Developmental vitamin D₃ deficiency induces alterations in immune organ morphology and function in adult offspring

Abstract

Vitamin D₃ deficiency and insufficiency are common in women of child-bearing age. This may be cause for concern because vitamin D₃ is a well known regulator of immune function and epidemiological evidence has suggested that immune disorders, including autoimmune diseases, could have developmental origins. However, it is not known whether a developmental deficiency in vitamin D₃ could lead to persistent changes in the immune system in adult offspring. Given the prominence of receptors for vitamin D₃ within immune cells we hypothesised that the developmental absence of vitamin D₃ may alter thymic development and thus produce associated functional changes in T cells. We have developed a model of developmental vitamin D₃ (DVD) deficiency in Sprague–Dawley rats, in which the vitamin D₃ deficiency is transient and restricted to gestation. First we demonstrate that DVD deficiency induced an increase in central but not peripheral immune organ size. Second when stimulated, lymphocytes from DVD-deficient rats exhibit a pro-inflammatory phenotype. This is the first study to show that a transient vitamin D₃ deficiency restricted to gestation can persistently alter aspects of immune phenotype and function in the adult offspring. Given an increased incidence of vitamin D₃ deficiency in women of child-bearing age these findings may be highly relevant for autoimmune disorders with a developmental basis.

Introduction

In recent decades there has been intense interest in the immunomodulatory effects of the active form of vitamin D₃, 1,25 dihydroxyvitamin D₃ (henceforth referred to as vitamin D₃) [1], [2]. The receptor for vitamin D₃ (VDR) is present in cells of the immune system [3] including macrophages, dendritic cells and resting and activated T cells [4]. Certain immune cells also have the ability to locally synthesise vitamin D₃ [5] suggesting that vitamin D₃ can signal directly within these cells.

Epidemiological studies have linked many different clinical disorders with exposure to low vitamin D₃ [6]. It has been postulated that low vitamin D₃ during gestation and early life may alter the development of the foetal immune system thereby leaving the individual vulnerable to the development of immune-related disorders such as diabetes and multiple sclerosis in later life [7], [8]. To the best of our knowledge only one study has examined immune function when vitamin D₃ deficiency was limited to gestation only [9]. We have developed a model of gestational developmental vitamin D₃ (DVD) deficiency in Sprague–Dawley rats [10]. In this model dietary vitamin is re-introduced at birth and is present in the diet through postnatal life. Importantly, this model shows no signs of hypocalcaemia or any aspect of a rachitic phenotype with calcium, phosphorus, parathyroid hormone and vitamin D₃ levels being normal in the adult DVD-deficient rats [11].

Hypovitaminosis D₃ is prevalent in modern populations largely due to a change in diet and outdoor activity. This appears to be of particular concern in young women. A study of non-institutionalised women of child-bearing age in the USA found that 19% of 20–39 year olds were deficient in vitamin D₃ [12]. Pregnant women are at an increased risk of vitamin D₃ deficiency due to the increased calcium requirements for foetal growth and a reduction in outdoor activity (and thus UVB exposure), particularly in the third trimester [13], [14]. The aim of this study was to broadly characterize the immune system of the adult DVD-deficient rat. Given the prominence of receptors for vitamin D₃ within immune cells, in particular the thymus [15], we hypothesise that the developmental absence of this vitamin will induce changes in how immune organs like the thymus develop and produce associated changes in resultant T cell function.