Hidden mutations in immune cells linked to autoimmune disease

Good news! This could be a breakthrough!

"New research suggests that autoimmune diseases may be driven by DNA mutations in immune cells that remove the natural brakes on the immune system. It reveals a previously hidden role for somatic mutations — DNA changes acquired throughout life — in diseases beyond cancer.

Researchers ... used a series of cutting-edge techniques to identify previously unseen changes in DNA that may contribute to thyroid autoimmunity, where the immune system attacks the thyroid gland. ...

The researchers used several advanced DNA analysis techniques.
Firstly, they used a method called NanoSeq, which they recently developed and allows detection of rare mutations invisible to traditional DNA sequencing methods, to look for genetic changes that may drive the disease. They found that many B cells had developed inactivating mutations in key genes that normally control the immune system.

Next, using additional methods that look at the DNA of individual cells and microscopic areas of tissue, the researchers found that many B cells in each patient carried several mutations in key genes.

Two critical immune-checkpoint genes, TNFRSF14 and CD274 (or PDL1), were often lost independently in multiple clones of mutated B cells in each patient. Some of these clones had even acquired as many as six driver mutations over many years, silently building up changes in DNA before symptoms appeared, a highly unexpected observation outside of cancer.

Importantly, artificial inactivation of these genes, in experimental studies or during cancer immunotherapy, is known to cause thyroid autoimmunity. The researchers have now found frequent mutations in these genes occurring in autoimmune patients. ..."

From the abstract:

"Our immune system contains multiple checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis posits that somatic mutations in immune-regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints1–3, but testing this has been challenging due to technical limitations.

Here, we use whole-exome and targeted NanoSeq, an accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed many B cell clones convergently acquiring loss-of-function mutations in the key immune checkpoint genes TNFRSF14 (HVEM) and CD274 (PD-L1), as well as less frequent mutations in other immune genes.

In highly inflamed biopsies, we detected tens to hundreds of independent immune checkpoint mutant clones. Laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing, and antibody synthesis localised these mutations to B cells, confirmed some to be self-reactive, and identified clones carrying multiple hits.

We found widespread TNFRSF14 biallelic loss, and clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small fraction of cells (typically <1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations.

Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution, providing new insights into the molecular basis of autoimmune disease."

Hidden mutations in immune cells linked to autoimmune disease "Mutations in immune cells may be the missing piece in the autoimmune disease puzzle."

Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity (no public access)