Of Mice and Men
Happy Weekend! Recently, I've been reading about the origin story of lab mice in an essay, The Mouse as a Microscope, by Alex Telford1.
As a human geneticist working in the drug development field, I, like many others, have often complained about mice being a poor animal model to study the complex human physiology. But I've also appreciated the big roles those small mammals have played in biomedical research, particularly in human genetics. A few days ago, I tweeted about a new discovery of a rare monogenic cause of childhood onset systemic lupus erythematosus (SLE)—gain of function mutations in UNC93B1, encoding a toll-like receptor (TLR)-trafficking protein—published in Nature Immunology. The discovery reminded me of another post from two years ago on the discovery of a gain of function mutation in TLR7 as a monogenic cause of childhood onset SLE. With Alex's story still fresh in my mind, an aspect of both the studies kept coming back to me: the roles lab mice have played in establishing the links of TLR7 and UNC93B1 with SLE.
SLE is an autoimmune disease. Individuals with SLE produce autoantibodies against their own DNA, commonly known as antinuclear antibodies (ANAs). Under normal physiological conditions, DNA never leaves its home, the nucleus. When it does, it causes trouble. It alarms the innate immune system. Humans have evolved by fighting against pathogens like viruses for thousands of years. Our immune system is pretty good at spotting a pathogen intruder. When a virus enters a human cell and start replicating, their nucleic acids are readily sensed by a special family of badass proteins, TLR7, TLR8 and TLR9, that live in the endosomes. Activation of TLRs leads to consequences such as cytokine storm, B cell activation etc. to fight against the intruder. In patients with SLE, there is constant activation of TLRs without any viral infection, either because of frequent release of nuclear DNA into the cytoplasm or abnormally sensitive TLRs.
This excerpt is provided for preview purposes. Full article content is available on the original publication.