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Brain Behav Immun. 2018 Jan;67:308-313. doi: 10.1016/j.bbi.2017.09.007. Epub 2017 Sep 18.

HLA-G coding region polymorphism is skewed in autistic spectrum disorders.

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Don C. Gnocchi Foundation IRCCS, Milano, Italy. Electronic address:
Don C. Gnocchi Foundation IRCCS, Milano, Italy.
Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna and Associazione Nazionale Famiglie di Persone con Disabilitá Intellettiva e/o Relazionale (ANFFAS), Macerata, Italy.
Section of Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Sassari, Italy.
Department of Health Sciences, University of Milano, Milano, Italy.
Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Italy.
Don C. Gnocchi Foundation IRCCS, Milano, Italy; Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy.


Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1×10-4; Danish pc=1×10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (pc=1×10-4; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2×10-3; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6×10-4 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.


Autistic spectrum disorder; Genetic polymorphism; HLA-G; Immune system; In utero immunology; Inflammation; KIR; NK cells

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