Interferon & Down Syndrome Abstracts

Journal of Neuroimmunology 110 (1-2): 66-75 (2000 Oct 2)

Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis

Hallam DM, Capps NL, Travelstead AL, Brewer GJ, Maroun LE
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, P.O. Box 19626, Springfield, IL 62794-9626, USA

The trisomy of human chromosome 21 (Down syndrome) is the leading genetic cause of learning difficulties in children, and predisposes this population to the early onset of the neurodegeneration of Alzheimer's disease. Down syndrome is associated with increased interferon (IFN) sensitivity resulting in unexpectedly high levels of IFN inducible gene products including Fas, complement factor C3, and neuronal HLA I which could result in a damaging inflammatory reaction in the brain. Consistent with this possibility, we report here that the trisomy 16 mouse fetus has significantly increased whole brain IFN-gamma and Fas receptor immunoreactivity and that cultured whole brain trisomy 16 mouse neurons have increased basal levels of caspase 1 activity and altered homeostasis of intracellular calcium and pH. The trisomic neurons also showed a heightened sensitivity to the increase in both Fas receptor levels and caspase 1 activity we observed when IFN-gamma was added to the neuron culture media. Because of the autoregulatory nature of IFN activity, and the IFN inducing capability of caspase-1-activated cytokine activity, our data argue in favor of the possibility of an interferon-mediated, self-perpetuating, inflammatory response in the trisomy brain that could subserve the loss of neuron viability seen in this trisomy 16 mouse model for Down syndrome.
J Interferon Cytokine Res 20 (2): 197-203 (2000 Feb)

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, Springfield, IL

The trisomy 16 mouse fetus is a well-studied model for Down syndrome (trisomy 21), the leading genetic cause of mental retardation in the newborn population. Human chromosome 21 and mouse chromosome 16 each carry a large cluster of genes that code for components of the interferon (IFN)-alpha/beta and IFN-gamma receptors, and Down syndrome cells display significantly increased sensitivity to IFN action. We have previously reported that in utero anti-IFN IgG treatment of mice pregnant with trisomy 16 fetuses results in a significant improvement in trisomy 16 fetus growth and morphology and that anti-IFN-gamma IgG treatment can prevent the premature death of trisomy 16 fetal mouse cortical neurons in culture. We have now used IFN receptor subunit knockout mice to produce mouse fetuses that carry three No. 16 chromosomes and one copy each of disabled IFN-gamma receptor (IFNGR) and IFN-alpha/beta receptor (IFNAR-2) component genes. We report here that this partial IFN receptor knockout trisomy (PIRKOT) mouse fetus has significantly improved growth and yields cortical neurons whose viability is the equivalent of that seen in their euploid counterparts.
Down's Syndrome: Research and Practice 5 (3): 143-7 (1998)

The Untoward Side Effects of Interferon Therapy Correlate Well with the Spectrum of Symptoms that Make Up the Down Syndrome

Maroun LE, Heffernan T, Hallam D
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL

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 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 Down syndrome. Taken together, these gene mapping and clinical observations suggest the possibility that the diverse symptoms of the Down syndrome could have a suprinsingly non-diverse underlying biochemistry.
J Theor Biol 181 (1): 41-6 (1996 Jul 7)

Interferon Action and Chromosome 21 Trisomy (Down Syndrome): 15 Years Later

Maroun LE
Southern Illinois University, School of Medicine, Department of Medical Microbiology Immunology, Springfield 62794-9230, USA.

A hypothesis relating interferon action and the chromosome 21 trisomy genotype and phenotype was presented in this journal in 1980. Since that time a number of additional genes involved in interferon action have been mapped to the distal Down Syndrome region of chromosome 21 and a growing literature has documented highly relevant pleiotropic effects of interferon in the brain. Thus, interferon continues to provide a potential basis for the phenotypic anomalies seen in the interferon supersensitive Down Syndrome patient. Further, the hypothesis that ribosomal RNA gene "satellite association" induced by interferon action is involved in the induction of chromosome 21 misdistribution at meiosis, is supported by extension of the cyclic correlation of Down Syndrome prevalence and virus epidemics, first observed by Stoller & Collmann in Australia from 1942 to 1964, to incidence data gathered by the CDC in the U.S. from 1968 to 1992. In addition, data from spontaneous abortuses and gametes assembled from the literature argue for a uniquely high frequency of chromosome 21 hyperploidy which suggests that the genes present on chromosome 21 play a role in its frequent misdistribution at meiosis. Taken together, these observations provide continued support for the hypothesis presented in 1980 that interferon action could be involved in the induction of both the trisomy 21 genotype and its resultant phenotype.
Teratology 51 (5): 329-35 (1995 May)

Anti-interferon Immunoglobulins Can Improve the Trisomy 16 Mouse Phenotype

Maroun LE
Department of Medical Microbiology/Immunology, Southern Illinois University School of Medicine, Springfield 62794, USA.

Mouse trisomy 16 is a well-studied model for human chromosome 21 trisomy (Down's 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, -beta, and -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.
J Theor Biol 86 (3): 603-6 (1980 Oct 7)

Interferon action and chromosome 21 trisomy

Maroun LE

Letter to the editor.
Biochem J. 179 (1): 221-5 (1979 Apr 1)

Interferon effect on ribosomal ribonucleic acid related to chromosome 21 ploidy

Maroun LE
Department of Medical Sciences, Southern Illinois University School of Medicine, P.O. Box 3926, Springfield, IL 62708, U.S.A.

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.