Publication highlights

Researchers at the Crick and Australian National University have shown how two proteins, TCF1 and LEF1, previously only studied in T cells, enable B-1 cells (a type of innate B cell which remains uncharacterised in humans) to apply the brakes on inflammation in mice and used this information to identify signs of B-1 activity in humans. They found that removing TCF1 and LEF1 in adult mice led to the production of a smaller number of dysfunctional B-1a cells that failed to restrain an immune assault on the brain resembling multiple sclerosis. Cells without TCF1 and LEF1 also produced significantly less of an anti-inflammatory compound, IL-10. Finally, the team analysed pleural fluid from people with pleural infections, finding an abundance of B-1-like cells which expressed both genes, as did malignant B cells in people with chronic lymphocytic leukaemia. They also conclude that TCF1 and LEF1 could be harnessed to increase the effectiveness of other immune cells.

Thanks to collaborative work between the Francis Crick Institute, the Australian National University and Shanghai Renji Hospital, Carola Vinuesa’s international team demonstrate the value of performing whole genome sequencing(WGS) and discovery of functional rare variants in patients with ambiguous diagnoses of human autoimmunity. In their article published in Nature Immunology, they identify two families featuring elevated IgG4, a mark of inflammation, and sicca symptoms, such as dry eyes or mouth, as well as various manifestations of systemic autoimmunity.

The team uncovered that these families have a shared rare genetic variation in the gene TNIP1, a gene that has not been shown to date to cause human disease but has been associated with systemic autoimmunity by genome-wide association studies. Their work reveals a previously unappreciated link between this gene and other events in autoimmune disease like damaged mitochondria. These findings also provide a rationale for pathway-targeted therapeutics such as TLR7 and TBK1 inhibitors in TNIP1-mediated disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects women and those of an Afro-Caribbean ethnicity. In its severest form, it can cause organ failure - like kidney failure - leading to poor patient outcomes. SLE is also highly variable, which means people are affected differently in terms of the symptoms they have, organs involved and how they respond to treatment. This makes it very difficult to manage. Current therapies for SLE indiscriminately suppress the immune system with many side effects; as yet there is no cure.

There is a strong genetic contribution to SLE. This review integrates the many genetic variants currently understood to cause or be associated with SLE. It highlights rare, ultra-rare and novel causal variants that have been identified in humans and shown in animal models to cause an SLE- like disease. It also evaluates the common variants that may be associated with SLE, identified by large population studies, and the cell types that most highly express these genes. This highlights an important role for age-associated B cells in the development of the disease, already shown to be consistently associated with SLE related kidney disease, which may prove an attractive target for therapeutics.