Specific sequences within HLA alleles can either increase risk of or protect against rheumatoid arthritis (RA). In addition to Mendelian inheritance, HLA alleles can also be passed between mother and child during pregnancy via chimeric cells in a phenomenon known as microchimerism.

Credit: Springer Nature Limited

“HLA-DRB1 alleles that encode the five amino acid sequence ‘DERAA’ are associated with protection against RA when present in an individual’s own genotype, yet in a previous study, RA prevalence was increased in women who had given birth to children with DERAA+ HLA prior to disease onset,” explains Sami Kanaan, corresponding author of a new microchimerism study.

To investigate this paradox, Kanaan and colleagues measured the presence of DERAA+ chimeric cells in the blood of both women with new-onset RA and healthy women, all of whom were DERAA−/−. In this cohort, women with RA were more likely to have DERAA+ chimeric cells than healthy women. In fact, carrying DERAA+ chimeric cells increased the risk of developing RA by 17-fold.

“Another previous study had reported the DERAA sequence in microbial proteins, and the presence of DERAA-directed T cells in DERAA−/− individuals that had the potential to cross-react with other synovium-expressed endogenous proteins containing DERAA, and thereby lead to RA,” says Kanaan. “We reasoned that DERAA+ chimeric cells could act in a similar way to microbial proteins and modelled a microchimerism scenario in vitro.” In this model, DERAA+ allogeneic cells elicited a response from CD4+ T cells from DERAA−/− patients with RA or healthy individuals, suggesting that chimeric cells can stimulate adaptive immune responses involved in RA.

carrying DERAA+ chimeric cells increased the risk of developing RA by 17-fold

“Our study indicates a specific mechanistic link between naturally acquired allogeneic cells and an autoimmune disease for the first time, following much prior research that has implicated microchimerism in autoimmunity by association, but has offered little insight into the underlying mechanism(s),” concludes Kanaan.