Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity

Abstract

During pregnancy, the fetus that grows within the maternal uterus is not rejected by the maternal immune system. To enable both tolerance towards the fetus and defence against pathogens, modifications of the maternal immune system occur during gestation. These modifications are able to bring about a natural improvement in disease activity of some autoimmune diseases, such as rheumatoid arthritis (RA). Various mechanisms of the immune system contribute to the phenomenon of pregnancy-related improvement of RA, and the cessation of these immunomodulatory mechanisms after delivery correlates with postpartum disease flare. HLA disparity between mother and fetus, glycosylation of IgG, immunoregulatory pathways, and alterations in innate and adaptive immune cells and their cytokines have important roles in pregnancy and in pregnancy-related amelioration of RA.

Key points

  • Immune tolerance during pregnancy is most pronounced at the feto-maternal interface, but also has a systemic effect that supports amelioration of rheumatoid arthritis (RA) by rebalancing pro-inflammatory and anti-inflammatory influences.

  • A pro-inflammatory microenvironment is crucial for normal implantation and parturition, whereas a tolerogenic environment is induced during the course of pregnancy to enable normal placentation and fetal growth.

  • With regard to innate immune cells, monocyte gene activity in the peripheral blood is higher during pregnancy than postpartum, and a tolerogenic subset of innate cells is at work in the placenta during pregnancy.

  • With regard to adaptive immune cells, there is no definite predominance of T helper 2 cells but a downregulation of effector T cell activity and an expansion of regulatory T cells, which support pregnancy-related RA improvement.

  • Galactosylation of IgG is a pregnancy-related phenomenon that renders disease-specific autoantibodies less pathogenic and could explain why a gestational increase in anti-cyclic citrullinated peptide antibody IgG galactosylation is associated with improved RA.

  • After delivery, the immunomodulatory effects mediated by fetal antigens and pregnancy hormones disappear, giving rise to T cell activity that, together with persisting monocyte activity, correlates with postpartum disease flares.

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Fig. 1: Immune events in pregnancy.
Fig. 2: Rebalance of pro-inflammatory and anti-inflammatory factors during pregnancy in rheumatoid arthritis.

Change history

  • 17 February 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Correspondence to Frauke Förger.

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Glossary

Decidua

The maternal part of the placenta.

Semiallogeneic graft

A transplant sharing half of its genes with the recipient

Allograft

An organ, tissue or cells transplanted between genetically non-identical members of the same species.

Microchimerism

The presence of a small number of genetically distinct cells in a host individual.

Preeclampsia

A complication of pregnancy characterized by hypertension and proteinuria and signs of damage to other organs, usually occurring after 20 weeks of pregnancy.

Mixed lymphocyte reaction

The proliferation response following co-culture of two populations of lymphocytes, used as a surrogate measure of T cell activation

Trophoblast invasion

Invasion of the uterus by fetal cells during human placentation.

Spiral artery remodelling

Transformation of spiral arteries into vessels of low resistance by trophoblast invasion.

Parturition

The process of labour and delivery.

Chorioamniotic membranes

Fetal membranes (amnion and chorion) making up the amniotic sac that surrounds and protects the fetus.

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Förger, F., Villiger, P.M. Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity. Nat Rev Rheumatol 16, 113–122 (2020). https://doi.org/10.1038/s41584-019-0351-2

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