Last Updated:
Mar 19, 2000

Interferon and Down Syndrome

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Summary by Dr. Len Leshin, MD, FAAP

Go to List of Past Abstracts Interferon is a protein in the class of proteins called "cytokines." It's produced in various types of cells, and it's action in the body depends on which type of cell is making it. There are three types: alpha, beta and gamma-interferons.

To have an effect on a cell, the interferon molecule (like other proteins) must fit into a "receptor" on the surface of the cell, like a key fitting into a lock. With interferon, one receptor handles the alpha and beta versions, while a second receptor handles the gamma-interferon.

Send Me Email Back in the late 1970s, it was found that the 21st chromosome carried the gene for producing the alpha-beta receptors. This fit quite nicely with the observation a few years previously that fibroblasts (a cell of the connective tissue, which forms collagen) from people with DS had an increased sensitivity to the antiviral activity of fibroblast interferon. This makes sense if you think about a lot of keys trying to fit into a few locks; the more locks there are, the more keys you can use, and the bigger effect noted. The effects were also noted to include sensitivity to interferon's cell growth inhibition. One specific researcher, Dr. Leonard Maroun of Illinois, noted this fact and has been working on this topic for the last 20 years:
Interferon effect on ribosomal ribonucleic acid related to chromosome 21 ploidy.
Maroun LE
Biochem J 1979 Apr 1;179(1):221-5
Antiviral and cell-growth-inhibitory activities of human interferon were shown to be related to the activity of a gene or genes present on chromosome 21. The 18s rRNA is vital to cell growth; it is capable of a viral-mRNA-recognition function and it is coded for by genes a portion of which are present on chromosome 21. A previously reported ability of human interferon to affect rRNA metabolism is characterized by a decrease in the sucrose-gradient-peak ratio of radiolabelled 28S to 18S rRNA in extracts from the cytoplasm of interferon-treated human fibroblasts. In the present report, interferon dose-response curves are presented demonstrating a direct relationship between a decrease in this ratio and interferon concentrations in the media. By using this virus-independent cytoplasmic rRNA assay, eight human fibroblast lines, differing in chromosome 21 ploidy, were tested for sensitivity to human interferon. Two monosomy-21, two euploid-21 and four trisomy-21 cell lines were tested. The monosomy-21 cell populations were significantly less sensitive to interferon than the other six cell types tested. Of the cell lines tested, the most sensitive, by a wide margin, was a trisomy-21 line. Trisomy-21 cell monolayer sensitivity, however, varied widely within the range from normal to supersensitive. These observations suggest that interferon's ability to affect rRNA metabolism is related to the activity of a gene or genes present on chromosome 21.

Yes, that's a mouthful. The bottom line here is that the fibroblasts from subjects with DS were very sensitive to the effect of interferon: namely, a decrease in cellular protein synthesis.

Interferon and Down Syndrome: 1980 to 1994

In 1980, Dr. Maroun subsequently theorized the following:

1. Interferon could be involved in the physical features and development of the child with DS. Since viral infections cause the body to produce interferon, exposure to interferon in the womb may cause an increased effect via growth inhibition of cells on the fetus. The more infections the mother had, the more interferon the fetus would be exposed to and the more "affected" the baby would be. A pregnancy free of viral infections might produce a baby with few of the features commonly associated with DS.

2. A study in 1965 seemed to show that an increase in the incidence of infectious hepatitis (hep A) was followed nine months later by an increase in the number of births of babies with DS, even if the mother of the baby showed no signs of infection with hepatitis. (This was before serum markers could prove exposure or non-exposure to hep A.) If a woman over 35 years of age had an oocyte sensitive to interferon,and there was an antiviral response in her body at the time of meiosis, the interferon could produce non-disjunction in the oocyte, leading to trisomy 21.

A medline search for this topic in the 1980s shows only a handful of studies. If you eliminate the studies just focusing on immunology and not interferon specifically, the remainder are involved with either mapping the receptor gene to the specific spot on the 21st chromosome, and confirming in different ways the increased sensitivity of DS cells to interferon. For example:

Synthesis of interferon-induced polypeptides in normal and chromosome 21-aneuploid human fibroblasts: relationship to relative sensitivities in antiviral assays.
Weil J; Epstein LB; Epstein CJ
J Interferon Res 1980 Fall;1(1):111-24
(Summary: the number of interferon receptors in DS is proportional to the number of genes coding for the receptors in human fibroblasts.)

However, two other interesting studies show up:

Expression of the 210 kDa neurofilament subunit in cultured central nervous system from normal and trisomy 16 mice: regulation by interferon.
Plioplys AV
J Neurol Sci 1988 Jun;85(2):209-22
Author Affiliation: Department of Pediatrics, Hospital for Sick Children, Toronto, Ont., Canada.
(Summary: an interferon inhibitor prevents the mouse trisomy neuron from overproducing neurofilaments, one of the abnormal items seen in the brains of adults with DS and adults with Alzheimer's. Then again, it's a mouse study and it's a cultured cell study.)
Commentary: Down's syndrome, interferon sensitivity and the development of leukaemia.
Zihni L
Leukemia Res 1994 18(1):1-6
Author Affiliation: Wellcome Institute for the History of Medicine, London, UK
(Summary: The author suggests that the occurrence of transient leukemoid reactions, myelofibrosis and leukemia in DS may all result from the increased sensitivity of DS cells to interferon with consequent autoimmune disease. She speculates that a therapy might be arrived at by blocking the effects of interferon.)

Interferon and Down Syndrome: 1995 to 2000

OK, here's where we catch up with Dr. Maroun again:

Interferon action and chromosome 21 trisomy (Down syndrome): 15 years later.
Maroun LE
J Theor Biol 1996 Jul 7;181(1):41-6
Author Affiliation: Southern Illinois University, School of Medicine, Department of Medical Microbiology Immunology
(Summary: Dr Maroun reiterates his theory that a viral response in the mother is responsible for the origin of trisomy and/or how much a child is "affected" by having Down syndrome, and lists the research in the preceding 15 years that supports his theory.)

So...could blocking interferon have any measurable effects in DS? Here are three studies that suggest it might:

Anti-interferon immunoglobulins can improve the trisomy 16 mouse phenotype.
Maroun LE
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois
Teratology 51:329-335 (1995)
Mouse trisomy 16 is a well-studied model for human chromosome 21 trisomy (Down syndrome). The late stage trisomy 16 mouse fetus exhibits significant growth retardation, inappropriately opened eyes, and convex rather than concave back curvature. The interferons (alpha, beta, and gamma) have potent growth retarding activity, and sensitivity to these cytokines is controlled by genes that map to mouse chromosome 16 and human chromosome 21. In experiments designed to determine if the interferons induce or aggravate the trisomy phenotype, mice pregnant with trisomy 16 fetuses were injected with a combination of anti-alpha, anti-beta, and anti-gamma interferon IgG. This maternal anti-interferon treatment was found to provide measurable benefit to the development and growth of the trisomic fetuses with significant return-toward-normal values observed for overall fetal growth, eye opening, and back curvature.

Interferon and trisomy 16 mouse fetal heart development and function.
Wiseman BF, Hallam DM, Heffernan TN, Werner RK and Maroun LE
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine
Cytogenetics and Cell Genetics 77:27 (1997)
Down syndrome is associated with anomalies of the brain, heart and immune system. The interferons play a central role in the immune system, have significant effects in the brain and can effect heart function. As cells from a person with Down syndrome are especially sensitive to the effects of interferon, we have been studying the role of interferon in the phenotypic consequences of trisomy. Using the trisomy 16 mouse system, we have been able to demonstrate that trisomy 16 mouse anomalies can be ameliorated by maternal treatment with anti-interferon antibodies.

Interferon therapy has been associated with various cardiotoxicities including arrhythmia and congestive heart failure. Because of these well-documented effects of interferon on the heart, we have examined the Bouin fixed hearts of the trisomy 16 mouse fetuses recovered from anti-interferon treated mothers. Hearts were examined for gross morphology and for atrial-ventricular spectrum defects using paraffin block serial sections. In contrast to the frequent observation of abnormalities in heart morphology seen in untreated trisomy fetuses, no anomalies were observed in the hearts of trisomy fetuses from anti-interferon treated mothers.

To extend these observations to the living trisomy fetus, we are monitoring euploid and trisomy fetal heart rate and arrhythmia using a 9.8 mm directional Doppler. The method has allowed the monitoring of fetal heart function in the absence of cardioactive anesthetic drugs. Significant arrhythmia was not observed in either the euploid or trisomy fetus. The heart beat rate of both trisomy and euploid fetuses increased steadily from 210+/-40 beats per minute at gestational day 16 toward the 286+/-57 beats per minute reported in the literature for the mouse newborn.

Anti-gamma interferon can prevent the premature death of trisomy 16 mouse cortical neurons in culture.
Hallam DM & Maroun LE
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine
Neurosci Letter 252(1):17-20, 1998
Cortical neurons were removed from trisomy 16 mice and survived in culture media longer if treated with anti-gamma interferon immunoglobulins.

Partial IFN-alpha/beta and IFN-gamma receptor knockout trisomy 16 mouse fetuses show improved growth and cultured neuron viability.
Maroun LE, Heffernan TN, Hallam DM.
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine
J Interferon Cytokine Res. Feb;20(2):197-203, 2000.
The trisomy 16 mouse is a model for Down syndrome, with many of the mouse versions of genes of the human 21st chromosome located on the mouse 16th chromosome. Trisomy 16 mice were bred to have a normal number of genes producing part of the interferon receptor. These mice grew bigger and had more brain cell viability than trisomy 16 mice with three of the genes producing the interferon receptor. This is additional proof that the overproduction of the interferon receptor has deleterious effects.

What else interesting is there? Well, Dr. Maroun makes an interesting point on his website that many side effects of interferon therapy (given for cancer) are also features seen in Down syndrome (DS):

Interferon side effects: neurotoxicity, memory loss, frontal lobe encephalopathy
DS: learning difficulties, small frontal lobes

Interferon side effects: cardiotoxicity
DS: heart defects

Interferon side effects: hypothyroidism
DS: hypothyroidism

Interferon side effects: autoimmune disease
DS: autoimmune disease

Interferon side effects: deafness
DS: hearing loss (mostly conductive but some neuronal)

Interferon side effects: growth inhibition
DS: short stature

Anti-interferon, Meiogen and Controversy

Dr. Maroun has set up a company called Meiogen Biotech in order to develop an anti-interferon ("Antiferon") drug for testing purposes. He states that testing humans is still 2 to 3 years and several hundred thousand dollars away, but he is attempting to get funding at the present time.

The first step on that road has been accomplished, as the US Patent Office has given Dr. Maroun a patent for the intellectual property rights for "Methods of Treatment of Down Syndrome Using Interferon Antagonists." According to Dr. Maroun, this "is an essential first step in the competition for funds in the financial markets."

This research does have its detractors. Critics have pointed out that the entire research to date has been based on animal models that may not be very good models for humans with trisomy 21. Also, the bulk of the research has been done by one investigator with no confirmatory studies to date.

My personal impression is that this is extremely experimental, and needs much more investigational work, but it seems like an interesting direction.

For more information on this company and research, visit Meiogen Biotechnology Corporation.

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