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Oct 29, 2024

Vitamin D deficiency: Does it influence autoimmune disease risk?

Vitamin D is essential not only for bone health but also for normal immune function. Vitamin D deficiency is linked to an increased risk of autoimmune diseases, but the mechanisms underlying this

Vitamin D is essential not only for bone health but also for normal immune function. Vitamin D deficiency is linked to an increased risk of autoimmune diseases, but the mechanisms underlying this association are not well understood.

A new study published in Science Advances now shows that disrupting a key enzyme involved in the conversion of vitamin D to its biologically active form can negatively impact the development of T cells.

This results in excessive production of T cells that can attack the body’s own tissue, a phenomenon known as auto reactivity.

This study — conducted in a mouse model — also showed that this increase in autoreactive T cells was mediated by the adverse effects of vitamin D deficiency on cells in the thymus, the specialized organ that influences the maturation of T cells and their ability to distinguish between healthy and infected or foreign cells.

Study author John White, PhD, a professor of physiology at McGill University in Montreal, Canada, told Medical News Today:

“Our study showed that vitamin D is necessary for normal thymic development, optimal ‘weeding out’ of self-reactive T cells, and thymic longevity.”

In addition to its role in bone health, vitamin D also modulates the function of the immune system. For instance, observational data suggest a link between vitamin D deficiency and an elevated risk of autoimmune diseases that involve the production of an immune response against the body’s own tissue.

T cells, a specialized type of white blood cell, play a crucial role in regulating this autoimmune response. T cells are involved in facilitating an immune response against microbes and the elimination of cells that might be infected or have cancer.

These functions of T cells rely on their ability to distinguish the body’s own proteins, known as self-proteins or self-antigens, from foreign proteins. The ability of T cells to recognize self-antigens and avoid a response against the body’s own tissue is known as T-cell tolerance.

T-cell tolerance emerges during the maturation of T cells from bone marrow-derived progenitor cells in the thymus, a gland located in the upper chest area.

Specifically, T-cell tolerance involves the selection of T-cell precursors that produce a robust reaction against foreign proteins but not self-antigens.

During the early stages of T cell development, the positive selection of precursor T cells capable of producing a robust reaction against foreign antigens occurs in the outer part of the thymus called the cortex.

The subsequent stages of T cell development occur in the central region of the thymus called the medulla. The T cells that produce a response to the body’s own healthy tissue are eliminated in the medulla in a process called negative selection.

Subsets of epithelial cells in the medulla express a fraction of the genes in the human genome, which together express most genes in the genome.

The expression of almost the entire repertoire of self-proteins in the thymus allows the development of tolerance of T cells to all the body’s tissues.

The receptor for the active form of vitamin D is expressed in the thymus, and vitamin D deficiency is associated with reduced thymus size.

Notably, the authors’ previous work had shown that vitamin D can enhance the expression of the autoimmune regulator (Aire) gene, and is thus critical for the development of T-cell tolerance and preventing an autoimmune response.

The development of the T cell population in the thymus during an individual’s lifetime is completed by the time of puberty.

This, along with the more robust impact of vitamin D on immune function in early life, suggests that vitamin D could influence T cell development in the thymus in early life to influence T cell tolerance.

In the present study, the researchers examined the pathways through which vitamin D potentially modulates T cell function in early life and, subsequently, the risk of autoimmune conditions.

Vitamin D is converted into its biologically active form in the body by the enzyme Cyp27b1. To understand the impact of vitamin D on immune function, the researchers used a mouse model genetically engineered to carry a mutation in both copies of the gene that expresses Cyp27b1, resulting in an ability to produce the active form of vitamin D.

These mice without the biologically active vitamin D showed reduced size of the thymus and a lower number of T cells in the blood, indicative of faster aging of the thymus.

These mice also had a smaller fraction of epithelial cells in the medulla expressing the autoimmune regulator (Aire) gene than wild-type control mice.

Moreover, there was a reduction in the number of medullary epithelial cells in the thymus that present self-antigens to the developing T cells. A previous study showed that the number of medullary epithelial cells presenting a particular self-antigen is correlated with the extent of T cell tolerance for that antigen.

These changes in the thymus of the mice unable to produce biologically active vitamin D were accompanied by an increase in markers indicative of reduced T cell tolerance, that is, an increase in T cells that produce a strong response to self-antigens.

Lastly, these mice also showed increased levels of autoantibodies in certain tissues, such as the lungs and the salivary glands, in late adulthood. However, such elevated levels of autoantibodies were absent in other tissues.

Older mice, but not younger adults, without active vitamin D also showed impaired glucose (blood sugar) regulation.

Summarizing these findings, White noted that: “We found that the development of epithelial cell populations in the thymus critical for negative T cell selection was impaired in mutant mice. Moreover, negative T cell selection itself was impaired.“

“Aging mutant mice also developed signs of autoimmunity and, in some cases, type 1 diabetes,“ he pointed out. “Just as interesting, we found that, in the absence of the active form of vitamin D, thymic aging was substantially accelerated,” which may further increase the risk of autoimmune conditions.