[François Gros, Permanent Secretary of the French Academy of Sciences]. / François Gros, secrétaire perpétuel de l'Académie des sciences.

François Gros was Permanent Secretary of the French Academy of Sciences from 1991 to 2000. His immense scientific knowledge, his tireless efforts to develop international relations, particularly with developing countries, and his exceptional personality have greatly contributed to the modernisation and influence of the Academy.

François Gros a été secrétaire perpétuel de l'Académie des sciences de 1991 à 2000. Son immense culture scientifique, son activité incessante pour le développement des relations internationales en particulier vers les pays en développement, et sa personnalité exceptionnelle ont grandement contribué à la modernisation et au rayonnement de l'Académie.

Modulation of autoimmune diabetes by N-ethyl-N-nitrosourea- induced mutations in non-obese diabetic mice.

Genetic association studies of type 1 diabetes (T1D) in humans, and in congenic non-obese diabetic (NOD) mice harboring DNA segments from T1D-resistant mice, face the challenge of assigning causation to specific gene variants among many within loci that affect disease risk. Here, we created random germline mutations in NOD/NckH mice and used automated meiotic mapping to identify mutations modifying T1D incidence and age of onset. In contrast with association studies in humans or congenic NOD mice, we analyzed a relatively small number of genetic changes in each pedigree, permitting implication of specific mutations as causative. Among 844 mice from 14 pedigrees bearing 594 coding/splicing changes, we identified seven mutations that accelerated T1D development, and five that delayed or suppressed T1D. Eleven mutations affected genes not previously known to influence T1D (Xpnpep1, Herc1, Srrm2, Rapgef1, Ppl, Zfp583, Aldh1l1, Col6a1, Ccdc13, Cd200r1, Atrnl1). A suppressor mutation in Coro1a validated the screen. Mutagenesis coupled with automated meiotic mapping can detect genes in which allelic variation influences T1D susceptibility in NOD mice. Variation of some of the orthologous/paralogous genes may influence T1D susceptibility in humans.

De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes.

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

COVID-19: individual and herd immunity.

Immunity to the SARS-CoV-2 virus ensures protection against reinfection by this virus thanks to the combined action of neutralizing antibodies and T lymphocytes specific to viral proteins, in particular the Spike protein. It must be distinguished from the immune response that ensures healing of the infection following contamination that involves innate immunity, particularly type 1 interferons, and which is followed by adaptive cellular and humoral immunity. The importance of the effect of interferons is highlighted by the occurrence of severe forms of the disease in genetically deficient subjects or in patients with antibodies neutralizing type 1 interferon. Herd immunity is not an individual biological property. It is a mathematical property that qualifies the fact that when the proportion of subjects with individual immunity is high enough, there is little chance that an epidemic can occur. The level of that proportion-the herd immunity of the population can be computed under theoretical, often unrealistic, hypotheses, and is difficult to assess in natural conditions.

L'immunité individuelle contre le virus SARS-CoV-2 assure la protection contre la réinfection par ce virus grâce à l'action conjuguée des anticorps neutralisants et des lymphocytes T spécifiques des protéines virales, notamment la protéine Spike (spicule). Il faut la distinguer de la réponse immunitaire qui assure la guérison de l'infection dans les jours suivant la contamination. Celle-ci fait intervenir l'immunité innée et tout particulièrement les interférons de type 1 puis l'immunité adaptative cellulaire et humorale. L'importance de l'effet des interférons est soulignée par la survenue de formes graves chez des sujets génétiquement déficients dans leur synthèse ou encore des patients présentant des anticorps neutralisant l'interféron de type 1. L'immunité collective caractérise la faible probabilité de développement d'une épidémie dans une population ayant un pourcentage élevé de sujets présentant une immunité individuelle. Le taux d'immunité collective nécessaire pour faire disparaître l'épidémie a été calculé dans des modèles mathématiques supposant la panmixie ; il est difficile à évaluer dans les populations réelles.

Revisiting the Hygiene Hypothesis in the Context of Autoimmunity.

Initially described for allergic diseases, the hygiene hypothesis was extended to autoimmune diseases in the early 2000s. A historical overview allows appreciation of the development of this concept over the last two decades and its discussion in the context of evolution. While the epidemiological data are convergent, with a few exceptions, the underlying mechanisms are multiple and complex. A major question is to determine what is the respective role of pathogens, bacteria, viruses, and parasites, versus commensals. The role of the intestinal microbiota has elicited much interest, but is it a cause or a consequence of autoimmune-mediated inflammation? Our hypothesis is that both pathogens and commensals intervene. Another question is to dissect what are the underlying cellular and molecular mechanisms. The role of immunoregulatory cytokines, in particular interleukin-10 and TGF beta is probably essential. An important place should also be given to ligands of innate immunity receptors present in bacteria, viruses or parasites acting independently of their immunogenicity. The role of Toll-Like Receptor (TLR) ligands is well documented including via TLR ligand desensitization.

Markers of microbial exposure lower the incidence of atopic dermatitis.

BACKGROUND: The hygiene hypothesis proposes that reduced exposure to infectious agents in early life would explain the increase of allergic and autoimmune diseases observed over the past decades in high-income countries. METHODS: We conducted a matched case-control study on incident atopic dermatitis (AD). Cases were 426 outpatient children with a first diagnosis of incident AD. Controls were 426 children attending a pediatric/dermatological visit for nonatopic disorders matched to cases (1:1). Particular attention was paid to the time elapsed between the markers of microbial exposure and disease onset, and we considered for controls the same time window of exposures from birth as his/her matched case. Odds ratios (ORs) were computed using multivariable conditional logistic regression models, according to center, sex, age, and period of enrollment, and including as potential confounders a family history of any allergy in parents, type of delivery, having siblings, keeping pets, age at weaning, and having had ≥4 infections. RESULTS: The OR of AD first occurrence was 0.35 (P-value = .039) for children who had experienced ≥4 infections compared with those with no infections. A decreasing trend in risk was observed with increasing number of siblings (P-value = .023), the protective effect reaching about 40% for children with 2 or more siblings (OR = 0.62; P-value = .048). Pet keeping, in particular daily contact with dogs, was inversely associated with AD risk (OR = 0.40; P-value = .004). CONCLUSIONS: These results support the hygiene hypothesis in its broad sense. Early-life environmental exposures, including pathogens and commensals, act as "microbes contact carriers" influencing immune system balance early in life.

Genetic drift in mammals.

Genetic drift is the fortuitous occurrence of genetic events that when they become fixed modify the genome of populations. They can take the form of mutations of single nucleotides (SNPs), the insertion or deletion of short sequences (Indels) or the repetitions of short sequences (CNV i.e. copy number variants) or long insertions or deletion (structural modifications). Their frequency is 10-9 to 10-8 depending on the species, or 50 to 100 per birth in humans. The incidence of these de novo mutations is higher when the father is old at conception. It thus appears that genetic drift, which constitutes the initial element of evolution, has a very strong dynamics. Its intervention in the appearance or disappearance of some major phenotypes is complicated by the uncertainties about the genetic mechanisms in heritability which, paradoxically, are only partially understood.

Causality in medicine.

This article is the result of a symposium organized at the French Academy of Sciences on May 31, 2016, entitled: Do we need to know the causes to understand and intervene? Questions on causality in the biological and medical sciences, and published in French in a book entitled: Causality in the biological and medical sciences (EDP Sciences, 2017).

The hygiene hypothesis in autoimmunity: the role of pathogens and commensals.

The incidence of autoimmune diseases has been steadily rising. Concomitantly, the incidence of most infectious diseases has declined. This observation gave rise to the hygiene hypothesis, which postulates that a reduction in the frequency of infections contributes directly to the increase in the frequency of autoimmune and allergic diseases. This hypothesis is supported by robust epidemiological data, but the underlying mechanisms are unclear. Pathogens are known to be important, as autoimmune disease is prevented in various experimental models by infection with different bacteria, viruses and parasites. Gut commensal bacteria also play an important role: dysbiosis of the gut flora is observed in patients with autoimmune diseases, although the causal relationship with the occurrence of autoimmune diseases has not been established. Both pathogens and commensals act by stimulating immunoregulatory pathways. Here, I discuss the importance of innate immune receptors, in particular Toll-like receptors, in mediating the protective effect of pathogens and commensals on autoimmunity.

Adjuvant treatment with the bacterial lysate (OM-85) improves management of atopic dermatitis: A randomized study.

BACKGROUND: Environmental factors play a major role on atopic dermatitis (AD) which shows a constant rise in prevalence in western countries over the last decades. The Hygiene Hypothesis suggesting an inverse relationship between incidence of infections and the increase in atopic diseases in these countries, is one of the working hypothesis proposed to explain this trend. OBJECTIVE: This study tested the efficacy and safety of oral administration of the bacterial lysate OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), in the treatment of established AD in children. METHODS: Children aged 6 months to 7 years, with confirmed AD diagnosis, were randomized in a double-blind, placebo-controlled trial to receive, in addition to conventional treatment with emollients and topical corticosteroids, 3.5mg of the bacterial extract OM-85 or placebo daily for 9 months. The primary end-point was the difference between groups in the occurrence of new flares (NF) during the study period, evaluated by Hazard Ratio (HR) derived from conditional Cox proportional hazard regression models accounting for repeated events. RESULTS: Among the 179 randomized children, 170 were analysed, 88 in the OM-85 and 82 in the placebo group. As expected most children in both treatment groups experienced at least 1 NF during the study period (75 (85%) patients in the OM-85 group and 72 (88%) in the placebo group). Patients treated with OM-85 as adjuvant therapy had significantly fewer and delayed NFs (HR of repeated flares = 0.80; 95% confidence interval (CI): 0.67-0.96), also when potential confounding factors, as family history of atopy and corticosteroids use, were taken into account (HR = 0.82; 95% CI: 0.69-0.98). No major side effect was reported, with comparable and good tolerability for OM-85 and placebo. CONCLUSIONS: Results show an adjuvant therapeutic effect of a well standardized bacterial lysate OM-85 on established AD.

Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes.

Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD) mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin) or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαß+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

Therapeutic use of a selective S1P1 receptor modulator ponesimod in autoimmune diabetes.

In the present study, we investigated the therapeutic potential of a selective S1P1 receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of age or to NOD mice showing recent onset diabetes. Peripheral blood and spleen B and T cell counts were significantly reduced after ponesimod administration. In pancreatic lymph nodes, B lymphocytes were increased and expressed a transitional 1-like phenotype. Chronic oral ponesimod treatment efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice. Treatment withdrawal led to synchronized disease relapse. Ponesimod did not inhibit the differentiation of autoreactive T cells as assessed by adoptive transfer of lymphocytes from treated disease-free NOD mice. In addition, it did not affect the migration, proliferation and activation of transgenic BDC2.5 cells into the target tissue. However, ponesimod inhibited spreading of the T cell responses to islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Treatment of diabetic NOD mice with ponesimod induced disease remission. However, here again, upon treatment cessation, the disease rapidly recurred. This recurrence was effectively prevented by combination treatment with a CD3 antibody leading to the restoration of self-tolerance. In conclusion, treatment with a selective S1P1 modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes.

Pet exposure and risk of atopic dermatitis at the pediatric age: a meta-analysis of birth cohort studies.

BACKGROUND: Findings on pet exposure and the risk of atopic dermatitis (AD) in children are inconsistent. OBJECTIVE: With the aim to summarize the results of exposure to different pets on AD, we undertook a meta-analysis of epidemiologic studies on this issue. METHODS: In August 2012, we conducted a systematic literature search in Medline and Embase. We included analytic studies considering exposure to dogs, cats, other pets, or pets overall during pregnancy, infancy, and/or childhood, with AD assessment performed during infancy or childhood. We calculated summary relative risks and 95% CIs using both fixed- and random-effects models. We computed summary estimates across selected subgroups. RESULTS: Twenty-six publications from 21 birth cohort studies were used in the meta-analyses. The pooled relative risks of AD for exposure versus no exposure were 0.72 (95% CI, 0.61-0.85; I(2) = 46%; results based on 15 studies) for exposure to dogs, 0.94 (95% CI, 0.76-1.16; I(2) = 54%; results based on 13 studies) for exposure to cats, and 0.75 (95% CI, 0.67-0.85; I(2) = 54%; results based on 11 studies) for exposure to pets overall. No heterogeneity emerged across the subgroups examined, except for geographic area. CONCLUSION: This meta-analysis reported a favorable effect of exposure to dogs and pets on the risk of AD in infants or children, whereas no association emerged with exposure to cats.

The etiology of autoimmune diseases: the case of myasthenia gravis.

Autoimmune diseases comprise a wide variety of disorders, from those that are acute and spontaneously regressive to chronic diseases. Their occurrence is the sign of a loss of tolerance to self-antigens. With few exceptions, the etiology of autoimmune diseases has not been clearly established. In all cases, it is complex, involving genetic, epigenetic, and environmental factors. In this article I will attempt to analyze the various factors that have a triggering or protecting role, with particular reference to myasthenia gravis.