L'hormone stimulant la thyroïde et les niveaux d'interleukine-8 chez les garçons avec un diagnostic de "trouble du spectre de l'autisme"

Aperçu: G.M.

Le "trouble du spectre de l'autisme" (TSA) affecte environ 1 enfant sur 68 aux États-Unis. Un biomarqueur TSA sanguin peut permettre un diagnostic précoce et / ou l'identification de nouvelles cibles thérapeutiques. Les échantillons de sérum provenant de garçons avec un diagnostic de TSA (TSA) ou avec un développement typique (TD) (n = 30 / groupe) ont été dépistés pour détecter les différences dans 110 protéines. 

L'équipe a trouvé onze protéines qui, ensemble, pouvaient confirmer les TSA avec une précision modeste. Deux des 11 protéines identifiées ici ont été testées en utilisant une plate-forme de détection différente et avec un échantillon plus important de garçons TSA et TD. Les deux protéines, l'hormone stimulant la thyroïde (TSH) et l'interleukine-8 (IL-8) ont été précédemment identifiées comme des biomarqueurs putatifs pour les TSA. Les taux de TSH étaient significativement plus faibles chez les garçons TSA, alors que les taux d'IL-8 étaient significativement élevés.

 

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J Neuroinflammation. 2017 Jun 2;14(1):113. doi: 10.1186/s12974-017-0888-4.

Serum thyroid-stimulating hormone and interleukin-8 levels in boys with autism spectrum disorder

Singh S^1,2, Yazdani U¹, Gadad B¹, Zaman S¹, Hynan LS^1,3, Roatch N⁴, Schutte C⁴, Marti CN⁵, Hewitson L⁴, German DC⁶.

Author information

1

Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9070, USA.

2

Present Address: Toxicology Division, CSIR-CDRI, Lucknow, 226021, Uttar Pradesh, India.

3

Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.

4

The Johnson Center for Child Health and Development, 1700 Rio Grande St., Austin, TX, 78701, USA.

5

Abacist Analytics, LLC, Austin, TX, 78701, USA.

6

Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9070, USA. dwight.german@utsouthwestern.edu.

Abstract

BACKGROUND:

Autism spectrum disorder (ASD) affects approximately 1 in 68 children in the USA. An ASD blood biomarker may enable early diagnosis and/or identification of new therapeutic targets. Serum samples from ASD and typically developing (TD) boys (n = 30/group) were screened for differences in 110 proteins using a multiplex immunoassay.

RESULTS:

Eleven proteins were found that together could confirm ASD with modest accuracy using multiple training and test sets. Two of the 11 proteins identified here were further tested using a different detection platform and with a larger sample of ASD and TD boys. The two proteins, thyroid-stimulating hormone (TSH) and interleukin-8 (IL-8), have been previously identified as putative biomarkers for ASD. TSH levels were significantly lower in ASD boys, whereas IL-8 levels were significantly elevated. The diagnostic accuracy for ASD based upon TSH or IL-8 levels alone varied from 74 to 76%, but using both proteins together, the diagnostic accuracy increased to 82%. In addition, TSH levels were negatively correlated with the Autism Diagnostic Observation Schedule subdomain scores.

CONCLUSIONS:

These data suggest that a panel of proteins may be useful as a putative blood biomarker for ASD.

PMID: 28577577

PMCID:PMC5457729

DOI:10.1186/s12974-017-0888-4

La protéine IL1RAPL1 de déficience intellectuelle liée au X régule la complexité de la dendrite

Aperçu: G.M.

Les mutations et les délétions de la protéine du récepteur de l'interleukine-1 comme le gène 1 (IL1RAPL1), localisée sur le chromosome X, sont associées à une déficience intellectuelle (ID) et à un "trouble du spectre de l'autisme" (TSA).  

Les données révèlent une nouvelle fonction spécifique pour IL1RAPL1 dans la régulation de la morphologie de la dendrite qui peut aider à clarifier la façon dont les changements dans les voies régulées par IL1RAPL1 peuvent conduire à des troubles cognitifs chez l'homme. 

J Neurosci. 2017 Jun 2. pii: 3775-16. doi: 10.1523/JNEUROSCI.3775-16.2017.

The X-linked intellectual disability protein IL1RAPL1 regulates dendrite complexity

Montani C^1,2, Ramos-Brossier M³, Ponzoni L^2,4, Gritti L^5,2, Cwetsch AW⁶, Braida D², Saillour Y³, Terragni B⁷, Mantegazza M⁸, Sala M⁵, Verpelli C^5,2, Billuart P³, Sala C^5,2.

Author information

1

CNR Neuroscience Institute, Milan, Italy c.sala@in.cnr.it.

2

Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.

3

Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.

4

Fondazione Umberto Veronesi, Milan, Italy.

5

CNR Neuroscience Institute, Milan, Italy.

6

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Genoa, Italy.

7

U.O. of Neurophysiopathology and Diagnostic Epileptology, Foundation Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Neurological Institute Carlo Besta, Milan, Italy.

8

Institute of Molecular and Cellular Pharmacology (IPMC), Laboratory of Excellence Ion Channel Science and Therapeutics (LabEx ICST), CNRS UMR7275 and University of Nice-Sophia Antipolis, Valbonne, France.

Abstract

Mutations and deletions of Interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene, localized on X chromosome, are associated to intellectual disability (ID) and autism spectrum disorder (ASD). IL1RAPL1 protein is localized at the postsynaptic compartment of excitatory synapses and plays a role in synapse formation and stabilization. Here we characterized the role of IL1RAPL1 in regulating dendrite morphology using primary neuronal cultures and Il1rapl1-KO mice. We identified, associated to hippocampal cognitive impairment, an increased number of dendrite branching points in CA1 and CA2 hippocampal neurons of Il1rapl1-KO mice. Similarly, iPSCs-derived neurons form a patient carrying a null mutation of IL1RAPL1 gene have higher number of dendrites. In hippocampal neurons, the overexpression of full length IL1RAPL1 and mutants lacking part of C-terminal domains leads to a simplification of neuronal arborisation. This effect is abolished when we overexpressed mutants lacking part of N-terminal domains indicating that the IL1RAPL1 extracellular domain is required for regulating dendrite development. We also demonstrate that PTPδ interaction is not required for this activity, while IL1RAPL1 mediates the activity of IL-1β on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help to clarify how any changes in IL1RAPL1-regulated pathways can lead to cognitive disorders in humans.SIGNIFICANCE STATEMENTAbnormalities in the architecture of dendrites have been observed in a variety of neurodevelopmental, neurodegenerative and neuropsychiatric disorders. Here we show that the X-linked intellectual disability protein IL1RAPL1 regulates dendrite morphology of mice hippocampal neurons and iPSCs-derived neurons form patient carrying a null mutation of IL1RAPL1 gene. We also found that the extracellular domain of IL1RAPL1 is required for this effect, independently of the interaction with PTPδ but IL1RAPL1 mediates the activity of IL-1β on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help to clarify how any changes in IL1RAPL1-regulated pathways can lead to cognitive disorders in humans.

Copyright © 2017 the authors.

PMID: 28576939

DOI: 10.1523/JNEUROSCI.3775-16.2017

IL-17A maternelle dans l'autisme

Aperçu: G.M.

Bien que le trouble du spectre de l'autisme (TSA) ait une base génétique forte, son étiologie est complexe, avec plusieurs facteurs génétiques susceptibles d'être impliqués ainsi que des facteurs environnementaux. La dysrégulation immunitaire a suscité une attention particulière en tant que mécanisme causal de la pathogenèse des TSA. L'ASD a été associée à des anomalies immunitaires dans le cerveau et la périphérie, y compris les troubles inflammatoires et l'auto-immunité non seulement chez les personnes concernées, mais aussi chez leurs mères. L'exposition prénatale à l'activation immunitaire maternelle (MIA) a été impliquée comme un facteur de risque environnemental pour la TSA. À l'appui de cette notion, les modèles animaux ont montré que la MIA entraîne une descendance avec des anomalies comportementales, neurologiques et immunologiques similaires à celles observées dans les TSA. Cela soulève la question de savoir comment l'exposition à la MIA peut entraîner un TSA chez les personnes sensibles. Des preuves récentes indiquent une voie d'inflammation potentielle reliant le TSA associé à MIA avec l'activité des lymphocytes T helper 17 (Th17) et leur cytokine effectrice interleukine-17A (IL-17A). L'IL-17A a été impliquée dans des études humaines et les taux élevés d'IL-17A dans le sang se sont révélés en corrélation avec la sévérité phénotypique dans un sous-ensemble d'individus avec TSA. L'IL-17A peut exercer de forts effets sur la survie et la différenciation des cellules et l'activité des cascades de transduction du signal, qui peuvent avoir des conséquences importantes lors du développement cortical sur la fonction neurale. Cet examen examine les voies de signalisation de l'IL-17A dans le contexte de l'immunité et de la fonction neuronale qui peuvent contribuer au développement d'un ASD associé à MIA. 

Exp Neurol. 2017 Apr 25. pii: S0014-4886(17)30105-X. doi: 10.1016/j.expneurol.2017.04.010.

Maternal IL-17A in autism

Wong H¹, Hoeffer C².

Author information

1

Institute for Behavioral Genetics, University of Colorado-Boulder, CO 80303, United States; Department of Integrative Physiology, University of Colorado-Boulder, Boulder, CO 80303, United States; Linda Crnic Institute, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, United States.

2

Institute for Behavioral Genetics, University of Colorado-Boulder, CO 80303, United States; Department of Integrative Physiology, University of Colorado-Boulder, Boulder, CO 80303, United States; Linda Crnic Institute, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, United States. Electronic address: charles.hoeffer@colorado.edu.

Abstract

Although autism spectrum disorder (ASD) has a strong genetic basis, its etiology is complex, with several genetic factors likely to be involved as well as environmental factors. Immune dysregulation has gained significant attention as a causal mechanism in ASD pathogenesis. ASD has been associated with immune abnormalities in the brain and periphery, including inflammatory disorders and autoimmunity in not only the affected individuals but also their mothers. Prenatal exposure to maternal immune activation (MIA) has been implicated as an environmental risk factor for ASD. In support of this notion, animal models have shown that MIA results in offspring with behavioral, neurological, and immunological abnormalities similar to those observed in ASD. This raises the question of how MIA exposure can lead to ASD in susceptible individuals. Recent evidence points to a potential inflammation pathway linking MIA-associated ASD with the activity of T helper 17 (Th17) lymphocytes and their effector cytokine interleukin-17A (IL-17A). IL-17A has been implicated from human studies and elevated IL-17A levels in the blood have been found to correlate with phenotypic severity in a subset of ASD individuals. In MIA model mice, elevated IL-17A levels also have been observed. Additionally, antibody blockade to inhibit IL-17A signaling was found to prevent ASD-like behaviors in offspring exposed to MIA. Therefore, IL-17A dysregulation may play a causal role in the development of ASD. The source of increased IL-17A in the MIA mouse model was attributed to maternal Th17 cells because genetic removal of the transcription factor RORγt to selectively inhibit Th17 differentiation in pregnant mice was able to prevent ASD-like behaviors in the offspring. Similar to ASD individuals, the MIA-exposed offspring also displayed cortical dysplasia which could be prevented by inhibition of IL-17A signaling in pregnant mice. This finding reveals one possible cellular mechanism through which ASD-related cognitive and behavioral deficits may emerge following maternal inflammation. IL-17A can exert strong effects on cell survival and differentiation and the activity of signal transduction cascades, which can have important consequences during cortical development on neural function. This review examines IL-17A signaling pathways in the context of both immunity and neural function that may contribute to the development of ASD associated with MIA.

Copyright © 2017 Elsevier Inc. All rights reserved.

PMID: 28455196

DOI: 10.1016/j.expneurol.2017.04.010