all things!
