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A Brief Historical Perspective on the Pathological Consequences of Excessive Type I Interferon Exposure In vivo

Interferon was described by Isaacs and Lindenmann in 1957 [1, 2], and its importance in antiviral host defense was first demonstrated in 1960 [3]. Virelizier and Gresser were the first to show that endogenous interferon type I mediated one example of genetically determined resistance to a viral infection, when they found that injection of an anti-type I interferon IgG overcame the innate resistance of C3H and A/J mice to mouse hepatitis virus [4]. These results were then extended by Haller and colleagues, using the same anti-IFN IgG to render a Mendelian-determined resistant strain of mice fully susceptible to the lethal effects of influenza A virus [5, 6]. Molecular confirmation of these data came through the definition of murine models lacking the type I interferon receptor and relevant downstream signaling molecules [7,8,9] and the study of human inborn errors of immunity, beginning with the identification of inherited complete STAT1 deficiency in 2003 [10, 11]. The phenotypes of Ifnar1, Ifnar2, Stat1, Stat2, Isg15, and Irf9-deficient mice and the corresponding human mutant states differ somewhat, in regard to the pattern of expression of interferon stimulated genes and susceptibility to viruses, suggesting that each of these components is essential in its own way for a proper interferon response [12]. Beyond the more specialized roles of interferon lambda and gamma in epithelial defense and macrophage activation respectively [13,14,15], definition of specific functions of individual interferon alpha subtypes and interferon beta has remained elusive, although their mere diversity and different patterns of evolutionary selection [16] suggest discrete and perhaps non-overlapping activities. Overall, 50 years of experimentation has established that type I interferons are globally essential for host defense against a variety of viruses in all species examined.

In parallel, another line of research established the paradoxical situation where excessive interferon production can be detrimental to the host [17]. Studies performed by Gresser and colleagues more than 40 years ago showed that when different strains of newborn mice were injected with potent preparations of partially purified or electrophoretically pure mouse type I interferon, they developed a syndrome characterized by inhibition of growth, delay in maturation of several organs, diffuse liver cell necrosis, and death between the 8th and 14th day of life [18, 19]. Remarkably, when type I interferon treatment was discontinued at 1 week of life, the mice seemed to recover and gain weight, but then died in the ensuing months with a progressive glomerulonephritis [20, 21]. In the A2G mouse strain, type I interferon induced a similar liver cell necrosis. However, in this case, recovery following discontinuation of treatment was followed by the development of large pulmonary cysts in the absence of any renal involvement [22]. Injection of newborn rats with potent preparations of rat type I interferon also resulted in a delay of growth and maturation of different organs, and the subsequent development of nephritis [23].

The above experiments indicated that exogenously administered type I interferon could have pleiotropic effects in mice, which might be separated temporally, sometimes by several months, from the initial exposure, and show a dependency on background strain. To explore the relevance of these observations in a more physiological setting, it was noted that the injection of newborn mice with lymphocytic choriomeningitis virus (LCMV) induced a phenotype apparently identical to that observed in type I interferon-treated suckling mice, and, similarly, surviving mice subsequently developed a progressive and lethal glomerulonephritis [24, 25]. A difference was observed in the severity of disease in different strains of mice infected with LCMV, which correlated with the amount of interferon produced and the duration of the interferonemia. Inoculation of LCMV-infected mice with a potent, purified sheep IgG anti-mouse type I interferon resulted in a hundred fold increase in the serum viral titer compared to virus-injected mice treated with control IgGs. As expected, control mice had significant serum interferon titers, whereas interferon was not detected in the serum of mice treated with anti-interferon IgG. Strikingly, however, prior inoculation with anti-interferon IgG inhibited the early manifestations of LCMV disease [26], as well as the later development of glomerulonephritis [27]. Furthermore, the same antibody abrogated the liver necrosis of Pichinde virus (another arenavirus) infected suckling mice [28]. It should be noted that, as first described in 1971 [29], in most instances, antibody to interferon exacerbates the manifestations of acute viral disease.

At around the same time, Lebon and colleagues showed that interferon alpha activity was present in normal amniotic fluid [30, 31] and in the placenta [32] in the absence of any viral infection. Although interferon was detectable at the feto-placental interface in the non-diseased state, it was not recorded in the blood of fetuses of women free from infection. Furthermore, it was shown that interferon alpha administered to pregnant women infected with human immunodeficiency virus did not cross the placenta [33]. In contrast, an acid labile alpha interferon activity was present in the sera of fetuses and children with congenital rubella [34], at as early as 20 weeks of gestation, raising the question as to whether this interferon might play an active role in the sequelae of such infection. Similarly, interferon alpha activity was detected in fetal blood after infection with cytomegalovirus, parvovirus B19 [35, 36], LCMV [37], and enterovirus [38], with the fetal origin of this interferon indicated by its absence from maternal blood sampled at the same time.

Following on from the body of work described above, in 1980, Gresser and colleagues suggested the possibility that as interferon did not cross the placenta, some embryotoxic effects ascribed to viral infection, such as rubella virus, might be related to interferon induced in the embryo itself [17]; that is, as a function of the host response to infection. Furthermore, they predicted that disease states might exist in humans where pathogenesis was directly consequent upon enhanced type I interferon signaling. Remarkably then, only 4 years later, Lebon and colleagues described increased levels of interferon alpha activity in the serum and cerebrospinal fluid of children affected by a presumed genetic disorder [39,40,41], with such activity detected in fetal blood at as early as 29 weeks of gestation [42, 43]. In doing so, they defined the first Mendelian disease associated with enhanced type I interferon signaling, now referred to as Aicardi-Goutières syndrome (AGS).

These studies coincided with the use of recombinant leukocyte interferon preparations as a therapy, and the first reports of both neurological disease [44,45,46], particularly confusion and spasticity, and an association with the onset of systemic lupus erythematosus (SLE), and other autoimmune phenotypes, apparently consequent upon iatrogenic exposure [47]. The neurotoxic potential of type I interferon was further emphasized by the work of Campbell and colleagues through the production of transgenic mice that chronically produce interferon alpha from astrocytes, thereby recapitulating the neuropathological features of AGS [48, 49].

Beginning in 2006, the subsequent unraveling of the genetic basis of AGS has underlined the prescience of the earlier pioneer studies. Thus, as originally described, AGS can be considered as a Mendelian mimic of congenital infection due to dysfunction of genes involved in either nucleic acid processing (TREX1, the RNase H2 complex, SAMHD1, ADAR1) or sensing (MDA5). Such defects result in a misinterpretation of self nucleic acids as non-self (viral) and the induction of an (inappropriate) interferon-mediated (antiviral) response. These observations, supported by in vitro and animal experimentation, subsequently led to the introduction of the type I interferonopathy concept in 2011, a set of Mendelian diseases where upregulated type I interferon signaling is considered directly relevant to pathogenesis [50]. Starting in the 1970s, systemic lupus erythematosus was the first human disease to be linked to enhanced type I interferon beyond infection [51,52,53,54,55,56]. It is of note that variants in a number of genes related to Mendelian type I interferonopathies are associated with lupus [57,58,59]. Conversely, the co-occurrence of lupus in that context is suggestive of a common pathogenic link [60,61,62,63], albeit the frequency of overt lupus is relatively low and clear phenotypic differences exist.

Given the focus here on type I interferon, we do not discuss the clear importance of type II and III interferons in host defense. However, we do note that the so-called interferon signature i.e. the increased expression of a programmed set of interferon stimulated genes, is not specific to type I interferon []. As such, the possibility that enhanced interferon signaling induced by types II and III interferons might also have detrimental effects on cell and organismal health is deserving of further investigation. Indeed, this is possibly the case for interferon gamma in hereditary hemophagocytic lymphohistiocytosis [64], and might be relevant to type III interferons and the gastrointestinal involvement sometimes observed in AGS [65].

Many questions central to a comprehensive understanding of the type I interferonopathy field remain, perhaps the most urgent being the source of the putative endogenous nucleic acid driving an interferon response, with two major possibilities currently favored, i.e., either products of DNA damage/repair or endogenous retro elements. Another interesting question relates to the importance of tonic interferon signaling, which may have roles beyond the maintenance of a baseline level of antiviral protection [66]. In the meanwhile, recent papers have again highlighted the importance of the host interferon-mediated antiviral response in disease, demonstrating a significant contribution to pathology in a mouse model of congenital ZIKV infection [67,68,69]. Here, we place these exciting new insights into historical perspective by emphasizing certain data generated in the 1970s and 1980s. In brief, either too little or too much type I interferon can be detrimental to the host, including the fetus.


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YJC acknowledges the European Research Council (GA 309449) and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” program bearing the reference ANR-10-IAHU-01. YJC thanks Carolina Uggenti for her help with referencing. JLC acknowledges the National Institutes of Health (R37AI095983 and R21AI137371). JLC thanks Emmanuelle Jouanguy, Shen-Ying Zhang, and Stéphanie Boisson-Dupuis. PL thanks Dominique Pennec for her constant assistance.


Image. The authors during a working lunch at Chez Fernand, Saint-Germain-des-Près, Paris (where Pierre Lebon’s son Remi is the head chef) (left to right: Pierre Lebon, Yanick Crow, Ion Gresser, and Jean-Laurent Casanova).

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Crow, Y.J., Lebon, P., Casanova, J. et al. A Brief Historical Perspective on the Pathological Consequences of Excessive Type I Interferon Exposure In vivo. J Clin Immunol 38, 694–698 (2018).

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