What are the fetal predispositions to autism?

The etiology of ASD remain unclear although genetic causes clearly contribute to the risks of developing the disease. The most striking evidence of the disease genetic compound was shown by studies on twins where the concordance rate on monozygotic twins was around 40-90% whereas dizygotic twin were between 0 and 10% concordant (1). Moreover family studies showed that there is a 3- to 8-fold higher risk for siblings of autistic children compared to the general population (2). The wide variety of phenotypes in ASD patients strongly suggest the involvement of several genes.

HLA proteins

The Human Leukocyte Antigen (HLA) is part of the Major Histocompatibility Complex (MHC) located on the chromosome 6 in human. It is a polygenic (containing multiple genes) and polymorphic complex (containing multiple variants of each gene) that plays a key role in innate and adaptive immunity (3). HLA proteins are expressed on the surface of all nucleated cells that present peptide antigen to receptors on T lymphocytes. Its role in autoimmune diseases such as diabetes (4) or rheumatoid arthritis (5) have been known for many years.
HLA molecules have been shown to play a crucial role in brain development and its plasticity (6-7). They have been suspected to be involved in autism over 30 years ago (8) and recent studies have confirmed this association (9).
The frequencies of HLA class I and class II among autistic children have been studied and compared to control healthy children.

HLA-A:
HLA-A*01 and HLA-A*02 alleles have been shown to be at least 2-fold time more present in a population of 35 autistic children when compared to 100 healthy control individuals (10) and this was confirmed in another independent study (9). More interestingly, HLA-B*07 was a 42-fold time more present in autistic children when compared to control. HLA-A*02 has been suspected to predispose children to have an immune imbalance (CD4 + naïve and memory T cells alteration) that may induce or aggravate the disease (11).

HLA-B:
Most of the studies did not report any association between HLA-B and autism. To our knowledge, HLA-B*07 is the only allele significantly associated with autism (10).

HLA-DRB1:
HLA-DRB1*04 (DRB1*0404 or DRB1*0401) and HLA-DRB1*11 alleles have been associated with an increased risk of autism while HLA-DRB1*13 alleles have been associated with protection from autism risk (12-14). DRB1 is a key factor in autism based on genetic and epidemiology evidences (15-18) and a subset of autism cases could be linked to an immune regulation through DRB1 as suggested by a recent study (19).

KIR proteins

Killer-cell immune globulin- like receptor (KIR) proteins are receptors present on the surface of Natural Killer cells (NK cells) and are binding HLA proteins. They can modulate NK cells activity depending on their nature: activating aKIR or inhibitory iKIR (20).

NK cells play a crucial role in innate immune reactions by producing inflammatory cytokines. KIR/HLA interactions could be involved in autoimmune disease development such as multiple sclerosis (21).

In a recent study, autistic children showed a higher association between aKIR (KIR2DS2)/HLA and a lower association between iKIR (KIR3DL1)/HLA (22). These data were confirmed by another study where aKIR (KIR 2DS5, 3DS1, 2DS1and 2DS4)/HLA were also highly present in autistic children (23). This highlights the hyperactivity of NK cells in autism as previously suggested (24) that could create an inflammatory environment harmful to brain development.

Complement 4B null allele (C4BQ0)

C4 proteins are part of the complement cascade and are involved in innate immunity. They are the product of two genes C4A and C4B and are part of the class III MHC. An altered expression of these proteins is involved in autoimmune disease (25), in particular the complement C4B null allele (no production of C4 B protein) has been associated with autoimmune disease such as lupus (26).

Several studies have shown that C4BQ0 is associated with autism. A low level of C4B protein is associated with brain autoantibodies production in autistic patient (27). Autism is associated with a higher frequency of C4B null allele but not C4A (28). In a more recent study, C4B null allele was also identified in autistic subjects at a higher frequency than in healthy controls (29-30). In 2010, C4B null allele was found in 37.5% of autistic patients but only in 8.75% of the control children (31).

The complement system play an important role in protecting brain from pathogens (32) and is involved in brain plasticity (33). A low level of C4 protein could have deleterious consequences on brain development during embryonic life.


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