This Issue Vaccines, immune system, autoimmune, sensory integration Next Issue Cytokines and hopefully news on the new Alzheimer's vaccine.

A reader requested good web sites for information on DS. I spent an hour looking around a few different search engines but didn't find anything I would recommend. I am asking readers to submit their favorite websites to me so that I can make a list in a future edition.
Thanks.

Sensory Integration
     Some parents swear by it. Some agencies charge big bucks for it. Generally, the studies do not show big improvements using SI. One study measured 9 areas in learning disabled kids getting SI versus those without. The SI group had gains in motor functions, but not the other areas like visual perception or language. Other studies found that the teachers were showing the children other skills during SI look symbolic play, and those skills are important.
     Just because there is no proof does not mean it would work for a specific child. Also, for some kids motor improvement would be wonderful.
     Humphries, T et al (1992) A comparison of the effectiveness of sensory integrative therapy and perceptual motor training in treating children with learning disabilities. J-Dev-Behav-Pediatr. 13(1). 31-40
     Cross, L and Coster, W (1997) Symbolic play language during sensory integration. Amer-J-Occup-Ther. 51(10) 808-14.

Immunology Basics
     There are many parts to the immune system. T cells are made in the thymus and are the real brains of the immune response. T cells are mainly involved in fighting viral infections because they can recognize intruders that have gone into the cell like viruses, but they are also involved in bacterial infections. T cells are divided into CD8 (cytotoxic), CD4 (helper), T suppressor and inflammatory cells.
     B cells are made in bone marrow and when "activated" by other cells or cytokines can multiply into IgG, IgM, etc. B cells mainly fight bacterial infections but are also involved in viral.
     Both the B and the T cell are "tested" before they are released into circulation. The body wants to make sure that they recognize foreign intruders but not self. In a working system, each is exposed to representative parts of their body in the thymus or marrow, and if the immune cell acts inappropriately, it is destroyed. Those that respond appropriately are released into circulation.
     The tricky part of this is the MHC. MHC's are receptor-like units on cells. Most cells have MHC I and only some have MHC II on them. They are involved in the testing of T cells before release, and they present foreign intruders that have gotten in the cell to the rest of the immune system. The MHC is part of what is matched in transplants. Certain MHC variations have been implicated in autoimmune diseases such as Type I Diabetes.
     There are many other players including neutrophils, macrophage, natural killer cells and the complement system that all interact to get a good immune response. In the next issues, I will discuss cytokines which are the chemical signals of the immune system. Some are located on chromosome 21. When the immune system is exposed to something foreign, it remembers a portion of the intruder (usually an amino acid sequence) called an epitope. Once it sees a foreign epitope, the immune system responds then subsides again, but some of the antibodies are kept in "memory" in case it sees it again. If it does see it again, it can mount a faster and stronger response.
     What is amazing is that the T and B cells are premade with millions of combinations of receptors that should be able to "fit" into the epitope of any intruder. It would be like carrying a key ring with millions of keys with the assumption that one could open any lock. The trick is to not have a key to your own house.

Autoimmune Diseases
     In an autoimmune disease, there are a few scenarios that can occur. One is that a part of the body that is normally restricted from exposure to the immune system is exposed. An example is after a vasectomy, the sperm that used to be hidden are now released into the male's system. The body hasn't seen them before, the and thinks of them as foreign and starts to make antibodies against them.
     Another scenario is that the marrow or the thymus may release immature or defective cells out into the body. They may think of self as foreign and attack because they were not properly screened. This could be a real problem with those with DS because they have lousy thymuses and do release immature t cells.
     Another option (but less understood) is the one when a virus stimulates an autoimmune disease. There seems to be a connection in some autoimmune diseases and certain MHC structures. It is as if the right combination of an MHC and a certain virus at the right time will get you to an autoimmune disease. That is why diseases like diabetes I will run in families; genetics determine individual's MHC sequences. So genetics gives you the risk and life gives you the exposure.
     That certain MHC will present a portion of a virus (the epitope), but that epitope can have the same amino acid sequence as a body part. Now the body gets rid of the virus, but in the immune memory is not only the viral sequence but a self sequence as well. Did the MHC present the wrong sequence to the immune system? Did it stimulate the wrong cytokines? Did it allow the immune system to tightly bind to itself and the epitope, causing an immune reaction? According to my teachers, it is not all worked out yet how MHC are involved in autoimmune, but it seems clear that they are.

Autoimmune and DS
     So what does all this information about immunity and autoimmunity have to do with my kid? Plenty. Between their immature t cells and the cytokines that are located on the 21st chromosome, these kids are prone to autoimmune disease. This is just beginning to be studied.
     Let's look at what these kids are prone to developing. My favorite is autism. The only real theory being thrown around in the journals these last few years is that it is autoimmune. Those with autism seem to have antibodies to their serotonin receptors, and neurofibrils in the brain. They sometimes have slightly higher antibodies counts (aka titers) to measles and sometimes other illnesses. What is interesting is of those that have high titers to measles, 90% of them also have antibodies to their own basic myelin protein, and 73% to neuron-axon filament protein. Another piece of evidence is those with autism seem to have similar MHC sequences. 46% of children with autism shares one sequence, and 32% another. That is compares to 7.5% and 10.1 % of the normal population used as controls.
     Leukemia is another risk in DS. Recently, there is very new and unproven evidence from many studies that some forms of leukemias maybe autoimmune. One epidemiology study found that the risk of getting Common ALL leukemia increased with having DS, exposure to organics, family history of bone/joint disease and MMR vaccinations.
     The risk of getting Null-Cell ALL was increased with family history of congenital heart disorders, measles and parental exposure to solvents or metals. Some of those links (MMR, measles and family history of bone disease) point to autoimmune problems. This may or may nor be a cause and effect issue.
     Then there is the hypothyroidism that many people with DS have. While it has been known for awhile that one form of hyperthyroidism, Graves, is autoimmune, the research pointing to the same cause for hypothyroidism in DS is very new. MHC genotypes in those with DS were looked at, comparing ones who had hypothyroid to those without. Those with the hypothyroid problem frequently share similar MHC II sequences, perhaps indicating autoimmune.
     Then there is our buddy disease Alzheimer's. The same group of researchers looked to see if there was a connection between AD family members and hypothyroid. 41.4% of familial AD family members had autoimmune thyroid disease.

Vaccines
     Vaccines work similarly to an exposure to a real viral or bacterial infection. The difference is the vaccine is tampered with so that it can not give the full disease. It should, however, give the body a look at the epitope so that the immune system remembers that disease. Some are "live viruses" that have been injured or "attenuated" so that they do not cause the disease. Some are dead vaccines where the bug has been killed. Some are part of the toxin the bug releases
     While there has been no real proof that vaccines can cause autoimmune diseases, certainly there is potential, especially for those vaccines that are live ones such as measles. The controversy regarding the MMR (a live vaccine) and autism has been argued for years. While statistically, there may be no increased risk, many parents can tell you their child changed after the vaccine. Also, no one has looked at the MMR in DS to see how these kids react. (I have heard 2 different parent reports of leukemia developing shortly after the MMR in their children with DS.) I recently had Jen's titer to the MMR series measured. Her measles titer was abnormally high. Does that mean the MMR caused her autism? No. But considering the timing of when I noticed her behavior changed was 2 days after her MMR, it means it makes it more possible.

Vaccines in DS
     Even though the MMR has not been looked at (or diptheria or chicken pox or polio) in DS, the newer hepatitis B vaccines has been looked at by quite a few researchers.
     While preschool children studies had nearly 100% successful seroconversion (antibodies were produced), adults with DS do not have the same success rate. It seems that once the person with DS hits the age 20, the immune response will probably not be protective. One study found that those over 20 had a 12.5% seroconversion rate. There were other studies that found similar success rates in the young, and poor success rates in those with DS who are adults.
     The only other vaccine studies was the whooping cough (aka pertussis) vaccine.
     This study found that none of the 24 kids with DS had any adverse reaction to pertussis vaccine. And even though their titers were somewhat lower than the normal controls, they had high enough levels to offer protection.
     One can hope that someone will eventually study what vaccines should be given to kids with DS. Live virus vaccines are contraindicated in those who are immune compromised, and DS causes immune problems. I am not suggesting that one not vaccinate. However, being a bit "slower" to get the MMR and breaking the MMR or other grous of shots into single vaccines may be a good idea. In addition, one should not give vaccines if the child is sick.

     Beckley, J et al. (1994) Epidemiological characteristics of childhood acute lymphocytic leukemia. Leukemia. 8(5). 856-64.
     Ewins, D. et al (1991) Association between autoimmune thyroid disease and familial Alzheimer's Disease. Clin-Endo. 35(1). 93-6.
     Garcia, O et al (1990). Hepatitis B at an open institution for the mentally retarded. Enferm-Infec-Microbiol-Clin. 8(3). 148-52
     Li-Volti, S. et al (1996) Safety and effectiveness of an acellular pertussis vaccine in subjects with Down's syndrome. Child's-Nerv-Syst. 12(2). 100-2
     Nicholson, L. et al (1994) Suseptibility to autoimmune thyroiditis in Down's syndrome is associated with the major histocompatability class II DQA 0301 allele.. Clin-Endocrinol-Oxf. 41(3):381-3.
     Singh, K. et al (1997) Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr-Neurol. 17(1), 88-90.
     Singh, K. et al (1998) Serological association of measles virus and HPV6 with brain autoantibodies in autism. Clin-Immunol-Immunopathol. 89(1) 105-8.
     Warren, R. et al (1996) Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J-Neuroimmunol. 67(2): 97-102

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