An Immunological Basis For Birdshot

We are so grateful to Dr Graham Wallace for writing the attached article, which explains the immunological process that leads to Birdshot.  Dr Wallace is a member of the Birdshot Research Network and is Senior Lecturer in Immunity and Infection at the University of Birmingham.  For those of you who attended the Birdshot Day in March 2012, you will remember that he gave a fascinating talk on ‘The Science of Birdshot’.  If you want to see his talk, we have posted it at:

http://www.youtube.com/watch?v=TNGAXyFrm00&feature=plcp

Here is Dr Wallace’s article on ‘An Immunological Basis For Birdshot’

The major histocompatability complex (MHC) is found on chromosome 6 in humans, and contains several genes which are involved in the immune response. Of particular significance are the genes that encode the human leucocyte antigens (HLA) which are fundamental to the immune system. HLA can be separated into two families: class I (A, B and C) and class II (DR and DQ). As class II molecules are not implicated in Birdshot I will not mention them again in the report. Each individual has two copies of HLA-A, B, and C on all cells of the body; one from their mother and one from their father. It is because of this genetic transfer from parent to child, that HLA class I were identified originally as transplantation antigens that must be matched for a successful tissue graft. The reason for this is the function of HLA class I which can be separated into two mechanisms;

(1)    HLA class I proteins present small pieces of proteins that have been broken up inside the cell on the surface and these are recognised by immune cells, called cytotoxic CD8 cells, which can kill other cells. This is particularly relevant for protection against viruses which enter human cells and replicate. Some virus proteins are broken down and presented by HLA class I.   That virally infected cell can be eliminated and the virus destroyed.

(2)    The second function of HLA class I is to protect normal cells from being eliminated by another group of cells called natural killer (NK) cells.  NK cells are also cytotoxic but do not recognise protein particles presented by HLA class I, as CD8 cells do. Rather, expression of HLA class I on a cell is recognised by protein called killer immunoglobulin-like receptor (KIR) on the NK cell and this interaction sends a “do not kill” signal to the NK cell and it moves on to check other cells. This benefit of this system is that some viruses cause HLA class I molecules to be removed from the surface of an infected cell thereby preventing recognition of viral fragments by CD8 cells. However such down-regulation of HLA class I will now make these cells susceptible to elimination by NK cells.

As HLA class I is found constitutively on all cells in the body they are not eliminated by NK cells. Bw4 is a region found on several HLA-B molecules.

KIR belong to specific families encoded by genes on chromosome 19 in humans. However, combinations of KIR vary between individuals and different cells may express more than one KIR. Both the inhibiting (KIRL), and activating (KIRDS) can be found on the same cell and it is the complex interaction of these molecules that control NK cells activation. (Fig 1)

Figure 1 – inhibitory KIRL recognise HLA class I molecules on cells and inhibit killing. Activating ligands induced by challenge are recognised by KIRS molecules. The balance between these signal determines outcome.

The MHC class I molecule, HLA-A*29, is associated with Birdshot uveitis.  KIR-HLA pairs implicated for weak inhibition such as KIR3DL1 + HLA-Bw4(T80)) in combination with activating KIR (KIR2DS2, KIR2DS3 and KIR2DS4) were found associated with increased risk in BCR HLA A*29 positive patients with BU. By comparison, association of strong inhibitory pairs such as KIR3DL1+HLA-Bw4(I80) in combination with KIR3DS1 was observed in HLA-A*29-negative controls. These results suggest that a profound effect of activating KIR (KIR2DS2/S3/S4) in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.

To confirm the role of HLA-A2902 in the disease the gene inducing the protein was obtained from a patient with Birdshot and used to create a transgenic mouse. These animals did develop ocular disease that was similar to Birdshot, but not until 12 months of age confirming the effect of ageing on the condition.

Figure 2 – the reason why certain combinations of HLA and KIR are maintained is because they are useful at protecting against infections, but in combination with other gene polymorphisms this can lead to autoimmune disease.

The challenge in Birdshot as in many other forms of disease is to determine what the effect of the various combinations have at a functional level. ie do cells from patients with certain combinations “kill” less efficiently and what does this mean for the patients. It will also be necessary to analsye other genes for variants that may give an additive effect to the HLA:KIR combination and lead to disease.

 

Clinical Trial on Ustekinumab

A single-centre pilot study is being undertaken in the United States to investigate the safety, tolerability and potential efficacy of subcutaneous injections of ustekinumab for uveitis.  The hope is, that if this drug works, it will have fewer side effects than the current protocol of steroids and immunosuppressants.

Ustekinumab is a human monoclonal antibody and is classed as a  ‘biologic’ drug.  It is currently used for people with psoriasis and some other conditions.

The study is due to complete in June 2013.  If this drug is effective, we will have yet another potential drug for Birdshot, for those people who find it hard to tolerate steroids and immunosuppressants.

Helminth (worms) Infections

The Institute of Immunology and Infection Research at University of Edinburgh has published a paper on Helminth (worm) infections and host immune regulation.  It looks at countries and areas where helminth parasites are endemic (i.e. many people carry these worms all their lives) and note that in these countries, there is a very low incidence of autoimmune diseases and allergies.  This suggests that the helminth parasites may protect against your immune system becoming disregulated.

The paper points out that there is now much interest in investigating helminths as a therapy, in both laboratory models and in human trials.  They believe that understanding and exploiting the way these parasites work are likely to highlight new strategies to control both infectious and immunological diseases.

See the full text at:

http://www.ncbi.nlm.nih.gov/pubmed/23034321?dopt=Citation

Dexamethasone Intravitreal Implant

The Department of Ophthalmology at University Vita-Salute in Milan, Italy has published a paper on their experience of treating difficult, uncontrolled and severe cases of noninfectious posterior uveitis (Birdshot is a noninfectious posterior uveitis) with dexamethasone intravitreal implants on top of systemic steroids.  They found that, of the 12 patients they studied, all had decreased uveitis activity, increased visual acuity and reduction in the macular thickness after 9 months.  Three patients were able to reduce their steroids.  Only 3 of the eyes had an increase in intraocular pressure.  Their conclusion is that dexamethasone may be a promising additional treatment for patients with sever posterior noninfectious uveitis which does not respond to immunosuppressants.

See the full text at

http://www.ncbi.nlm.nih.gov/pubmed/23038070?dopt=Citation

Quality of Life follow-up questionnaire

Last week we sent out a very short follow-up quality of life questionnaire to participants of our 1st questionnaire who kindly gave us their email address to allow us to follow-up.

We’d really  like to see how things may have changed for you since undertaking the 1st survey.  We do hope that you will all complete this as soon as possible as it will provide helpful data to supplement the original data .

If you have not received the email with the link to the survey and you think you should have, please get in touch with me at annie@birdshot.org.uk so that I can resend the link to you.

Many thanks to all who have already completed it.  We do appreciate your continued help with this useful research.

Annie

Orphan drug status for GEVOKIZUMAB

Gevokizumab is a monoclonal antibody that shuts down inflammation brought on by a protein in our bodies called interleukin-1 beta.

The pharma that produces Gevokizumab has been focusing on diabetes but now, with the orphan drug status , it means that it will get financial help to trial the drug on non-infectious and pan uveitis.

We don’t know, at this stage, whether is will work on Birdshot, but it is exciting to see new drugs coming on to the market.  It is even more exciting to see pharmas getting orphan drug status for new medications.

Read the full article at:

http://www.bizjournals.com/sanfrancisco/blog/biotech/2012/08/xoma-gevokizumab-uveitis-orphan-drug.html

OCT on Retinas of Birdshotters

Three people from Lausanne, Switzerland, including Carl Herbort who has been very supportive of BUS, have looked at the retinas of 28 Birdshot eyes and retrospectively evaluated the OCT findings of these eyes, to see what changes there are in the retina over a long period of time.

They looked at the OCT results in early Birdshot (less than 1 year), intermediate (1 to 6 years) and late (more than 6 years).

What they found was that in early Birdshot, the retinal thickness was significantly elevated (i.e. it was thicker than usual) because of the inflammation and vasculitis.  The thickness begins to diminish in intermediate Birdshot and by late Birdshot, the retina is significantly thinned.  They also observed that 92% of these eyes had developed an epiretinal membrane by late Birdshot.  An epiretinal membrane is a thin sheet of fibrous tissue that grows over the retina.  For those of us with Birdshot, an epiretinal membrane may develop because the vitreous (the jelly inside our eyes) pulls away from the retina due to the inflammation. Epiretinal membranes can cause visual problems, although most of us with an epiretinal membrane do not even notice any issues.

The interesting thing about this research is that if some-one has had a delayed diagnosis, their OCT results may help determine approximately how long they have had Birdshot for.

For more information on this piece of research, follow the link:

http://www.ncbi.nlm.nih.gov/pubmed/22909176

New Study Links Bisphosphonates to Vision Problems Risk

We have posted before about oral bisphosphonates (including Fosamax) and emerging evidence that first-time use of these is associated with a greater risk of developing two inflammatory diseases: uveitis and scleritis.

We have also posted on the risks of bisphosphonates in relation to atypical femur fractures.

The article highlights both these risks and can be found at:

http://www.prweb.com/releases/2012/9/prweb9883870.htm

The important thing to remember is that you need advice about your drug regime and the interactions of each of your medications, as well as the potential benefits and risks, so you can make an informed decision.  The risks highlighted in this article may be outweighed by the benefits in individual case – only you and your consultant can decide between you.

We, with Birdshot, who take high doses of steroids need to protect our bones.  So, becoming informed about our condition, our medication regimes, interactions and risks and benefits is really important.

Worms Again!

We have posted before about helminthic therapy – worms that can modulate the immune system and prevent it from attacking the body’s own tissues and organs.

Well, the time has come for mid stage trials on this therapy.  Currently, 220 people with Crohn’s Disease in the US are being enrolled on a mid stage trial and in Europe a further mid stage trial is being started.

The drug is called Trichuris Suis Ova (TSO) and consists of thousands of microscopic parasite eggs, suspended in saline solution – the drug is swallowed just like a tablet.  The parasites are killed off in our stomachs, but the hypothesis is that, before they die off, they are able to modulate our immune systems.

If these trials go well, we are not too far off from having this new drug available on the market.

Read the full story at:

http://www.reuters.com/article/2012/08/30/us-usa-health-parasites-idUSBRE87T14720120830

Autoimmune Researcher Gets Money

At long last it looks as though the world has finally woken up to the fact that autoimmune diseases are the modern day health problem.  There are over 100 different autoimmune diseases, many of them rare, and more and more people are being diagnosed with autoimmune diseases and no-one knows why.

A researcher in Australia, Chris Goodhew has received a grant from GlaxoSmithKline and he will look at why the immune system is attacking in the first place.  He has a vested interest as his mother has an autoimmune disease, lupus!

It is really good to see a major pharma investing in auto-immune diseases.

Read the full article at

http://www.canberratimes.com.au/act-news/80000-boost-for-autoimmune-researcher-20120911-25qs6.html