The Untoward Side Effects of Interferon Therapy Correlate Well with the Spectrum of Symptoms that Make up the Down Syndrome
Maroun, Heffernan and Hallam
There is an ongoing effort to identify individual genes on Chromosome 21 that may independently each subserve one of the many diverse symptoms that constitute the Down syndrome. In contrast, the interferon system points to a multigene, multilocus, system distributed across Chromosome 21 that can explain each of the individual symptoms of the Down syndrome as a consequence of the concerted action of multiple genes which share in common a role in interferon action. To date, at least ten such genes have been identified on Chromosome 21. This number is likely to grow as new genes are identified, and their role in interferon action is uncovered. The recently discovered human SIM2 gene is presented here as an example. Its Intron 3 sequence reveals a clustering of interferon response elements that suggests an unexpected role for this gene in interferon action. We also present here a comparative analysis of the complex of untoward side effects of interferon therapy that reveals a striking similarity to the spectrum of symptoms that make up the Down syndrome. Taken together, these gene mapping and clinical observations suggest the possibility that the diverse symptoms of the Down syndrome could have a surprisingly non-diverse underlying biochemistry.
Maroun LE, Heffernan T, Hallam D. The Untoward Side Effects of Interferon Therapy Correlate Well with the Spectrum of Symptoms that Make up the Down Syndrome. Down Syndrome Research and Practice. 1998;5(3);143-147.
doi:10.3104/hypotheses.91
* From a paper presented at the 6th World Congress on Down Syndrome, Madrid,
Spain, October 1997.
Introduction
It has been known for many years that cells from individuals with Down syndrome
are excessively sensitive to interferon effects (Tan
et al., 1974). Two observations suggest that this interferon hypersensitivity
could underlie many Down syndrome pathologies:
Numerous genes involved in interferon action are located in the region of
human chromosome 21 responsible for most of the Down syndrome pathologies.
The "distal" half of chromosome 21 contains a large cluster of genes that
direct the synthesis of interferon receptors and receptor components. These
genes control sensitivity to each of the various types of interferons. In
addition, the same "Down Syndrome Region" (DSR) contains genes whose activities
are controlled by the interferons and at least one gene that is involved
in this control mechanism (ETS-2, a "transcription factor"). These genes,
along with their potential role in brain function, have been described previously
(Maroun, 1996).
Other genes mapped to Chromosome 21 and thought to be important in brain
function are also candidate interferon responsive genes. For example, we
have now found an unusual cluster of interferon response elements in Intron
3 of the human SIM2 gene (Figure 1).
Figure 1. Interferon response elements in Intron 3 of the Human Chromosome
21 SIM2 Gene.
The presence on Chromosome 21 of genes that are targets of interferon action
provides an attractive explanation of the many-fold increase in interferon
sensitivity seen in cells from people with Down syndrome in spite of the
observation of only a fifty percent increase in interferon receptor numbers
(Epstein, 1986).
A clear correlation is observed for many of the pathologies seen in a person
with Down syndrome with the side effects seen in patients undergoing interferon
therapy.
One of the most compelling arguments for the involvement of interferon action
in the Down syndrome is based on a remarkable similarity of the spectrum
of symptoms seen in Down syndrome and with those seen in patients who have
been treated with interferon. Although the effects of interferon on growth
were predictable given interferon's anticellular effects, the brain, heart
and immune system function effects are surprising in their similarity to
the pathology seen in the Down syndrome. It is possible that interferon's
ability to slow cell growth may subserve each of these pathologies at their
most fundamental level.
This comparison is presented in tabular form in Table 1 along with pertinent
references.
Table 1. A comparable spectrum of anomalies are seen in both
Down syndrome and interferon-treated patients
| Down Syndrome Pathologies |
Interferon Side Effects |
| Learning Difficulties (Carr, 1985) |
Neurotoxicity (Mattson et al., 1983), Memory Loss (Iivanainen
et al., 1985) |
| Small frontal lobes (Wisniewski et.al., 1985) |
Frontal lobe encephalopathy (Mattson et al., 1984) |
| Heart Pathology (Sei et al., 1995) |
Cardiotoxicity (Sonnenblick and Rosin, 1991) Arrhythmia (Martino
et al., 1987) |
| Leukopenia (Cossarizza et al., 1990) |
Leukopenia (Quesada et al., 1986) |
| Autoimmune disease (Levo, 1977) |
Autoimmune disease (Burman et al., 1985) |
| Hypothyroidism (Mitchell et al., 1994) |
Hypothyroidism (Fentiman et al., 1985) |
| Hearing Loss (Roizen et al., 1992) |
Deafness (Kanda et al., 1995) |
| Short Stature (Piro et al., 1990) |
Growth Inhibition (Kikawa et al., 1995) |
Anti-interferons can reverse or prevent the untoward effects of the interferons.
Because interferons can do so many apparently unrelated things, it has been
traditional to demonstrate that a newly found biological activity was indeed
due to interferon by reversing or preventing the effect of added interferon
by simultaneously adding anti-interferon (usually an antibody) to the culture
media. In all cases where the effect was due to the added interferon, the
effect was, as would be expected, reversed or prevented by the anti-interferon
treatment. This ability of an anti-interferon to reverse or prevent interferon
actions has been extended to include "in vivo" whole animal
observations including the extension of these observations to the animal
model for Down syndrome (Maroun,
1995). Injection of anti-interferon immunoglobins into mothers carrying
trisomy 16 mouse fetuses resulted in significant return-to-normal values
for fetal growth, eye closure, and back curvature (Maroun,
1995). In contrast to the unpredictable growth of the untreated trisomy
fetuses, the growth of the treated trisomy fetuses was essentially keeping
pace with that of their euploid littermates (Figure 2).
Figure 2. Improvement in the growth of trisomic mouse embryos treated
with anti-IFN antibodies. Modified from Maroun, 1995.
In these experiments the reduction in interferon bioactivity was observed
to be well tolerated. This is consistent with what is observed with "Knockout"
mice whose genes for interferon receptors have been rendered inactive (Hwang
et al., 1995). The same is true in humans who carry a mutation in their
interferon receptor genes (Newport
et al., 1996) (Jouanguy
et al., 1996). Patients who have circulating anti-interferon antibodies
as a consequence of interferon therapy show the expected decrease in the
efficacy of further interferon treatment but no other untoward effects have
yet been observed (Quesada
et al., 1986). Taken together, the observations discussed here suggest
that the in vivo neutralization of interferon in individuals with Down syndrome
could be both safe and potentially beneficial.
Acknowledgements
This project was supported in part by the American Heart Association and
the Excellence in Academic Medicine program of Southern Illinois University
School of Medicine.
Correspondence
L.E. Maroun, Ph.D. Southern Illinois University School of Medicine. Dept.
of Medical Microbiology/Immunology. P.O. Box 19230, Springfield, Illinois
USA 62794-1220. (Tel: (217) 785-2181, Fax: (217) 524-3227, E-mail:
lmaroun@siumed.edu)
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