IMMUNE MEDIATED DISEASES/AUTO-IMMUNE DISEASES (both terms are commonly used to describe the same condition)

I do not claim to be any kind of expert in this field, but I have the experience of living with an affected dog.  I have tried to understand the basic principles of immune mediated disease so that I can monitor my own dog's health and be aware of the signs and symptoms which could be the beginnings of a relapse.  The following notes are taken from Dr Jeff Sampson's (BSc, DPhil) recent talk which followed The Whippet Club's AGM on 25th March 2006, and from information in notes from the seminar on auto immune disease in dogs which took place back in 2002.  More information can be gained from Mrs Jo Tucker, founder member of C.I.M.D.A. (Canine Immune Mediated Disease Awareness) at jo@cimda.fsnet.co.uk or at 7, Osidge Lane, Southgate, London, N14 5JL.  My own experiences of the problem follow on after the notes with "Reggies Story", which is just an in-sight into how auto immune disease can show it's symptoms, and how it is possible to live happily with an affected dog.

What is meant by Auto Immune Mediated Disease?

The mammalian immune system is an incredibly complex system that protects against invasion by foreign bodies, for example bacteria and viruses.  In order to achieve this protection, the immune system must have some way of recognising when something is "foreign".  Often, the basis of identification will be a protein or proteins that form part of the foreign body, perhaps a protein on the surface of a bacterium or in the viral coat.  In order for the immune system's discrimination to be absolute it must be able to recognise all of the foreign proteins whilst ignoring the tens of thousands of proteins that actually form the fabric of the mammal.  This problem is often described as being able to distinguish between self-proteins, that is those that form the normal mammalian make-up, from non-self proteins, thoses that are part of a foreign body that need to be recognised and destroyed.

During the development of the embryo it is probable that the immune system learns what is self and learns not to react to self-proteins.  this means that the immune system that operates after birth is geared to distinguish self from non-self and only mount an immune response to non-self that will, hopefully, result in the destruction of the foreign body carrying the non-self proteins.  Auto immune mediated diseases result from a breakdown in the immune system's discrimination such that it actually recognises certain self proteins as foreign and initiates the pathways that will lead to their destruction.  Depending on the extent of destruction of these self-components, various consequences will ensue.  Auto immune mediated diseases occur when the destruction induced by the immune response to these self-proteins removes an important physiological function.  For example, one form of auto immune disease, immune mediated haemolytic anaemia (Reg's first problem) is the result of the recognition of a normal protein present on the surface of a red cell as foreign, non-self, and the resultant destruction of red blood cells by the immune system causes severe anaemia.

Auto immune mediated disease is essentailly an umbrella term to describe a number of different diseases that result from the immune mediated destruction of an important physiological function.  Some examples in the dog are:

Addison's Disease (Hypoadrenocorticism) is most often caused by the auto-immune destruction of the adrenal gland. Clinical signs will only occur when over 80% of the gland has been destroyed.

Hypothyroidism is mechanically similar to Addison's disease, but this time the immune system attacks the thyroid gland.

Immune Mediated Haemolytic Anaemia (IMHA) is where the immune system attacks and kills the red blood cells.

Immune Mediated Thrombocytopenia (IMTP) is caused when there is an auto immune destruction of the blood platelets or the stem cells that give rise to blood platelets, which are the essential ingredient in the blood clotting process.

Immune Mediated skin diseases such as Pemphigus folliaceus, P. vulgaris, P. erythematosus & P. vegetans occur as a result of formation of auto-antibodies against certain skin epidermis molecules.

Immune Mediated Polyarthritis appear in erosive form (e.g. Rheumatoid arthritis) or non-erosive form.

Systemic Lupus Erythamatosis (SLE) a multi systemic version that can affect many parts and systems of the body.

Myasthenia Gravis can be caused by a formation of antibodies to the neurotransmitter receptors, although it can also be caused by a congenital deficiency in these receptors.

Are these diseases thought to be inherited?

Pedigree analysis certainly suggests that auto immune diseases do occur more frequently in certain lines and this is one of the hallmarks of an inherited disease.  However, the research to date is far from complete.  Some in depth studies have been performed in certain breeds.  for example, analysis of Bearded Collie pedigrees in America suggests that auto immune disease could be inherited as a simple autosomal recessive condition, although for this interpretation to be valid the analysis assumed that there was incomplete penetrance, i.e. some genetically affected dogs never actually showed clinical signs.  Other analyses of pedigrees in other breeds suggest a more complex pattern of inheritance, for example in the Standard Poodle the mode of inheritance of Addison's disease appears to be polygenic, but with a major predisposing gene in the affected population.

So, the research is still not advanced enough to give precise modes of inheritance, but what is clear is that auto immune mediated disease will have an inherited component to it.  Unfortunately, it is not as simple as that because the research also shows strong involvement of environmental factors.  A fair summary is that dogs inherit a genetic predisposition for auto immune mediated disease, and that the mode of inheritance may well vary from breed to breed, but that for full clinical expression there needs to be some kind of environmental cue or trigger.

If there is doubt about the precise mode of inheritance of the genetic predisposition, there is even more doubt and debate about the so-called environmental trigger factors. Many auto immune diseases occur in "seasonal trends" and natural infection and vaccine-induced exposure to antigens may also cause a trigger.  One thing that can be said from recent research is that the "health" of the immune system in general seems to be a critical factor.  Anything that places stress on the system, for example an already ill dog, could act as a trigger for the clinical expression of an auto immune disease in a genetically predisposed dog.  Age and sex factors also have to be considered.  Auto immune disease is most common in young to middle-aged adults, although some variants do not show until the later years.  Some appear to be more common in females and hormaonal influences may also affect the onset of the disease. (IMHA is reported to occur in females after their season and after whelping.)

Implications of auto immune disease for dog breeding

Unfortunately, we are still some way from a thorough understanding of the mode of inheritance of these problems and the possible environmental triggers that are significant.  The good news is that there is research going on and progress is being made, but it is fair to say that we are still some way off getting definitive answers and identifying specific genes that might be involved.  In the meantime, breeders might have to cope with the problem using whatever information is available.  I think most people would agree that breeding from an affected animal is not desirable.  However, even this is not that straightforward because some of these conditions are late onset occurring after a dog has been bred from.

The greater problem is how one deals with relatives of affected dogs.  As with many inherited conditions, breeders don't have the best tools at the moment to address the problem through informed, selective breeding, which means that whatever is done has to be a compromise between limiting the spread of the problem to future generations whilst trying to ensue the production of future generations that display good breed temperament and type.  As is always the case, individual breeders will have to approach the problem and make their own decisions but there are certainly things that they need to consider very carefully.  Should breeders really repeat matings where it is known that one or more affected dogs are present in previous litters?  It is up to the individual breeder to make that decision and live with the consequences. Would it be wise to  to line breed to dogs that are known to have produced affected offspring?  In these circumstances, line breeding will certainly increase the frequency of the genes responsible for the genetic predisposition and thus will likely result in the increase of auto immune diseases in future generations.  If breeders do decide to breed from close relatives of dogs that are affected with an auto immune disease, as well they might, then they have to research potential mates and their genetic background closely to avoid the risk of increasing the frequency of disease in future generations

REGGIE'S STORY

Crufts 2001 was the one which got postponed due to the foot and mouth outbreak.  It took place in May and I was delighted to have Reg there for the second time.  He was just approaching 4 years of age and was looking really well, fit and healthy.  The judge must have thought so too as he was awarded 3rd in Post Graduate and 3rd in Mid Limit.  I was absolutely thrilled with these placings, as I'd never have dreamt that he would have got anything.  A couple of weeks later, just after his birthday, he went a bit off-colour.  Just a bit sickly and off his food, but nothing out of the ordinary.  However, after several days there was no improvement, so I popped him off to the vet.  His temperature was a bit high, so we assumed it was a bit of a tummy bug and he was prescribed some antibiotics.  Reg didn't get any better, in fact, he just got worse.  Over time, his weight and condition began to decline.  I could not tempt him with any sort of food, and believe me, I tried everything.  I had noticed that his wee and poo were a strange orangey colour, but assumed that this was something to do with the antibiotics. 

Early one Friday morning, I noticed that his gums, and in particular, his tongue had a horrible grey tinge to them.  This is when I really began to panic, and rushed him straight to the vet.  He was given a steroid jab, but it wasn't until the Monday that they decided to do blood tests.  This showed a dangerously low red blood cell count, and a second test called a Coombes Test was carried out which confirmed Immune Mediated Haemolytic Anaemia.  It was straight on to a high dose of prednisolone (about 30mg), which is an immunosuppressive steroid.  The idea being that you destroy the body's immune system so it stops attacking itself. The orangey discharge in his wee and poo was the body excreting the destroyed red cells.  The outlook was not great and I prepared myself for the worse.  Reggie, however, had different ideas.  He began to pick up and started taking an interest in the roast chicken I was offering.  The Prednisolone proved to be a wonder drug.  Each week, the red cell count would improve, and we gradually began to lower the steroid dose.  We also introduced another drug, Azathioprine, which is another immunosuppressive, but not a steroid.  The side affects are not so bad, but it is not as aggressive as the Prednisolone, so is not used in the initial treatment stages.   Left - Reggie when he first began to get poorly

By September, his blood counts were normal again, and we had weaned him off all of his drugs.  I thought things were great, and I even got him back in the show ring where he amazed me by gaining his Kennel Club Stud Book number.  We went through Christmas and the New Year and I kept taking him for regular blood tests and checked the colour of his gums daily to keep an eye on things.  The figures fluctuated a tiny bit here and there and his platelet levels seemed to drop slightly, but never to the point where it was deemed a problem. I had taken an interest in Immune Mediated problems and tried to do my "homework".  I also attended a seminar which was held in Coventry and hosted by CIMDA (Canine Immune Mediated Disease Awareness).  June 2002, Reg had his 5th birthday.  I took him for one of his regular blood tests and had to wait the usual 24 hours for the results.  For some reason that evening, I decided to do an extra check of his gums and I noticed tiny "pin-prick" blood spots all over them.  I rolled him over to discover areas of bruising around his abdomen.  I knew that these were the tale-tell signs of Thrombocytopenia, and phoned the vet immediately.  She advised me to give him a huge dose of steroids, (of which I still had some in the house for such an emergency) and then to bring him in the next morning.  I knew that a relapse case would often not respond as well to drug therapy.  The blood test results confirmed dangerously low platelet counts and he was to continue on a massive 60mg of Prednisolone a day.

Again, we were so lucky.  Reg responded to the aggressive treatment and we got him back on the straight and narrow.  We introduced Azathioprine once more and gradually managed to lower the steroid dose.  Over a period of about 10 months, we reduced the dose to 5mg of Prednisolone every three days.  This is the maintenance dose on which he has been ever since, and I have no intention of ever trying to wean him off completely again.  I know that the chances of him coming back from yet another relapse are too slim to risk it.

I am so very proud of Reggie.  He has proved to be a real fighter and such a brave soldier throughout.  He endures his regular blood tests without so much as a grumble.  He even coped well when fate dished out yet another blow.  In April 2003, he broke a bone in his ankle.  I think it may well have been caused by the long-term use of steroids, although my vet would not confirm a connection between this and weak bones.  After that healed successfully, he damaged several tendons in his other back leg.  This took much longer to strengthen and heal, although it enabled him to attend the South West Whippet fun-day fancy dress contest as Long John Silver, complete with "wooden" leg and parrot!  And the final straw was when, completely out-of-the-blue, a Dalmatian attacked both he and Archie.  They sustained nasty injuries and I was concerned that the stress may trigger another relapse, but once again, Reg was OK.   Right - Reggie dressed as Long John Silver, complete with leg cast !

I know how lucky I am to still have him with me.  Many dogs do not survive auto-immune problems, but I take nothing for granted.  I treasure every moment I have with him.  He's back in the ring and competing very successfully in the Veteran classes.  I like to show him off as proof that it can be done, and as long as his health is OK, he will be at Crufts 2005.  There has been much heartache and an awful lot of money spent, but he is thoroughly worth it.  I often joke that my vet could open a new wing of their surgery with the profits they have made from Reg's misfortunes - as long as they name it after him!  And no, he has no insurance!!!

I have never let him be used at stud, because we do not fully understand how these problems could be passed on genetically.  I would have dearly loved to have one or several of his offspring, but that would have been selfish on my part.

I hope this page has proved of some interest to those who have taken the time to read through it.  Throughout this ordeal, there has been one person who has been a real support and source of useful information.  Her name is Jo Tucker and she is an angel in disguise.  She formed CIMDA and has been responsible for initiating so much of the research into Immune Mediated disease in dogs. 

Footnote It is with great delight that I can add a most amazing achievement to the above story.  Reg competed at Crufts 2006 and under breed specialist, Miss Lucinda Aldrich-Blake, won first prize in the Veteran Dog class.  A great thrill for anybody, but the icing on the cake for me, just proving that auto immune disease does not have to mean the end !
Photos courtesy of Miss D McGrath (above) and "I Did That" (right)