In brief (April 2014) – Interferon beta and multiple sclerosis; vitamin A and immunity

It has been a while since I shared a selection of the scientific articles I had recently read , so here it is:
interferon beta and multiple sclerosis, or how the identification of a new immune cell type may give yet another clue as to how interferon beta exerts a therapeutic effect,
vitamin A and immunity, or how lack of vitamin A affects the development of the immune system and its priorities.

  • Interferon beta and multiple sclerosis

Interferon beta (IFNβ) has been used in the treatment of multiple sclerosis (MS) for about two decades. Its belongs to a group of proteins called cytokines (often referred to as the messengers of the immune system), and it is known to play an important role in the fight against viral infections. Since clinical trials showed that IFNβ might help prevent and/or limit relapses or disease progression in MS, it has been widely used in the management of MS. However, the molecular mechanisms underlying its efficacy are still poorly understood, and, along with them, the reasons why IFNβ therapy does not work in up to 50% of patients.

Many studies have looked into how IFNβ may exert its therapeutic effect in MS, and so far data suggest that it may do so by modifying the blood-brain barrier (and thereby limiting inflammation and associated damages in the central nervous system), or by antagonizing deleterious immune responses driven by a type of immune cells called Th17 cells (T lymphocytes that produce the cytokine IL-17; these cells are helpful when it comes to fighting off bacterial or fungal infections, but prove harmful in several autoimmune diseases). Researchers from the University of Copenhagen now provide a new potential clue to further understand IFNβ efficacy in the treatment of MS: they describe a new type of regulatory T (Treg) cells called FoxA1+ Treg cells (Treg cells are a subset of immune cells specialized in controlling immune responses). These newly identified FoxA1+ Treg cells are present in the central nervous system of mice with MS-like disease and are found in the blood of MS patients responding to IFNβ therapy in greater proportions than in the blood of patients for whom IFNβ treatment does not work. In their study, the researchers describe the molecular characteristics of FoxA1+ Treg cells and their immunosuppressive properties, and they show that adding IFNβ to in vitro cultures of regular T cells promotes the formation of FoxA1+ Treg cells.

Of course, the very existence, specific identity, and characteristics of FoxA1+ Treg cells need to be confirmed by other studies, and it will be interesting to know if these cells are also present in other tissues besides the central nervous system and in the context of other inflammatory autoimmune diseases. For now however, the identification of FoxA1+ Treg cells provides a new mechanism worth exploring to further decipher the modes of action of IFNβ in MS and hopefully understand why it does not work in some patients.

(Liu Y et al, Nature Medicine 20 March 2014, doi: 10.1038/nm.3485)
For a few more details: A new Treg subset on the block

  • Vitamin A and immunity

Vitamin A plays an important role in fetal and early childhood development. The most widely known deleterious consequence of vitamin A deficiency is perhaps childhood blindness, which affects hundreds of thousands of children every year. It has been known for a while that vitamin A and one of its metabolite, called retinoic acid, are involved in several aspects of the immune system. Two studies published this year have now looked at how vitamin A deficiency affects immune system development in utero and immune responses in adulthood. Both studies explored the effect of vitamin A deficiency on the immune system in mice, either by feeding them a diet completely lacking vitamin A, or by genetically modifying the mice to disrupt the retinoic acid signaling pathway, thereby abolishing any effect vitamin A/retinoic acid normally exerts.

In one study, the researchers found that vitamin A deficiency during gestation led to smaller secondary lymphoid organs in the offspring (the secondary lymphoid organs are where adaptive immune responses are mounted). Even when the female mice were switched to a normal diet containing vitamin A immediately after giving birth, their offspring still had reduced secondary lymphoid organs compared to control mice. Later in adulthood, the mice that had reduced secondary lymphoid organs because of a lack of normal retinoic acid signaling in utero and perinatally were less able to control viral infection than control mice. Altogether, the data presented in the study show one more instance of the importance of vitamin A during fetal development, with vitamin A deficiency occurring during this period leading to long-lasting changes in the immune system.

In the other study, the researchers looked at how vitamin A deficiency in adult mice affected the type of immune response they could mount. Vitamin A deficiency is known to affect different immune cell types, decreasing the general ability to mount immune responses and fight off infections. However, the researchers found that vitamin A deficiency, though indeed making mice more susceptible to bacterial infection, actually increased the ability of mice to control infection by a parasitic worm. The authors of the study therefore suggest that vitamin A deficiency do not simply diminish the ability to mount effective immune responses, but also leads to a shift in the type of immunity that is prioritized.

* Perhaps a useful reminder: the fact that a lack of vitamin A has harmful consequences does not mean that an excess of vitamin A is beneficial.

In the first study, the researchers observed that the offspring of female mice kept on a high-vitamin A diet during gestation had larger secondary lymphoid organs than the offspring of mice fed a diet with normal amounts of vitamin A. As the study was focused on vitamin A deficiency, the research team did not look further into the effects of excess vitamin A intake. However, in a commentary published along the study results, another researcher (not involved in the study) raised the interesting question of how such enlarged secondary lymphoid organs resulting from excess vitamin A during development might affect the immune responses later in life, and especially those unwanted uncontrolled immune responses that may lead to chronic inflammatory and autoimmune diseases.

(van de Pavert et al, Nature 3 April 2014, doi: 10.1038/nature13158)
(Spencer et al, Science 24 January 2014, doi: 10.1126/science.1247606)
(Eberl G, Nature 3 April 2014, doi: 10.1038/nature13216)

For a few more details: Vitamin A and the immune system

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