Rheumatoid arthritis (RA) is an autoimmune disease affecting the joints. RA occurs more often in females than males. RA causes chronic pain and inflammation, and can eventually erode bones, disfigure joints, and damage other tissues. While there are treatments that can lessen the symptoms and inflammation of RA, some patients have ongoing disease and there is no cure. Therefore, researching what might trigger RA could be useful in preventing this debilitating disorder. Studies have shown that risk is associated with specific human leukocyte antigen (HLA) class II alleles. HLA class II proteins present antigens to CD4+ T cells, which, in turn stimulate B cells to produce antibodies targeting those antigens. Some HLA class II alleles confer protection to RA. These protective alleles share a common amino acid sequence: DERAA.
During pregnancy, fetus and mother exchange cells with each other. Microchimerism is the phenomenon in which a small number of cells that came from another person are present in an individual. Intriguingly, a previous study showed that women who lack HLA alleles encoding for DERAA but have had children with DERAA+ alleles are at greater risk for RA. The laboratory of Dr. J. Lee Nelson (Clinical Research Division) demonstrated a method of testing for DERAA+ microchimerism using quantitative PCR. The study was published in the journal Proceedings of the National Academy of Sciences USA. The qPCR-based assay was sensitive enough to detect the DERAA sequence in one in 360,000 cells. This would allow the authors to find rare DERAA+ cells that might be present as microchimerism. The authors then tested peripheral blood mononuclear cells (PBMC) for DERAA in healthy women and women who were recently diagnosed with RA. They discovered that around half of the DERAA- women with RA had DERAA+ microchimerism, but only five to eight percent of healthy DERAA- women had DERAA+ microchimerism.
The researchers next set out to find a possible mechanism for this increased risk. They created a coculture system to mimic the microchimerism condition. They cultured PBMC from women who did not have DERAA alleles with either DERAA+ or DERAA- allogeneic cells. Upon analyzing the PBMC at the conclusion of the experiment, the researchers found that CD4+ T cells were significantly more activated in cocultures with DERAA+ cells when compared to DERAA- cocultures. These results were similar whether the responding cells came from DERAA- RA patients or DERAA- healthy controls. A previous study showed that a subset of CD4+ T cells in RA patients responds to a DERAA sequence from a protein located in the joints called vinculin1. In DERAA+ individuals, these potentially crossreactive T cells are likely deleted in the thymus upon encountering DERAA from HLA class II, protecting them from RA.
“This paper is noteworthy in that it is the first time that a specific mechanism has been described by which naturally acquired microchimerism can contribute to an autoimmune disease,” said Dr. J. Lee Nelson, senior author on the paper. Dr. Nelson said, “These results raise the question whether a similar mechanism is operative in other autoimmune diseases such as scleroderma or multiple sclerosis. Dr. Kanaan added “In the next phase of the current work we plan to initiate an international collaboration that will allow the team to discern the role in rheumatoid arthritis of the specific source of microchimerism – most notably whether the microchimerism was acquired from the individual’s mother or for females from a prior birth or other pregnancy outcome.”
This work was supported by the Wong Foundation and the National Institutes of Health.
Fred Hutch/UW Cancer Consortium members Drs. Vijayakrishna Gadi and J Lee Nelson contributed to this research.
Kanaan SB, Sensoy O, Yan Z, Gadi VK, Richardson ML, Nelson JL. Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism. Proc Natl Acad SciU S A. 2019 Sep 24;116(39):19600-19608. doi: 10.1073/pnas.1904779116.
Additional citation:
1. van Heemst J, Jansen DT, Polydorides S, Moustakas AK, Bax M, Feitsma AL, Bontrop-Elferink DG, Baarse M, van der Woude D, Wolbink GJ, Rispens T, Koning F, de Vries RR, Papadopoulos GK, Archontis G, Huizinga TW, Toes RE. Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis. Nat Commun. 2015 May 5;6:6681. doi: 10.1038/ncomms7681.