Who are the maternal populations at risk?

A large number of epidemiological studies have investigated the relation between a family history of autoimmune diseases and autism incidence. More specifically, maternal health and immune system could dramatically impact fetal growth and development including brain formation.
The association between maternal autoimmune diseases and ASD might be attributable to two factors:

  • A common genetic background between ASD and the maternal autoimmune disease.
  • An alteration of the fetal environment by the maternal autoimmune disease through the production of autoantibodies and inflammatory cytokines by the maternal immune system that can attack the brain during its development and impair its formation (this point will be developed in the section " Maternal inflammation and Autism").

Maternal autoimmune disease and genetic predisposition

Several studies reported an increased risk for autistic children with a mother affected by rheumatoid arthritis (RA), celiac disease or type I diabetes (1-2).

Rheumatoid arthritis (RA):
Rheumatoid arthritis is a chronic inflammatory joint disease that affect up to 1% of the population in USA. Several lines of evidence incriminate the HLA class II gene complex that has been associated with an increased risk for both RA and autism. In particular, the third hypervariable region on the HLA-DRB1 gene has been associated with RA but also with autism (3), with the strongest association being found for HLA-DRB1*0401 and HLA-DRB1*0404 alleles (4) or HLA-DRB1*0101 allele (5). On the other hand, HLA-DRB1*13 allele protects from RA and autism (5). These results strongly suggest a common genetic etiology between RA and autism.

Type 1 diabetes
Type 1 diabetes (T1D) is a chronic, progressive autoimmune disorder char­acterized by the destruction of a particular set of cells within the pancreas that secrete insulin (6). Few common genetic profiles have been found between autism and T1D.

Among them, HLA-DR4, an allele present in the DRB1 locus has been associated, in different studies, with mothers of autistic children (7-9), where they were up to 5.5 times more likely to have HLA-DR4 than control individuals (10). Moreover, HLA-DR4 is also associated with T1D (11, 12). The immune system is involved in brain development and plasticity (13). HLA-DR4 was proposed to alter maternal immune system during pregnancy thus impacting brain development (14).

The complement C4B null allele has also been found in both diseases (15-17). A greater risk of ASDs after a history of maternal T1D has been observed (1).

Psoriasis is a chronic, long lasting disease of the immune system whose symptoms are visible on the skin in the form of itchy, red plaques. An increased incidence of psoriasis has been detected in mothers of children with autism (19). The killer-cell immune globulin-like receptor (KIR) proteins, present on the surface of NK cells and interacting with HLA ligands have been strongly associated with autism (20). In particular, a NK cells activating KIR, KIR2DS1 showed high association with autism and has been associated with psoriasis (21).

Celiac disease
Celiac disease is an autoimmune disease where the immune system attacks the individual small intestine in response to gluten (22). Although risks for schizophrenia was found to be increased in individuals with a parent having a celiac disease (23), very little work has been done to link this autoimmune disorder to autism. Previous studies failed to show an association between celiac disease in autistic children (24). However, celiac disease in the mother is associated to autistic children (25).

Ulcerative colitis (UC)

Ulcerative colitis is an autoimmune disorder, classified as an inflammatory bowel disease (IBD) that affects the large intestine (the rectum and part or all the colon). A study comparing the rate of UC in parents of autistic children (n=111, 2.7%) to parents of healthy control children (n=330, 0.3%) showed a strong association of autism with maternal UC (26).

Antiphospholipid syndrome (APS)

Antiphospholipid syndrome is an autoimmune disease where the immune system attacks protein that are in the blood leading to clots formation. A European study of babies born from mothers with APS showed that 5% of them developed autism by the age of 24 months and 7% developed autism by the age of 5 years old (27). Another study reported several cases of autism in APS-exposed children with an incidence of 8% (28).

In conclusion, the present examples strongly suggest that maternal autoimmune disease increase the risks of autism in their children. This neurodevelopmental disorder could find its roots during pregnancy where the fetal environment can be severely compromised. This damages brain formation by altering critical steps of its development which can lead to autism.

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