http://libnt2.lib.tcu.edu/staff/lruede/singhfeature.html

 

 

FEATURE ARTICLE


 

Autism, Autoimmunity and Immunotherapy: a Commentary by Vijendra K. Singh, Ph.D.
Department of Biology & Biotechnology Center, Utah State University, Logan
Scientific Board Member, Autism Autoimmunity Project

Autism is an early-onset biological disorder that causes severe deficits of higher mental functions, as well as behavioral manifestations. There is no single, clear-cut cause and no complete cure for autism. Causally speaking, immune factors, neuro-chemical factors, genetic susceptibility factors and environmental factors (such as microbial infections and chemical toxicity) have been implicated. I view autism as a very complex, multifactorial disorder. In this article, I will attempt to describe succinctly the role of autoimmune etiology and immune therapy for autism.

As a neuroimmunologist, I have been interested in the immunology of the nervous system, i.e., the immune basis and immune therapy for brain diseases and mental illnesses. I have studied autism as an autoimmune disorder for over fifteen years. As a result, I firmly believe that up to eighty percent (and possibly all) cases of autism are caused by an abnormal immune reaction, commonly known as autoimmunity. The autoimmune process in autism results from a complex interaction between the immune system and the nervous system. I recently postulated a "Neuroautoimmunity Model of Autism" which I discussed at two recent conferences: first, the Biomedical Treatments for Autism and PDD Conference held in Orlando, Florida (May, 1999); and second, the Neuro-Immune Dysfunction Syndromes (NIDS) Conference held in Bethesda, Maryland (June, 1999). Briefly, I hypothesized that an autoimmune reaction to brain structures, in particular the myelin sheath, plays a critical role in causing the neurological impairments of patients with autism. I suggested that an immune insult to developing myelin (after a natural infection or vaccination) causes "nicks" or small changes in the myelin sheath. These changes ultimately lead to life-long disturbances of higher mental functions such as learning, memory, communication, social interaction, etc.

I believe that autism can be treated successfully using some of the therapies proven effective in treating other autoimmune diseases. I am exploring specifically the role of autoimmune factors, (e.g., viruses, autoantibodies, T cells, and cytokines) because they serve as the prime targets of therapy with immune-modulating agents. I emphasize the need to focus on immunotherapies, and I urge doctors to examine autoimmunity as a novel target on which to focus in treating autistic patients. There is enormous potential for restoring brain function in autistic children and adults through immunology.

Autoimmune Etiology in Autism

A disease is commonly referred to as "autoimmune" when the etiology and pathogenesis is not well known or established. Autoimmunity is an abnormal immune reaction in which the immune system becomes primed to react against body organs, and the end result is autoimmune disease. Several factors contribute to the pathogenic mechanism of autoimmune diseases. These illnesses are commonly believed to be triggered by infectious agents; further, they are generally linked to genes that control immune responses. They cause immune abnormalities of T lymphocytes (one type of white blood cell); they induce the production of autoantibodies; they involve hormonal factors; and they generally show a gender preference. This is also the case with autism: several autoimmune factors have been identified in patients with autism, suggesting the pathogenetic role of autoimmunity in autism. While some of the key features are listed below, I will focus more on the current research relating to three topics: viral studies; autoimmune testing; and autoimmune therapy. Some generalities regarding the genetics and immunology of autism are below:

Viral Studies in Autism

Viruses have been linked to autism, but this relationship is far from fully explored. Certain viral infections can easily be acquired during fetal life, infancy or early childhood. They can enter the brain through the nasopharyngeal membranes or induce an autoimmune response against the brain, thereby altering the development of brain function. Since autism is an early-onset disorder, usually diagnosed before the age of 30 months, it was suggested that viruses might serve as teratogens (agents that cause developmental malfunctions) contributing to autism.

Earlier studies implicated congenital rubella virus (RV), simply because children with this infection also showed autistic behaviors. Moreover, several autistic children did not produce antibodies to rubella vaccine even after the repeated rubella immunization. Although the reason for this problem has never been investigated, I think this is due to a defect in T lymphocytes—these agents of immune response are not functioning properly in these children. In an unpublished pilot study, I found that the RV-induced lymphocyte proliferation response in autistic children was only one-fourth of the response in normal children, which clearly suggests a defect of T cell-mediated immunity (a defense mechanism that helps fight virus infections).

A few cases of autism have also been described among children with congenital cytomegalovirus (CMV). Interestingly, an autistic child with CMV responded favorably to treatment with transfer factor, but there was no follow-up to the study in which this was reported. A few years ago I and coworkers conducted a study of IgG antibodies to CMV; we found no statistical difference between autistic children and normal children (V. Singh, D. Schubert and R. Warren, 1992; unpublished data). Simply put, this means that CMV is probably not related to autism.

More recently, I conducted a study of measles virus (MV) and human herpesvirus-6 (HHV-6) in autism. This was done by two types of laboratory analysis: (a) virus antibody levels of MV and HHV-6; and (b) brain autoantibody titers in the same samples as those assayed for virus antibodies. This study showed two things in particular: first, that the virus antibody levels in the blood of autistic children were much higher when compared to normal children; and secondly, the elevated virus antibody levels were associated with the brain autoantibody titer. Interestingly, the viral antibody and brain autoantibody association was particularly true of MV antibody and MBP autoantibody (i.e., 90 percent of autistic children showed this association). This observation led me to hypothesize that a measles virus-induced autoimmune response is a causal factor in autism, whereas HHV-6 via co-infection may contribute to pathophysiology of the disorder. Although as yet unproven, I think it is an excellent working hypothesis to explain autism, and it may also help us understand why some children show autistic regression after the measles-mumps-rubella (MMR) immunization.

Testing for Autoimmunity in Autism

Recent advances have clearly shown that autoimmunity plays a key role in the pathogenesis of autism. Since the brain is the affected organ in autism, the autoimmune response will be directed against this organ. This response is commonly identified by certain autoimmune factors which I have identified in autistic children. The list includes brain-specific autoantibodies, viral antibodies, cytokine profile or immune activation markers, as well as antinuclear antibodies. Collectively, they are essential for identifying a brain-specific autoimmune response, which can afterward be treated with immune therapy. By performing blood tests we can determine if a patient shows autoimmunity to brain tissues, if he or she is a candidate for experimental immune therapy, and if the response to therapy is effective. Therefore, this type of immune evaluation is very important in helping children with autism.

Brain autoantibodies:  this test detects antibodies to two brain proteins, namely the myelin basic protein (MBP) and neuron-axon filament proteins (NAFP). The incidence of MBP antibody in the autistic population (70% positive) is over twenty times higher than that of the normal population (3% positive); hence, it serves as a primary marker of the autoimmune reaction in autism. In contrast, the incidence of NAFP antibody in autistic patients (55% positive) is only about twice that of normal controls (27% positive), making it a secondary marker of autoimmunity in autism. It is, however, recommended that the two markers be tested simultaneously.

Cytokine profile:  two immune activation markers or cytokines, namely interleukin-12 (IL-12) and interferon gamma (IFN-g), play key roles in the induction of autoimmune diseases, i.e., they initiate an autoimmune reaction. They are selectively elevated in autistic patients and should be measured as a sign of altered cellular autoimmunity—a function of Th-1 type white blood cells.

Virus serology:  this test measures levels of antibodies to measles (rubeola) virus (MV) and human herpes virus-6 (HHV-6). The antibody levels are elevated, which is a sign of a present infection, past infection, or reaction to measles-mumps-rubella (MMR) vaccine. The HHV-6 and measles viruses are etiologically-linked to autism because they are related to brain autoantibodies and demyelinating diseases.

Antinuclear antibodies:  this test assays for antinuclear antibodies (ANA). They are non-specific antibodies but are often present in patients with autoimmune diseases. Approximately one-third of autistic children tested have positive titers of ANA (V. Singh, 1992; unpublished data).

Immunotherapy in Autism

The aforementioned laboratory findings clearly point to an autoimmune pathogenic mechanism in autism. The idea that autism is an autoimmune disorder is further strengthened by the fact that autistic patients respond well to treatment with immune modulating drugs. Immune interventions can produce immune modulation—a state of suppression or stimulation. Depending on the nature of the immune abnormality, the goal of therapy should be to normalize or reconstitute the immune response instead of inducing immune suppression or stimulation. This will maintain a balance within the normal immune response, avoiding major fluctuations of overt immune activity which could be detrimental to the patient. Immune therapy should always be done in consultation with physicians. The following immune interventions can be used:

Steroid therapy:  steroids such as Prednisone and/or ACTH (adrenocorticotropin hormone) are commonly used as anti-inflammatory and/or immunosuppressive drugs for treating patients with autoimmune diseases, inflammatory diseases, etc. In autism, however, there is only one study that showed improvement of autistic-like symptoms in children when they were treated with an ACTH analogue. This result indicated that steroids are potentially useful in alleviating clinical symptoms of autism. Steroids are the first course of treatment for patients with autoimmune diseases and infantile spasm; however, their efficacy has not been evaluated in autism.

Intraveneous immunoglobulin (IVIG):  this type of treatment has been used to treat children with autism. Open-label trials of both low-dose and high-dose IVIG have shown that most but not all autistic children respond favorably to this treatment. My collaborators and I recently found that the high-dose IVIG was better than the low-dose IVIG (J. Bradstreet, V. Singh and J. El-Dahr, paper presented at the International Symposium on Autism, Netherlands, December 28-30, 1999). Clinically, children so treated have shown improvements in language, communication, social interaction and attention span. In a double-blind study, (V. Singh, 1997; unpublished data) the IVIG treatment was found to decrease brain autoantibody titers in five patients (they were positive pre-therapy but became virtually negative post-therapy) who also showed clinical improvement of autistic characteristics. In spite of the success of IVIG, this treatment is not for everyone. Before this treatment is administered, a proper immune evaluation is highly recommended to assess the nature of the immune problem.

Oral tolerance with autoantigens:  this treatment is a means of inducing immune suppression by feeding patients autoantigen. I have shown that the candidate autoantigen in autism appeared to be a myelin basic protein (MBP); this suggested that the MBP-containing myelin products can be used to treat autistic patients. Indeed, one such product known as Sphingolin has been used with success. Recently, the parents, school psychologists, and other professionals have anecdotally reported tremendous improvements of autistic symptoms in their children. These reports are undoubtedly quite encouraging and promising, but a well-designed clinical trial is warranted.

Plasmapheresis:  although it is not commonly recommended, this procedure is used for treating patients with infections, autoimmune diseases, immune complex diseases, etc. Because this method removes harmful substances (e.g., autoantibodies) from the blood, it is considered a viable immune therapy. The method has been used to treat certain brain disorders, for example Rasmussen’s encephalitis (RE) and obsessive-compulsive disorder (OCD), in which autoimmunity has been implicated as a basis of the disorder. Plasmapheresis produced positive responses in patients with these disorders, and the responses were much better with plasmapheresis when compared to the IVIG treatment. In each case, the benefit to the patient was associated with the lowering of the anti-neuronal antibody titers. Since autistic patients also have positive titers of brain autoantibodies, they should also respond to plasmapheresis. Although this treatment has long been suggested for use in autism (V. Singh, 1997), plasmapheresis has thus far not been tried in patients with this disorder.

Conclusion

The evidence is rapidly accumulating to suggest that autism is an autoimmune disorder. The autoimmune response is most likely directed against the brain myelin, perhaps secondary to a viral infection. Measles virus is a candidate but other possibilities remain to be explored. More importantly, the patients respond to treatment with immune therapies. Therefore, I conclude that autoimmunity offers strong prospects for drug discovery and therapy for autism. Naturally, it deserves prompt attention from all those who want to help people with autism.

Selected Reading

Singh, V. K., "Plasma Increase of Interleukin-12 and Interferon-gamma: Pathological Significance in Autism" (Journal of Neuroimmunology, vol. 66, pp. 143-145 [1996]).

Singh, V. K., "Immunotherapy for Brain Diseases and Mental Illnesses," (Progress in Drug Research, vol. 43, pp. 129-146 [1997]).

Singh, V. K., "Serological Association of Measles Virus and Human Herpesvirus-6 With Brain Autoantibodies in Autism" (Clinical Immunology and Immunopathology, vol. 89, pp. 105-108 [1998]).

Singh, V. K., "Autoimmunity and Neurologic Disorders" (Latitudes, vol. 4, pp. 5-11 [1999]).

Dr. Singh received his doctorate from the University of British Columbia, Vancouver, Canada. His post-doctoral fellowship was completed in neurochemistry and neuroimmunology. Spanning over twenty years' experience in neurobiology and immunology research, Dr. Singh studied brain diseases, particularly infantile autism and Alzheimer's disease. Having authored over a hundred scientific publications, he is both a pioneer and an international authority on autoimmunity in autism. Dr. Singh is a member of the American Association for the Advancement of Sciences, the American Association of Immunologists, and the New York Academy of Sciences. He is listed in American Men and Women in Science (United States, R. R. Bowker, publisher) and The International Who's Who of Intellectuals (Cambridge, England, International Biographical Centre).

For further information, please contact Dr. Vijendra Singh, Ph.D., at the Biotechnology Center, Department of Biology, Utah State University, 4700 Old Main Hill, Logan, UT 84322-4700 [E-mail: singhvk@biology.usu.edu].

Reprinted from AAPN, The Autism Autoimmunity Project Newsletter, vol. 1, number 2, December 1999.
 
 

Links

"Autoimmunity and Neurological Disorders," interview with V. K. Singh in Latitudes, newsletter of the Association for
Comprehensive NeuroTherapy, http://www.latitudes.org/index.html, vol. 4, no. 2, Spring 1999, by Sheila
Rogers:  http://lib.tcu.edu/www/staff/lruede/latitudes

"V. K. Singh:  Selected Research on Autism," http://www.gti.net/truegrit/ : Findings in Immunology

"Vijendra K. Singh, Ph.D.:  Selected Work on Alzheimer's Disease,"  (http://lib.tcu.edu/www/staff/lruede/alzheimers)
 
 

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