Prenatal Administration of Betamethasone Causes Changes in the T Cell Receptor Repertoire Influencing Development of Autoimmunity

Abstract

Prenatal glucocorticoids are routinely administered to pregnant women at risk of preterm delivery in order to improve survival of the newborn. However, in half of the cases, birth occurs outside the beneficial period for lung development. Glucocorticoids are potent immune modulators and cause apoptotic death of immature T cells, and we have previously shown that prenatal betamethasone treatment at doses eliciting lung maturation induce profound thymocyte apoptosis in the offspring. Here, we asked if there are long-term consequences on the offspring’s immunity after this treatment. In the non-obese diabetic mouse model, prenatal betamethasone clearly decreased the frequency of pathogenic T cells and the incidence of type 1 diabetes (T1D). In contrast, in the lupus-prone MRL/lpr strain, prenatal glucocorticoids induced changes in the T cell repertoire that resulted in more autoreactive cells. Even though glucocorticoids transiently enhanced regulatory T cell (Treg) development, these cells did not have a protective effect in a model for multiple sclerosis which relies on a limited repertoire of pathogenic T cells for disease induction that were not affected by prenatal betamethasone. We conclude that prenatal steroid treatment, by inducing changes in the T cell receptor repertoire, has unforeseeable consequences on development of autoimmune disease. Our data should encourage further research to fully understand the consequences of this widely used treatment.

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India

“…route, and lymphocyte suppression was also comparable for the BetaP plus BetaA. A concern for clinical use is that corticosteroids have large effects on the developing immune system of the fetus that could alter immune function in the child and adult …”

“…A concern for clinical use is that corticosteroids have large effects on the developing immune system of the fetus that could alter immune function in the child and adult. [33][34][35] The study has limitations as we studied only fasted healthy Indian-Asian women. Extrapolation to other populations of different racial backgrounds, a wide range of BMI, nonfasted, and pregnant women must be done with caution.…”

Environmental exposures during pregnancy: Mechanistic effects on immunity

“…A mouse study showed significant reduction in thymic size and cell numbers after prenatal betamethasone in the three mouse strains tested (Gieras et al, ). Only in the lupus‐prone MRL/lpr strain, did prenatal glucocorticoids induce changes in the T cell repertoire (CD4 + , CD8 + , and CD4 − CD8 − ) that resulted in increased numbers of autoreactive T cells (Gieras et al, ). Similarly, a study performed in rats demonstrated that prenatal dexamethasone, another glucocorticoid, exposure increases the susceptibility to autoimmunity, namely, experimental autoimmune encephalomyelitis (EAE) and adjuvant‐induced arthritis (AIA) in offspring (Sun et al, ).…”

“…Although a previously discussed study associated the glucocorticoid dexamethasone with immunosuppression (Coe & Lubach, 2000), other studies have found a connection between prenatal glucocorticoid exposure and autoimmunity. A mouse study showed significant reduction in thymic size and cell numbers after prenatal betamethasone in the three mouse strains tested (Gieras et al, 2017). Only in the lupus-prone MRL/lpr strain, did prenatal glucocorticoids induce changes in the T cell repertoire (CD4 + , CD8 + , and CD4 − CD8 − ) that resulted in increased numbers of autoreactive T cells (Gieras et al, 2017).…”

Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes

“…However, studies regarding the effects of prenatal GCs on the development of autoimmunity are limited. Recently, using a mice model, Tolosa and colleagues demonstrated that prenatal administration of betamethasone increases apoptosis of developing thymocytes and induces changes in the TCR repertoire decreasing the frequency of pathogenic T cells and protecting from T1D development in NOD mice ( 184 , 185 ). Conversely, an epidemiological study in Danish cohorts indicated the existence of an increased risk for T1D and T2D in young children who received prenatal steroid treatment ( 186 ).…”