Thursday, 15 May 2014

UVB light a new treatment for MS or a reason why MD is a grumpy old git!

Breuer J, Schwab N, Schneider-Hohendorf T, Marziniak M, Mohan H, Bhatia U, Gross CC, Clausen BE, Weishaupt C, Luger TA, Meuth SG, Loser K, Wiendl H. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Anal Neurol. 2014. doi: 10.1002/ana.24165. [Epub ahead of print]

OBJECTIVE:Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity.
METHODS: Effects of UVB light were analyzed in a MOUSE model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing-remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of the peripheral blood.
RESULTS: Regulatory T cells (Tregs), which are induced locally in the skin-draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg-inducing tolerogenic dendritic cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation, because ablation of Langerhans cells abolished the UVB-induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D.
INTERPRETATION: Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin-derived tolerogenic DCs and Tregs. Our data could have implications for the understanding or therapeutic modulation of environmental factors that influence immune tolerance. 


There are three main types of ultraviolet light UVA, UVB and UVC. UVC is very damaging but is filtered out by the clouds and does not penetrate the skin much. This study suggests that ultraviolet light B (can give you a suntan/sunburn and too much could lead to cancer) can influence the immune response and it is is well known that this can occur. 

Warts can become rip roaring with sunlight, maybe because immune responses are inhibited and the wart virus goes bonkers.

Does this mean that we should be running out to get a bit of UVB in a tanning salon or elsewhere. Well, be careful remember UV light is damaging and so watch out! 

There are easier and cheaper ways to get vitamin D. 

In this study they demonstrated that UVB treatment and augment the generation of regulatory cells, that would hopefully inhibit immune responses. What they did not show is that this treatment influences the course of MS. Further studies are needed.

In this study human studies and the mouse studies both go the same way,  so mouse is like man. This it is interesting and needs to be reproduced and developed further BEFORE you rush out and get UVB lamps and start burning yourselves..Be warned. 

This paper is a bit scary for me as it is creating a flash back.... and so ProfG may wish to comment

As a old duffer you get many different life experiences and can sometimes have a different view to the norm. 

As a young student my first task was to investigate something that was part of dermatitis dogma. It was related to a cell called a Langerhans cell in the skin..similar to a microglia in the brain. 

The dogma developed by Jon Wang and Co was that if you remove Langerhans cells in the skin, which you could do using ultra violet light (UVB. However to do this effectively you need big exposures), then when you put a sensitizating agent on the skin that has no Langerhans cells you get immune tolerance rather than sensitization. Presumably due to tolerogenic dendritic cell and T reg function.

This was dogma...if you are an EAEer, it's like saying Tregs stop you getting EAE or Th17 are the bees knees...of course its all true before you bombard me with what ever.

Now my project was to repeat this as a starting point to my studies, but rather than use mice, the project was to use guinea pigs (Is this transparent..given the UK Governments request for transparency about animal work?) . 

So experiment performed and hypothesis failed....repeated, failed again....repeated failed again, etc. etc....2 days off, bar Christmas in a whole year (Amercian says big deal someone from France may say I am bonkers:-) later yes no summer holiday and no free weekends. Eventually you just have to believe your own work. I deplete the Langerhans cells with ultra violet B, ultra violet C and even cellotape, that's scotch tape in American and always the same result...anti-dogma.

So time to tell the world that dogma was wrong and your first trip abroad to Amsterdam to present at the ECTRIMS of skin disease and the abstract is...........rejected. So no trip to Amsterdam...Bummer. Who gets an abstract rejected to a meeting?...No one?..Bar Me?. No wonder I have turned into a bitter and twisted person. Scarred for life!

Next and shortly after my boss is away on a jolly and so one of the demigods of Dogma of skin disease (I would add a good friend of the Lab), comes to the lab, so I have to entertain them and show them my work....5 hours later and I am constructively ground into the dust by the literature according to the demigod. So I spend all weekend planning new experiments to answer their points and have another meeting. Ground into dust again but some experimental plans are made. My boss comes back from their meeting abroad and when I tell them what happened he gets my supervisor to send a snotty letter to the demigold saying it will take 5 years to answer their questions posed and they are an *******. Through a bit more reading I realise that the knowledge that they asserted was on dodgey ground and was more grey than black and white.

Fast forward a year and some other mushroom food merchant from the demigods lab comes for a visit and uses the same old confident assertion that their views were right....however this time I had the confidence and importantly the knowledge to go to the bookshelf pick out the paper and show them that they were wrong and manipulating the facts.....fast forward another year and I caught the demigod out in public. They were manipulating the literature.

However fast forward a bit again and Jon Wang and his buddies have done more work in mice. It turns out in one mouse strain you get immune tolerance when you shine UVB on the skin of mice and apply a sensitizing compound but in a different strain of mouse and you get just what I found, the opposite, in the guinea pig many years earlier and they didn't quote me..Bitter not me:-). 

However maybe not all humans are created the same and so this is a reason why we should let the researchers develop their idea more before rushing out to get a lamp. So lets see if it repeats. 

Anyway I eventually got to Amsterdam a year later after the conference to collect some antibodies for work from the Free University in Amsterdam. However, because I wanted to use the antibodies to see the number of Langerhans cells in human skin I had had a suction blister on my skin to get skin to use the antibodies a few days earlier

                                          Langerhans cells

They use a machine to suck the air to create a skin blister, actual a circle of 5 blisters. However, as it can leave a bit of a scar,or is red for a year, they do this under your knicker line. However coming back from Amsterdam (I never inhaled) I got stopped by UK customs looking for drugs and got strip searched and interrogated for 2 hours. 


Explaining what a monoclonal antibody and a suction blister is whilst paraded in your Birthday Suit is enough to make you a bit bitter and twisted:-),

P.S. This is true in my mind at least...names have been changed to protect the identity of Jon Wang

10 comments:

  1. And I thought scientific academia was boring. It's almost a case for Inspector Morse to find that the demigod had actually been turned into mushroom food

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  2. Thank you MouseDoc - funny story btw :-)

    The way I understood this is that it is more than just VitD - that only UVB rays can do to the t-cells so that taking tablets alone won't have the whole effect on the immune system.

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  3. So why do people focus on low vit d rather than low uv light when looking at MS susceptibility?

    Have been confused as to why vit d hogs the limelight when it could potentially be an effect of uv light instead, with vit d just being a surrogate marker for uv exposure.

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  4. No wonder why you hate tregs so much. But I think there is enough evidence that tregs are deficient in ms and many of the first line therapies seem to restore tregs function and or population to normal levels. Even in therapies like HSCT, tregs are restored to normals after reset.

    Of course this may not prevent EAE (or ms) after it is initiated but it could shut down activity faster than those with faulty tregs.

    Just because your method failed does not mean you should throw out the baby with the bath water. This is all part of understanding what causes ms and good people (including your enemies) continue to look at ways to better utilize tregs.

    http://www.ncbi.nlm.nih.gov/m/pubmed/17698561/

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    Replies
    1. This not an anti t reg rant. They are bone fide cells that regulate the development of autoimmunity
      This is not about throwing babies away however i do not think we should be promoting people buying UVB lamps whi h was the question if you read the unrelated blogger comments

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  5. Cool story, Prof Mouse :-)

    By the way, is there any evidence around on should I protect myself from the sun exposure after the alemtuzumab? I asked my neuro, but got no satisfactory answer. Also did not found anything on the interwebz. From my layman's point of view, I am predisposed to cancers while my immune cells counts are low, right?

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    Replies
    1. It is a percieved risk becuase your immune gets rid of cancers. However remember the drug is gone quite soon and cells can regenerate whereas if you are on drug eg fingolimod.
      We have recently had a look at this and the paper is in the ether. I would say most of second generation drugs are similar.

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    2. I'm just a little bit cancerophobic. Thanks as usual MouseDoc.

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