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Exploring vitamin D and how it activates immune system tolerance

Spanish researchers unveil the mechanism that plays a key role in controlling the body’s immune response against autoimmune diseases such as multiple sclerosis. It all begins with vitamin D.

Health

EU-backed researchers from the Josep Carreras Leukaemia Research Institute and Germans Trias i Pujol Hospital in Spain have made an important discovery regarding the body’s immune response against multiple sclerosis and other autoimmune diseases. In their study supported by the EU-funded RESTORE and INsTRuCT projects, they revealed the epigenetic mechanism by which vitamin D activates the immune tolerance of dendritic cells, which plays a crucial role in controlling the immune response against such diseases. Their findings have been published in the journal ‘Cell Reports’. Dendritic cells are groups of immune cells found in blood and tissues such as the skin and the inner lining of the nose, lungs, stomach and intestines. They play a vital role in initiating adaptive immune responses and serve as messengers between the innate and adaptive immune systems, processing antigen material and presenting it on the surface of the cell. When activated, dendritic cells travel to local lymph nodes and present the antigen to lymphocytes – immune cells of the adaptive immune system – to trigger an immune response. In multiple sclerosis, the immune system does not function as it should. The body’s immune cells attack the myelin sheath that protects the nerve fibres in the brain and spinal cord, leaving the nerves unprotected and causing progressive neurological damage. When dendritic cells are treated with vitamin D, they develop immune tolerance, which suggests that treatment with tolerant dendritic cells could slow disease progression in people with multiple sclerosis. A clinical trial testing this hypothesis is currently being conducted at the Germans Trias i Pujol Hospital in Barcelona as part of the RESTORE project.

Discovering the immune tolerance activation mechanism

However, despite evidence supporting this hypothesis, the actual mechanism through which this tolerance is induced was unknown, until the Spanish research team discovered it. In their study, the research team shows for the first time that when the vitamin D receptor binds with the STAT3 protein, this activates TET2 – a DNA demethylating agent – which in dendritic cells helps activate immune tolerance genes. This interplay among vitamin D receptors, the STAT3 protein and the protein coding gene TET2 opens up possibilities for modulating the immunogenic properties of dendritic cells. As stated in the study, this research “could be clinically relevant both in the context of pathological situations where tolerogenic properties are not desired, like in the tumor microenvironment or in metastatic processes …, as well as in those where they are intentionally pursued …, including their therapeutic use in the treatment of inflammatory conditions, such as rheumatoid arthritis and multiple sclerosis.” The RESTORE (NEURONAL SELF-RENEWAL BY ANTIGEN-SPECIFIC TOLERIZATION IN MULTIPLE SCLEROSIS REINSTALLING THE BALANCE BETWEEN INFLAMMATION AND REGENERATION) project brings together researchers and clinicians from Belgium, Germany, Spain and the Netherlands in search of a cure for multiple sclerosis. The INsTRuCT (INnovative Training in Myeloid Regulatory Cell Therapy) consortium is a network of European scientists aiming to develop novel myeloid regulatory cell-based immunotherapies. For more information, please see: RESTORE project website INsTRuCT project website

Keywords

RESTORE, INsTRuCT, dendritic cell, multiple sclerosis, autoimmune disease, STAT3, TET2, tolerance, vitamin D