© Rita Serda/FEI ImageImmune cell communication, dendritic cells stimulated with adjuvant silicon microparticles interact with T cells. Taken using an FEI microscope, magnification 16,000x.
Dr. Singh, how did your interest in immune response and the nervous system develop?
From the beginning, my career has been devoted to the study of the nervous system. Initially, I was focusing on neurochemistry - the biochemistry of the nervous system. I was interested in specific proteins and the neuronal pathways that are found in the brain; proteins play important roles in the cellular signaling that takes place between different neurons and other cells in the brain. I also began studying immunology and was fascinated by the fact that there are chemical messengers in immune system function as well.
Then, about 20 years ago, I was struck by an article I read on the mind-body relationship that proposed a biological basis for this connection. I began to pay attention to how neurotransmitters and neuropeptides interact with other body organs, and I became interested specifically in the interaction between the nervous system and the immune system. Some neuropeptides and neurotransmitters have a clear influence on the immune response. The fact that central nervous system diseases such as multiple sclerosis (MS) had been heavily investigated as an immune disorder heightened my interest. I decided to focus on the immunology of the nervous system in health and in disease. This is a very important component of the mind-body relationship.
As you know, medical history shows us that an understanding of the mind-body relationship existed in ancient times. Old literature, in fact, documents that some of this understanding came from my homeland of India. All these factors have shaped my current area of research-which is the autoimmune response in autism.
You specify autism. Will the information you share with us also be relevant to our readers who are interested in Tourette syndrome (TS), and attention deficit disorder / hyperactivity?
Yes. I would say there is a connection of immune function with just about all nervous system disorders. To that end, I recently completed a review article that may be of some interest: "Immunotherapy for Brain Diseases and Mental Illnesses" (V. K. Singh, Progress in Drug Research, vol. 48, pp 129-146, 1997; Monograph Series).
I am convinced that the immune system is important not just for the nervous system, but for basically any disease in the body. To give an example, until recently we did not know that cardiac diseases involved an immune response, and now there is good evidence that supports the role of an inflammatory response in heart disease, which may be triggered by a pathogen such as a virus or bacterium. And inflammation is nothing but an abnormal immune response. I'm suggesting that the immune system plays a central role in the normal health of our body, and the nervous system is vastly impacted by the immune response.
I have a list of nervous system diseases where either brief reports or extensive research connects them to immune pathogenesis and treatment. Included in the list are conditions such as autism, obsessive compulsive disorder (OCD), MS, Alzheimer's disease, schizophrenia, major depression, etc. Ten to 15 years ago, I was trying to communicate my theory of the role of the immune system in Alzheimer's disease. People laughed at me; the medical community's response was "What? The immune system? No way!" As research has progressed, it has become quite clear that immune factors contribute to Alzheimer's disease - this has resulted both from my own research as well as the research of others.
As our knowledge increases we begin to understand more about the nervous system, and I think the immune system has taken on a central role. Preliminary reports suggest that immune abnormalities are linked to OCD. Strep bacteria are being studied for OCD [obsessive-compulsive disorder] and certain cases of Tourette syndrome, though a great deal remains to be investigated. Recent and current research focuses on autism and an autoimmunity connection; this is also in the early stages.
Could you summarize the mechanism involved in immune function as it relates to the nervous system?
The main component in nervous system disease is really "autoimmunity," which is a misguided immune response to the body's own organs. If you examine central nervous system diseases closely, you will find that for almost each condition there is a suspicion of autoimmune process involvement. In some diseases, such as MS, there is a large body of research to support this, and in others it has not been as clearly established as it needs to be - like for Alzheimer's and autism-but and I think this will happen in the future.
The underlying mechanism is likely to involve molecular and cellular interactions. Cytokines, autoantibodies, and other immune factors culminate the disease process. The research is quite intricate and extensive, but more is needed. We've learned a lot from the research on MS, and I think the knowledge from that will be applied to autism and other nervous system disorders. Similarly, with Alzheimer's disease, there is a very important role for cytokines and lymphocytes. The basic mechanism appears to be autoimmunity, which is subject to therapy.
You referred previously to research on strep and OCD. Our organization has received calls from families who tell us that their child's symptoms were fairly mild until there was a viral infection which seemed to precipitate a major increase in obsessive compulsive behaviors, or perhaps a marked increase in tics. A parent recently reported that his daughter, who had a history of mild tics and OCD, developed severe phobias following a bout with a sore throat. Could these reports point in the same direction?
Yes, they could. Let's start with OCD and the work of Dr. Susan Swedo's group regarding strep infection. They were actually giving an immune therapy known as plasmapheresis when they observed an association between group A streptococcus infection and OCD. While providing therapy to address the infection, it was found that the patient's OCD symptoms reduced by plasmapheresis. It was also learned that there was a decrease in antineuronal antibody titers in response to therapy. So with plasmapheresis they were able to reduce the antibody titers as well as see behavioral benefits to the patients. Subsequent studies with intravenous immunoglobulin treatment (IVIG) have also shown positive responses, to varying degrees. Research in that area has to progress further-no one really yet understands what these antineuronal antibodies are. It is suspected that they might involve an immune response to certain hormones that are found in the brain.
What are antineuronal antibody titers? And what does a reduction imply?
An antibody titer is the level of a given antibody; that is, how much of that antibody is present, most commonly in the serum. An antineuronal antibody is an antibody that specifically reacts with nerve cells known as neurons, and/or processes-axons, dendrites, or nerve-endings. So, when a treatment results in a lowered antibody titer, it implies that immune factors such as autoimmunity somehow cause the disease that was being treated.
How does your work with antibodies relate to the role of serotonin in these conditions?
Again, there needs to be more research done on this topic. But I can tell you that I was involved in a pilot study of OCD patients with a psychiatrist, Dr. Gregory Hanna, here at the University of Michigan. I had proposed that patients with OCD may have antibodies to brain serotonin receptors. I suggested this because many OCD patients respond to Prozac, and that treatment involves serotonin re-uptake mechanisms.
The preliminary findings were presented at the American Academy of Child and Adolescent Psychiatry annual meeting in 1996. We found evidence of brain serotonin receptor antibodies in OCD patients who were not on any therapy. Those who were on serotonin re-uptake inhibitor therapy did not have these autoantibodies. In other words, the therapy was actually altering the autoimmune response which resulted in improved symptoms. We did not have funds to research it further, but if someone would like to explore this area I would be happy to collaborate with them, or I may work on this topic if I can generate some grant funding.
What therapeutic approaches related to autoimmune problems are being used for central nervous system disorders?
Therapies for central nervous system disorders have primarily been designed with the goal of correcting the problem of neurotransmitters. This is done through pharmacological interventions, and I consider it a very important approach. It does work in some situations. But when we think about autoimmunity involvement I think we have to change the strategy. The strategy should be based on the nature of the immune problem, and then we should administer an immune response therapy that would be specific to the patient's needs.
There are two things that should be considered. We should not only administer the therapy, but we should also monitor the patient to see if there is a normalization of the immune response, otherwise it is pointless to continue to give immune therapy. In the first instance, you must do proper evaluations in order to identify what is wrong before you select and administer immune therapy. Therapy will depend on the nature of the immune problem in each patient. Then the patient should be monitored for the outcome of the therapy.
How do you identify the nature of the immune problem?
The immunologic evaluation of patients requires a battery of tests or an immune panel. The tests should be properly requested and, more important, the results must be properly interpreted. The data interpretation of immune tests is not an easy task; it requires extensive knowledge and experience of clinical immunology and immunodiagnostics. Some of these tests are: serum immunoglobulin and immunoglobulin subclasses, blood lymphocyte count, and different lymphocytes such as T- or B-lymphocytes, NK cells, etc. And nowadays there are some research-oriented tools, and special cytokines have been identified as mediators of the immune process. They should be examined as well. Two of these cytokines are interferon-gamma and interleukin-12. Interleukin- 12, especially, has been regarded by many immunologists as the initiator in the early stages of the autoimmune mechanism; it would be the inducer, if you like, of early events that cause autism.
Also, autoantibodies need to be identified, and they should be organ-specific. For example, if there is nervous system involvement then we should find brain autoantibodies. Furthermore, the specificity might be based on what part of the brain is involved - is it the neurons? Is it the glial cells that are involved? Is it the myelin-producing cells that are affected? Those are additional questions that can be addressed based on the analysis of the brain autoantibodies. Then the important question is: what triggers that misguided autoimmune response? Is it an environmental factor such as a virus, bacterium, or pollutant? That needs to be determined, and we can accomplish this through blood tests for some of the agents.
We know that with OCD there is a connection with the group A streptococcal infection, whereas with other autoimmune diseases a virus may be suspected. But the nature of these agents remains elusive. In autism, we recently found that the process of autoimmunity seems to be related to a measles virus infection although other viruses such as human herpes virus-6 (HHV-6) may also be linked. This finding was based on virus serology and brain autoantibodies. It is very early to say if these are the triggering agents. But new knowledge within the last year or so in this area is providing new clues to the pathophysiology of autism. For example, the work done in my own laboratory and that of Dr. Andrew Wakefield in London has pointed toward a measles connection. But let me emphasize that we are far from proving this.
What response does the medical community have to your work?
There's been a great response. I think the work is being embraced gradually by researchers and physicians in the field. The trick is to convey the message. Physicians don't have the time to sit down and review new findings. But my experience has been that once they attend a conference on the topic and listen to my presentation that has actual hardcore science behind it, then they get excited. The same thing happens with researchers. You see a nice dialogue begin. And, at the end, both groups are receptive to it and offer me nothing short of compliments.
What are the current autoimmune therapies? Do they require single or repetitive administration?
Let me touch on the various autoimmune treatments being used for autism. I think they also have implications for other neuropsychiatric disorders such as OCD, and perhaps TS, someday. What seems to be coming about is the use of three or four treatments. At least two seem particularly promising to me. One is IVIG-immunoglobulin therapy. It is expensive and requires treatment on a regular basis, perhaps every 6 or 8 months. It is done by infusion, intravenously. IVIG was originally designed for patients with viral infections and severe combined immune deficiencies. The purpose of this treatment is to reconstitute the immune response. It is generally done by bringing immunoglobulin levels to normal status. There are other mechanisms involved but they are not well understood as far as how the treatment helps the patients with autism.
IVIG can be administered at a hospital or a medical center. Even though it is a very safe procedure, there is always a rare chance of adverse reactions especially after long-term use. This was noted in a couple of patients with the neurological disorder Guillain-Barre Syndrome, and there was one case report where after ten years of treatment the patient in his late 40s had an acute reaction. Aside from that, it is a reasonably safe treatment.
For autistic children, IVIG was first used by Dr. Sudhir Gupta, at the University of California, Irvine, and others are doing it now. Some children with autism have experienced a significant reduction of symptoms; some have had moderate or mild improvement, and still others have shown no benefit at all. The good thing is that a significant number showed clinical improvement. One more comment is that in a double-blind fashion we have found, at least in a handful of patients that we studied, that the IVIG therapy not only improved behavior of the children, but it also produced change in the antibody levels. We have found that after the IVIG therapy the antibody titers to myelin basic protein and neurofilament protein actually went down below the detection limit. This exciting finding documents the therapeutic result of IVIG and should be explored further.
Before we discuss other treatments, is IVIG commonly administered or would a parent have a hard time finding someone to do it?
It is not commonly administered. Remember, it is an experimental treatment. Also, not every physician who deals with autistic children is familiar with this research. Physicians dealing with autism are often psychiatrists or neurologists, and they may not get involved in the autoimmune function with autism unless they have been to a conference on the topic or decided to review the literature. The more we talk about these issues the more doctors will hear about it, and it will become a good treatment possibility.
There are two other approaches that I think are important, but I must emphasize that clinical treatment is not well established. One is the use of immune suppressor anti-inflammatory agents, namely steroids such as ACTH or prednisone; this is a conventional approach to treating autoimmunity. I have heard firsthand from a number of parents of autistic children that their child was given steroids soon after the diagnosis, and symptoms improved. The treatment was later discontinued because they were concerned there could be toxicity on a long-term basis, and I understand that. But if an autoimmune factor for autism is determined through research, then there may be some room for treating children with steroids; there was one study from Europe that supported this approach (*see note). Again, the idea is to first identify what is wrong before pursuing the treatment.
The other treatment, which readers must understand is based on anecdotal reports, is Sphingolin treatment. Sphingolin is a trade name for a bovine brain myelin preparation. This commercial product is sold as a nutritional supplement and can be used to correct the immune response against the myelin basic protein. So, if the child is found to have antibodies to myelin basic protein or even neurofilaments, which are rich in myelin components, then you may think about giving this treatment. Many of those who have done so are noticing very positive responses. I have parents who insist they would not consider taking their autistic child off this treatment; I have a folder full of parent correspondence on this, but studies are yet to be done. The important thing is to first check whether the child has antibodies to myelin basic protein or neurofilament. If there are no antibodies, don't do this treatment.
We do not yet know how Sphingolin works, but the mechanism of oral tolerance induction might be involved. While the exact mechanism of oral tolerance is not known, it is an exciting topic of research for hard-core immunologists today. Let's say that we have a situation where the autoimmune response to myelin is being defined reasonably well in autistic children. When you feed autoantigens-in this case the Sphingolin-to these children, it can result in remarkable recovery. This is anecdotal but recorded not only by school psychologists, teachers, and parents, but also by physicians who are involved. This is very exciting. Dosage should not be high; it should be quite low to have this benefit to the patient. I'm not a physician and don't prescribe treatment, so I am not advising your readers on a specific approach. But from a research standpoint, in my opinion, the adult dose is generally two capsules per day, hence the child would take only one or one-half. We are trying to raise funds for a clinical trial of this.
What is the plasmapheresis technique that you mentioned near the beginning of the interview when speaking of OCD?
This is an interesting modality. It was designed many years ago as a clearance mechanism. What happens is that pathogenic molecules such as viruses, or immune complexes, or autoantibodies circulate in the blood. The idea was to filter them out. This therapy has been used for patients receiving bone marrow transplants as well as for patients with autoimmune idiopathic thrombocytopenic purpura and those with severe infections. It also has a role for autoimmune problems, for example, with OCD as mentioned previously. To receive the therapy, a patient is connected to a cell separator and plasma is allowed to go through a filtration system much like in kidney dialysis. But let me make the point here that this procedure has not been investigated in autism. I have suggested this as one option that should be considered if all other immune problems exist.
I suggest that any of these treatments should be evaluated initially as a single approach only. I know some people are combining different treatments, but then the response may be paradoxical and it is difficult to explain what is going on.
We have printed information on ACN Latitudes from physicians and families on the allergic response in autism, Tourette syndrome, learning problems, and ADD / ADHD. This response includes food sensitivity, traditional environmental allergens, and chemical sensitivity. How does this concept fit with your model?
Allergies to foods are widely recognized in autistic children, and allergies are immune responses. Some of those are also related to an autoimmune phenomenon-at least new research is telling us that. Whether allergy to gluten or casein, as we often see in children with autism, is connected to autoimmunity - is it a consequence or the cause;' of it - we don't know. But when hearing from parents, one gets the impression that removal of these foods from the diet helped the child's general health improve more than it improved the actual autistic characteristics. When you try to overcome allergy to foods, you bring about a change in the digestive tract and that results in more normal health overall. But it has been my experience that this does not necessarily improve the behavior as much as if you administer autoimmune therapy such as IVIG therapy or Sphingolin treatment; these actually produce changes in behavioral characteristics. That's the main difference, and we are bringing about changes that we can explain biologically.
Speaking of gastrointestinal function, the use of secretin therapy, which has received considerable attention lately, is also worthy of additional research. In my opinion it is not directly connected to autoimmunity. However, based on our pilot study of nine children who received secretin administered by Dr. Jeff Bradstreet of Palm Bay, Florida, we found that about half the children showed changes in the antibody titer to brain proteins like myelin basic protein and neurofilaments; measles antibodies did not change. And what is really unique is that the serotonin levels chanted with the secretin therapy. Secretin increased the serotonin levels in some but not all of them, and as a group they had an increase of about 35%, which is quite remarkable. I believe secretin is working more through mechanisms involving the neurotransmitters than by affecting the autoimmune response. But if it did affect the autoimmune response, that would not surprise me, because we know that a lot of gastrointestinal peptides-and secretin is no exception to this-are known to influence and modify neuronal activities, meaning they influence the pathways of neurotransmitters and neuropeptides, and thereby affect the brain's function.
*Buitelaar, J. K. et al, "The use of adrenocorticotrophic hormone (4-9) analog ORG 2766 in autistic children: effects on the organization of behavior." Biological Psychiatry vol. 31, 1992, pp. 1119-1129.
Comment: There are many natural steps that can be taken to calm an overactive immune system: