Background/Purpose: As in many autoimmune diseases, rheumatoid arthritis (RA) has a female predominance and strong genetic susceptibility from the HLA region. The shared epitope (SE), motif of five amino-acids ⁷⁰Q(or R)-K(or R)-R-A-A⁷⁴ on the third hypervariable region of DRβ1, accounts for the highest genetic risk. In contrast, HLA-DRB1 alleles that express ⁷⁰D-E-R-A-A⁷⁴ in the same positions are associated with protection from RA. Many RA patients do not carry the SE and, in women with RA, disease risk can be influenced by SE-positive alleles carried by their children (1). Two previous studies showed that, compared to healthy women, women with RA who are SE-negative more frequently harbor SE-positive microchimerism (Mc), a long-term legacy derived from feto-maternal exchange of cells during pregnancy (2, 3). In this study, we asked whether RA women who are DERAA-negative have less DERAA-positive Mc compared to healthy controls.

Methods: To detect and quantify Mc with DERAA-encoding alleles, a quantitative polymerase chain reaction (qPCR) assay was developed with primers and fluorogenic probes specific for the DERAA sequence and validated for specificity and sensitivity against an extensive panel of HLA well-characterized cell lines. We tested 53 female subjects who were genotypically negative for DERAA-encoding alleles, 26 RA patients and 27 healthy controls, similar for age, parity and gravidity. DERAA-Mc qPCR was conducted on DNA extracted from peripheral blood mononuclear cells (PBMC). Logistic regression modeled DERAA-Mc prevalence, and negative binomial regression modeled DERAA-Mc quantitative levels.

Results: DERAA-Mc was identified in 42.3% (11/26) of women with RA and in 7.4% (2/27) of healthy women (P = 0.0041). The odds ratio for DERAA-negative RA patients of being DERAA-Mc positive was 9.2 [1.8‒47.9] (95% confidence interval {CI}). Quantitatively, DERAA-positive Mc was 313.8 [38.3‒2573.3]_95%CI times more abundant in PBMC of RA patients compared to controls (P < 0.0001). Among RA patients, DERAA-Mc levels increased 28.1 [4.0‒195.8]_95%CI fold if genotype was SE+/+ compared to SE+/− or −/− (P = 0.0008) and increased 3.3 [1.6‒6.8]_95%CI fold with increasing parity (P = 0.0014).

Conclusion: Unexpectedly, the presence of Mc carrying HLA alleles that encode RA-protective alleles was significantly increased in women with RA. This result aligns with a recent report that found increased RA risk in women who had a DERAA-positive child born prior to disease onset (also unexpectedly) (1). Furthermore, DERAA-Mc levels were especially high among RA women with a SE+/+ genotype. While the explanation for these observations is unknown, results support the concept that RA in women can be influenced by “reverse inheritance” from her children and suggest complexity in immunological interactions across generations (4).

References:

1. G. I. Cruz et al., Ann. Rheum. Dis. (2017), doi:10.1136/annrheumdis-2016-210662.

2. J. M. Rak et al., Arthritis Rheum. 60, 73–80 (2009).

3. Z. Yan, et al., Arthritis Rheum. 63, 640–644 (2011).

4. J. L. Nelson, N. C. Lambert, Nat. Rev. Rheumatol. (2017), doi:10.1038/nrrheum.2017.88.

Funding: This work was supported by NIH grants HL117737 and AI 45659.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/acquisition-of-protective-alleles-in-women-with-rheumatoid-arthritis-through-microchimerism/