How Vitamin D Modulates Immune System Activity Detailed in Study

Vitamin D can influence the immune system’s tolerance to certain proteins by changing how DNA is packaged in specific immune cells called dendritic cells, according to a new study.

Its findings could have implications for treating diseases like multiple sclerosis (MS) that are characterized by the immune system attacking healthy tissue.

The study, “The epigenetic mechanism by which vitamin D modulates the tolerance of the immune system,” was published in Cell Reports.

For the immune system, the world is black and white: Everything that is a part of the body should be left alone, and anything that’s not part of the body is assumed to be a threat and will be attacked.

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The immune system’s ability to not attack — to “tolerate” — the body’s own tissues is called immune tolerance. In MS and other autoimmune diseases, what happens is effectively a breakdown of tolerance as the immune system attacks healthy cells.

Dendritic cells are a class of immune cells that play key roles in regulating immune tolerance. Prior research had demonstrated that treating these cells with vitamin D prompted them to take on more tolerogenic (tolerance-promoting) characteristics. However, the molecular mechanisms underlying these changes were unclear.

A team of scientists in Spain conducted a series of experiments using human cells to unravel these mechanisms.

The researchers first looked at how methylation patterns were affected by treatment with vitamin D. Methylation is a type of epigenetic modification — chemical changes that can alter how DNA is “packaged” inside the cell, which affects how various genes are “read.” Broadly, methylation is a modification that “turns off” genes.

Results suggested that in the presence of vitamin D, a number of genes important for regulating immune activity and promoting tolerance become unmethylated. In essence, these genes that had been “turned off” get switched on by the action of vitamin D.

Further experiments confirmed that these unmethylated genes were indeed more active.

Vitamin D acts by binding to a protein receptor in cells, aptly called the vitamin D receptor or VDR. In further experiments, the researchers showed that in the presence of vitamin D, this receptor was going into the nucleus (where most of the cell’s genetic material is stored) and physically associating with genes that became unmethylated.

They also showed that VDR activates a molecular pathway called JAK2-STAT3, and the VDR protein physically interacted with the activated version of the STAT3 protein. Both VDR and STAT3, in turn, interacted with a protein called TET2 — which is known to be able to actively remove methylation from DNA.

Blocking the JAK2-STAT3 pathway was found to lessen the tolerance-promoting effects of vitamin D.

“This reinforces the idea that the activities of VDR and the JAK2-STAT3 pathway coordinate the acquisition of tolerogenic properties of DCs [dendritic cells] in the presence of vitamin D,” the scientists wrote.

“Our results raise the possibility that tolerogenic properties can be reverted, not only in the context of vitamin D but also in others,” the team concluded. “These findings could be clinically relevant … in the context of pathological situations where tolerogenic properties are not desired,” such as in treating cancers that evade immune destruction.

And these tolerance-promoting properties might be restored in disease situations “where they are intentionally pursued … including their therapeutic use in the treatment of inflammatory conditions, such as rheumatoid arthritis and multiple sclerosis,” the researchers added.