Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome

Journal of Neuroinflammation

Paul Ashwood⁴  Randi J Hagerman³  Flora Tassone¹  Judy Van de Water²  Kirin Basuta¹  Tamanna Noyon⁴  Milo Careaga⁴ 

[1] Department of Biochemistry and Molecular Medicine, UC Davis, Davis, CA, USA;Division of Rheumatology, Allergy and Clinical Immunology, UC Davis, Davis, CA, USA;Department of Pediatrics, University of California at Davis, Davis, CA, USA;MIND Institute, UC Davis Medical Center, Sacramento, CA, USA

关键词: Metabotropic glutamate receptor;    Cytokine;    Immune;    Fragile x syndrome;   

Others  :  1151579
DOI  :  10.1186/1742-2094-11-110

 received in 2014-03-05, accepted in 2014-05-27,  发布年份 2014

【 摘 要 】

Background

Fragile X syndrome (FXS) is the leading cause of inheritable intellectual disability in male children, and is predominantly caused by a single gene mutation resulting in expanded trinucleotide CGG-repeats within the 5’ untranslated region of the fragile X mental retardation (FMR1) gene. Reports have suggested the presence of immune dysregulation in FXS with evidence of altered plasma cytokine levels; however, no studies have directly assessed functional cellular immune responses in children with FXS. In order to ascertain if immune dysregulation is present in children with FXS, dynamic cellular responses to immune stimulation were examined.

Methods

Peripheral blood mononuclear cells (PBMC) were from male children with FXS (n = 27) and from male aged-matched typically developing (TD) controls (n = 8). PBMC were cultured for 48 hours in media alone or with lipopolysaccharides (LPS; 1 μg/mL) to stimulate the innate immune response or with phytohemagglutinin (PHA; 8 μg/mL) to stimulate the adaptive T-cell response. Additionally, the group I mGluR agonist, DHPG, was added to cultures to ascertain the role of mGluR signaling in the immune response in subject with FXS. Supernatants were harvested and cytokine levels were assessed using Luminex multiplexing technology.

Results

Children with FXS displayed similar innate immune response following challenge with LPS alone when compared with TD controls; however, when LPS was added in the presence of a group I mGluR agonist, DHPG, increased immune response were observed in children with FXS for a number of pro-inflammatory cytokines including IL-6 (P = 0.02), and IL-12p40 (P < 0.01). Following PHA stimulation, with or without DHPG, no significant differences between subjects with FXS and TD were seen.

Conclusions

In unstimulated cultures, subjects with FXS did not display altered dynamic immune response to LPS or PHA alone; however, subjects with FXS showed an altered response to co-current stimulation of LPS and DHPG, such that subjects with FXS failed to inhibit production of pro-inflammatory cytokines, suggesting a role of group I mGluR signaling in innate immune responses in FXS.

【 授权许可】

   
2014 Careaga et al.; licensee BioMed Central Ltd.

【 图 表 】

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