Autism and the Immune system – Special (Momeni)

Autism Research and Treatment
Volume 2012 (2012), Article ID 868576, 6 pages
doi:10.1155/2012/868576Clinical StudyHigh

Complement Factor I Activity in the Plasma of Children with Autism Spectrum Disorders

Full study at Link

Naghi Momeni,1 Lars Brudin,2 Fatemeh Behnia,3 Berit Nordström,4 Ali Yosefi-Oudarji,5 Bengt Sivberg,4 Mohammad T. Joghataei,5 and Bengt L. Persson11School of Natural Sciences, Linnaeus University, 39182 Kalmar,  Sweden
2Department of Clinical Physiology, Kalmar County Hospital, 39185 Kalmar,  Sweden
3Department of Occupational Therapy, University of Social Welfare and Rehabilitation Sciences, Tehran,  Iran
4Department of Health Sciences, Autism Research, Faculty of Medicine, Lund University, Box 157, 22100 Lund,  Sweden
5Cellular and Molecular Research Centre, Tehran University of Medical Sciences (TUMS), Tehran,  IranReceived 17 June 2011; Revised 22 August 2011; Accepted 22 August 2011Academic Editor: Judy Van de Water Copyright © 2012 Naghi Momeni et al.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Autism spectrum disorders (ASDs) are neurodevelopmental and behavioural syndromes affecting social orientation, behaviour, and communication that can be classified as developmental disorders. ASD is also associated with immune system abnormality. Immune system abnormalities may be caused partly by complement system factor I deficiency. Complement factor I is a serine protease present in human plasma that is involved in the degradation of complement protein C3b, which is a major opsonin of the complement system. Deficiency in factor I activity is associated with an increased incidence of infections in humans.

In this paper, we show that the mean level of factor I activity in the ASD group is significantly higher than in the control group of typically developed and healthy children, suggesting that high activity of complement factor I might have an impact on the development of ASD.1.


Autism spectrum disorders (ASDs) are characterized by impairments in social interaction, communication, and repetitive or restricted patterns of interests, or behaviours, and are classified as developmental disorders in DSM-IV [1].  ASD is about 4-5 times more prevalent in boys than in girls. The ratio is estimated to range from 5.5 : 1.4 to 16.8 : 4.0 [2].

Recent research clearly indicates that the underlying causes of autism are neurobiological disorders and combinations of different factors, such as environmental and genetic factors, and abnormality in the communication between neurons, probably associated with an abnormal set of neuropeptides in the brain [3–9].

The symptoms of ASD have been linked with elevated plasma levels of serotonin [10, 11] and opioid [12], abnormal levels of melatonin [13], altered levels of activity of the serine protease prolyl endopeptidase [14], and infectious and immunological factors such as abnormalities of T cells, B cells, natural killer (NK) cells, and of the complement system [15–21].

The complement system comprises a group of proteins which, when activated, provide one of the first lines of defence by promoting lysis and the removal of invading microbes.

Activation of the complement system in response to an infection or foreign antigen is achieved via three complement pathways, the classical pathway, which is activated by antigen-antibody complexes, the lectin pathway, which is activated by the interaction of microbial carbohydrates with mannose-binding proteins in the plasma and tissue fluids, and the alternative complement pathway, which is activated by C3b binding to microbial surfaces and to antibody molecules.

All of the three pathways converge with the activation of the central C3 component. This leads to a final common pathway with assembly of the C5–C9 components to form a cell surface transmembrane pore (membrane attack complex) [22, 23]. It has been shown by comparison with healthy control children that several differentially expressed proteins are related to the complement system in children with ASD [22]. The alternative pathway consists of six proteins: C3, factor B, factor D, factor H, factor I, and properdin. The plasma glycoprotein factor I (C3b/C4b inactivator) is a serine protease that acts as a regulator of the complement C3 cascade. Factor I has a molecular weight of about 88 kDa, consists of two disulfide-linked polypeptide chains (50 kDa and 38 kDa, respectively), and is synthesized as a single-chain precursor in the liver [24, 25]. Factor I cleaves C3b and C4b in a reaction, where fI is dependent on various cofactors, such as factor H, C4b-binding protein CR1 and membrane cofactor protein (MCP) [26]. Factor I-mediated cleavage of the α chain of C3b liberates 3 fragments with molecular weights of 68 kDa, 43 kDa, and 2 kDa. Degradation of C3b by fI abrogates the action of this protein in the C3 pathway [27]. Complement C3b is the major opsonin of the complement system which facilitates the phagocytosis process by coating antigens (each of the phagocytes expresses a complement receptor such as CR1, CR3, or CR4 that binds C3b, C4b, or C3bi) [28, 29]. Factor I deficiency can be conferred by a C3 deficiency, since this also increases susceptibility to pyogenic infections by Neisseria meningitides, Haemophilus influenza, and Streptococcus pneumonia and increases the incidence of immune complex diseases due to impaired complement-mediated function [30].

Immune system abnormalities have been associated with autism [15–20], and it has been suggested that children with ASD might have an increased incidence of bacterial inflammation [31]. Immunological aspects of the early onset of autism have recently highlighted the fact that immune dysfunction may occur in some children with autism [31, 32].Having previously discovered altered levels of the serine protease prolyl endopeptidase in children with ASD [14], the aim of this study was to investigate if an association exists between serine protease fI deficiency and the development of ASD.

4. Discussion

The aetiology of ASD is still largely unknown despite the fact that many factors such as genetic, environmental, immunological, and neurological aspects are thought to influence the development of ASD [39].

A dysregulated immune response has been reported among children with ASD. Protein products of immune activation, such as cytokines, can be linked to core features of ASD, such as difficulties to regulate affect, sleep, nutritional uptake, and can also affect behaviour and social communication [39].

This study highlights an elevated level of factor I that may contribute to a dysregulation of the immune response associated with the complement system.

Recent research proposes an extensive communication between the immune and nervous systems, affecting both the development of the central nervous system [32] in the promotion of health as well as disease. Early damage during critical periods in neurodevelopment of the foetus has in a mouse model study been shown to affect cognitive development. It is reasonable to suggest that complement factor I might contribute to ASD, while changes in the complement system may predispose the mother or foetus to infections during development, possibly causing resultant abnormalities in brain development [22].

Also, the frequency of autoimmune diseases has been reported to be significantly higher in families with a child with ASD [40] than in families with children with typical development.The pathophysiology of ASD is poorly understood. Children with ASD are prone to recurrent viral and bacterial inflammations.

There are also some reports of immune system abnormalities in children with ASD [15–20]. An association between ASD and immune system abnormalities together with the vulnerability of the ASD group with regard to inflammatory processes may indicate an impaired mechanism in this system. It is known that phagocytosis is an important part of the body’s defence mechanism. This mechanism requires an active complement system and a functioning C3b protein.

C3b is degraded by fI, and abnormal fI activity might cause an abnormal and uncontrolled degradation of C3b protein, resulting in the loss of the phagocytosis function for this particular protein (a function which partly protects the body from invasion of foreign organisms).

Altered levels of other serine protease activities, such as that of proline endopeptidase (PEP), have also been found in a group of children with ASD when compared to a control group [14]. The results of the present study, together with our previous findings on altered levels of PEP activity, may indicate a connection between the onset of ASD and serine protease dysfunction.

The higher plasma fI activity observed in the male group as compared to that of the female group (Figure 2) is paralleled by a higher occurrence of ASD in male children.

Also, the higher plasma fI activity in children younger than six years of age may indicate that the inflammatory process is more active in younger ages or that we may be dealing with two subgroups of children with ASD with different onsets of the disease.5.


The preliminary findings of this study together with our previous report [14] suggest that there may be an association between abnormal serine protease activity and the development of ASD. Further research is needed, however, to establish a possible role of serine proteases in the aetiology of ASD.

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