You stash your drugs in a lupus textbook (Dr. Foreman)
It’s never lupus (Dr. House)From House MD
But today it is! I assume that Hugh Laurie’s character would have loved the recent work of Brown and colleagues published in Nature. Dr House had diagnosed lupus only once within eight seasons of the series, and the case described in the article is atypical enough to interest even him.
Systemic lupus erythematosus (SLE) is considered a polygenic autoimmune disease in which one’s own adaptive immunity attacks their tissues and organs, such as skin, brain, lungs, kidneys, blood vessels, and joints. Anyone can develop lupus. However, women are affected 4-12 times more often than men, with the most significant risk at ages 15 to 44 years.
Just like House diagnosed only one lupus case, Brown and colleagues used a single case of a Spanish girl who was diagnosed with severe SLE at the age of 7 to dive deeper into this yet uncurable disease. They have found a de novo mutation in a gene encoding Toll-like receptor 7 (TLR7), which leads to the substitution of tyrosine on histidine in position 264 (Y264H). But what is TLR7? Toll-like receptors are proteins expressed on the surface and inside cells that drive innate immune response. So far, we know several types of TLRs that literally recognize molecular patterns of different pathogens. For instance, TLR4 senses components of bacterial cell-surface — lipopolysaccharides. On the other hand, TLR7 — the focus of this study — is an intracellular guard and senses single stranded viral RNA attaching to guanosine. This newly detected mutation is gain-of-function (GOF), which means it enhances the function of encoding protein. In our case, it selectively increased TLR7 sensing of guanosine.
TLR7 GOF mutation causes overactivation and increased response against guanosine and can give rise to SLE and likely other B-cell-driven autoimmune disorders. Also, the variant discovered in this research may play a crucial role in the disease development during infections caused by single-stranded RNA viruses. Then it promotes the survival of BCR-activated immature B cells with the further formation of self-reactive B cells and autoantibody production.
Since SLE is generally a polygenic disease, the description of monogenic cases and rare pathogenic variants are intriguing. Therefore, to receive more insights into disease mechanisms, Brown and colleagues introduced the mutation into the mice model by CRISPR. As expected, mice developed symptoms of lupus. In particular, the authors established that enhanced TLR7 signaling leads to aberrant survival of BCR-activated immature B cells. These B-cells are known to be contributors to self-reactivity. Oppositely TLR7-deficient mice lacked pathogenic B cell subsets, as well as follicular helper T cells, and had decreased plasma cells.
Recent data together with existing evidence of increased TLR7 signaling in a large percent of lupus patients confirm the pivotal role of TLR7 in driving human SLE. Therefore, potentially blocking TLR7 can be a widespread therapeutic target in patients with SLE. Here Brown and colleagues have clearly demonstrated the value of a single clinical case in understanding the precise mechanism of disease. There are many endotypes of diseases and personalized medicine that should help us to provide the best treatment for each individual patient. Hopefully, one day we will add SLE cases on a monogenic diseases list with Leber congenital amaurosis, spinal muscular atrophy, and other diseases approved for gene therapy.
Article author: Taras Baranovskyi. Taras is a medical doctor at Immunotherapy Clinic in Kyiv, Ukraine. His research is focused on developing new approaches for overcoming the antimicrobial resistance of Klebsiella pneumoniae. Also, Taras is a part of a team which spreads knowledge of immunology through the ‘Cup of Immunology’ project.
Want your article featured in Antibuddies blog? Contact editor-in-chief- Dr. Sutonuka Bhar at firstname.lastname@example.org.
Share this article in twitter by clicking below:
Check out Antibuddies’ blog post “Mutation in innate immune receptor can cause lupus”.Tweet