Systemic lupus erythematosus, Antiphospholipid syndrome: The anti-brain antibody theory of Autism

A large set of studies have described the presence of antibodies targeting proteins localized in the central nervous system of autistic children. Moreover, an accumulation of evidences tend to point the prenatal period as a critical time where noxious events leading to autism could take place. Therefore, these so called anti-brain autoantibodies could be produced by the mother and be transmitted to the developing fetus during pregnancy. Indeed, two maternal autoimmune disorders: systemic lupus erythematosus and antiphospholipid syndrome, that give rise to autoantibody production, could be involved in autism development.

  1. What are Systemic lupus erythematosus (SLE) and anti-phospholipid syndrome?

SLE is an autoimmune disease affecting several organs and significantly increasing your risks for developing thrombotic events (blood clots formation), especially when associated with antiphospholipid antibody production. This disease is associated with a hyperactivation of B cells producing a high variety of autoantibodies (more than 100 antibodies have been described to date).
Antiphospholipid syndrome is an autoimmune disease where the immune system attacks proteins that are in the blood leading to clots formation.
These two disorders, producing autoantibodies, are very often associated. Antiphospholipid antibodies have been found in 50% of SLE patients and 20% of APS patients have also SLE, thus leading to a striking increase in thrombotic events (1).

  1. Maternal SLE, APS and autism in children: some statistics.

SLE is one of the most frequent disease reported in mothers of autistic children with an incidence of 16% while only 2% of mothers with healthy children are affected (2).
An European study including babies born from mothers with APS showed that 5% of them developed autism by the age of two and 7% by the age of 5 years old (3). Another study (4) reported a high incidence of autism cases in APS exposed children (8%), in addition to a high rate of prematurity and small for gestational age (weight < 2500g) in these babies (17% of APS offspring).

  1. SLE and APS: autoantibodies production, neurotoxicity and disruption of fetal neurodevelopment.

Brain development is a complex and sensitive process where early and disruptive events can have long lasting and damaging consequences on fetal brain development.
The central nervous system is reactive to maternal autoantibodies, as seen in animal studies where mice injected with the sera from mothers with autistic children developed autistic-like behavioral changes (5). Thus prenatal exposition to autoantibodies could contribute to ASD. It is important to point at again that maternal antibodies can cross the placenta and reach the fetus. Furthermore, the blood-brain barrier is not fully formed in the developing fetus and the brain is still susceptible to many immune and environmental factors.
Anti-phospholipid antibody (aPL) such as anti-β2 glycoprotein can bind to brain tissue (6) and disrupt the connections between the neurons (7) leading to deficit in learning and memory as well as anxiety in animal models exposed for a prolonged time (8).
Other antibodies such as anti-DNA, anti-N-methyl-D aspartate receptor, cross-reactive antibodies specifically present in women with systemic lupus erythematosus, have been shown to be neurotoxic to the developing brain in mouse models (9)

Besides the detrimental effect of autoantibodies during brain development, SLE and APS could induce a placental vascular insufficiency that could promote brain damage in the offspring (ischemia) and increase the risk of developing neurodevelopment disorder.

By inducing the production of anti-brain antibodies that can injure the developing fetal brain, it is now clear that SLE and APS put you at higher risk for having an autistic child.
The early detection and suppression of auto-antibodies from the bloodstream during pregnancy could help to prevent their potential noxious effects on fetal health.
At Braverman Reproductive Immunology, we routinely screen for several auto-antibodies and we have developed a tailored strategy to counteract and/or minimize auto-antibody production through the pregnancy.

For more information read our blog “Rituximab and Apheresis: novel dual therapy in use at Braverman Reproductive Immunology to prevent antibody-mediated inflammation during pregnancy” ( http://www.preventmiscarriage.com)

References

  1. Bazzan M, Vaccarino A, Marletto F. Systemic lupus erythematosus and thrombosis. Thromb J. 2015 Apr 23; 13:16.
  2. Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999 Jun; 14(6):388-94.
  3. Mekinian A, Lachassinne E, Nicaise-Roland P, Carbillon L, Motta M, Vicaut E, Boinot C, Avcin T, Letoumelin P, De Carolis S, Rovere-Querini P, Lambert M, Derenne S, Pourrat O, Stirnemann J, Chollet-Martin S, Biasini-Rebaioli C, Rovelli R, Lojacono A, Ambrozic A, Botta A, Benbara A, Pierre F, Allegri F, Nuzzo M, Hatron PY, Tincani A, Fain O, Aurousseau MH, Boffa MC. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2013 Feb; 72(2):217-22.
  4. Abisror N, Mekinian A, Lachassinne E, Nicaise-Roland P, De Pontual L, Chollet-Martin S, Boddaert N, Carbillon L, Fain O. Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome. Semin Arthritis Rheum. 2013 Dec; 43(3):348-51.
  5. Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: A pregnant dam mouse model. J Neuroimmunol 2009; 211: 39–48.
  6. Caronti B, Calderaro C, Alessandri C, Conti F, Tinghino R, Pini C, Palladini G, Valesini G. Serum anti-beta2-glycoprotein I antibodies from patients with antiphospholipid antibody syndrome bind central nervous system cells. J Autoimmun. 1998 Oct;11(5):425-9.
  7. Chapman J, Shoenfeld Y. Neurological and neuroendocrine-cytokine inter-relationship in the antiphospholipid syndrome. Ann N Y Acad Sci. 2002 Jun; 966:415-24. Review
  8. Shoenfeld Y, Nahum A, Korczyn AD. Neuronal-binding antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer. Lupus 2003; 12:436–42.
  9. Lee JY, Huerta PT, Zhang J, Kowal C, Bertini E, Volpe BT et al. Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat Med 2009; 15: 91–96.
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