Increased serum osteopontin levels in autistic children: Relation to the disease severity

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Abstract

Autoimmunity to brain may play an etiopathogenic role in autism. Osteopontin is a pro-inflammatory cytokine that has been shown to play an important role in various autoimmune neuroinflammatory diseases. Osteopontin induces IL-17 production by T-helper 17 lymphocytes, the key players in the pathogenesis of autoimmune disorders. Anti-osteopontin treatment reduces the clinical severity of some autoimmune neuroinflammatory diseases by reducing IL-17 production. We are the first to measure serum osteopontin levels, by ELISA, in 42 autistic children in comparison to 42 healthy-matched children. The relationship between serum osteopontin levels and the severity of autism, which was assessed by using the Childhood Autism Rating Scale (CARS), was also studied. Autistic children had significantly higher serum osteopontin levels than healthy controls (P < 0.001). Increased serum osteopontin levels were found in 80.95% (34/42) of autistic children. Children with severe autism had significantly higher serum osteopontin levels than patients with mild to moderate autism (P = 0.02). Moreover, serum osteopontin levels of autistic patients had significant positive correlations with CARS (P = 0.007). In conclusions, serum osteopontin levels were increased in many autistic children and they were significantly correlated to the severity of autism. Further wide-scale studies are warranted to shed light on the etiopathogenic role of osteopontin in autism and to investigate its relation to IL-17 and brain-specific auto-antibodies, which are indicators of autoimmunity, in these patients. The therapeutic role of anti-osteopontin antibodies in amelioration of autistic manifestations should also be studied.

Highlight

► Increased osteopontin was detected in autistic children, studies are needed to reveal whether the increase is a consequence of or has a role in autism.

Introduction

The etiology of autism is not well understood. Autoimmunity to CNS, as evidenced by the presence of brain-specific auto-antibodies in some autistic children, may have a role in the pathogenesis of autism in a subgroup of patients (Cohly and Panja, 2005). Previous studies reported seropositivity of anti-myelin basic protein auto-antibodies in 58% of autistic children. These antibodies have been observed to be associated with viral serology as measles and herpes virus 6 (Singh et al., 1993, Singh et al., 1998). Autoantibodies to neuron–axon filament protein, glial fibrillary acidic protein and caudate nucleus were also reported to be increased in patients with autism (Singh et al., 1997, Singh and Rivas, 2004). More recently, seropositivity of anti-myelin-associated glycoprotein and antineuronal antibodies were reported in 62.5% and 54.5%, respectively of autistic children (Mostafa et al., 2008, Mostafa et al., 2010b). There is also an increase in the frequency of autoimmune disorders among autistic families (Comi et al., 1999, Sweeten et al., 2003, Croen et al., 2005, Atladóttir et al., 2009, Mostafa and Kitchener, 2009, Keil et al., 2010, Mostafa and Shehab, 2010, Mostafa et al., 2010a, Mostafa et al., 2010b). In spite of the fact that the origins of autoimmunity in autism are unknown, the major histocompatibility complex genes and their products might be involved (Warren et al., 1991, Odell et al., 2005, Mostafa and Shehab, 2010).

Osteopontin, also known as early T-cell activation protein of gene-1 product, is a secreted 314 amino acid pleiotropic broadly expressed phosphoglycoprotein that exists both as a component of the non-collagenous bone matrix to regulate biomineralization in the bone tissue, and as a soluble cytokine (Wesson et al., 2003). Osteopontin is not only present in the bone, but is also produced by a number of cell types including immune cells (such as mast cells, activated macrophages, leukocytes and activated T lymphocytes), chondrocytes, smooth muscle cells, epithelial cells, and endothelial cells (Denhardt et al., 2001, Nagasaka et al., 2008, Braitch and Constantinescu, 2010, Samitas et al., 2011). Osteopontin participates in wide range of biological processes, including bone remodeling, cancer and immunity to infectious disease (Denhardt et al., 2001, Gravallese, 2003, Zhao et al., 2011).

Osteopontin is implicated in the pathogenesis of various inflammatory disorders because it stimulates T cell proliferation during inflammation (Ashkar et al., 2000). Osteopontin is now considered as a potent chemo-attractive and pro-inflammatory mediator which is involved in a variety of physiologic and pathologic events, such as cell adhesion, proliferation, migration, inflammation, apoptosis, vascular remodeling, and wound healing (Giachelli and Steitz, 2000). Osteopontin also functions as a T-helper (Th) 1 cytokine that promotes cell-mediated immune responses, so it plays a role in chronic inflammatory and autoimmune diseases (Lund et al., 2009). Osteopontin-related autoimmune diseases include; autoimmune neuroinflammation [such as multiple sclerosis (MS)], rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, type 1 diabetes mellitus and autoimmune myocarditis (Chabas et al., 2001, Aspord et al., 2004, Comabella et al., 2005, Sato et al., 2005, Wong et al., 2005, Shin et al., 2006, Kariuki et al., 2009).

Since autism may be one of the pediatric autoimmune neurodevelopmental disorders, this study was the first to investigate the serum levels of osteopontin, which is a pro-inflammatory cytokine, in autistic children. The relationship between serum levels of osteopontin and the disease severity was also studied.

Section snippets

Study population

This cross-sectional study was conducted on 84 children, of whom 42 had classic-onset autism and 42 were healthy children, over a period of 6 months from the beginning of September 2010 to the end of February 2011.

The autistic group comprised 42 children (36 males and 6 females) recruited from the Autism Research and Treatment Center, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia. Patients were fulfilling the criteria for the diagnosis of autism according to the 4th edition of

Study measurements

Clinical evaluation of autistic patients: This was based on clinical history taking from caregivers, clinical examination and neuropsychiatric assessment. In addition, the disease severity was assessed by using the Childhood Autism Rating Scale (CARS) (Schopler et al., 1986) which rates the child on a scale from one to four in each of fifteen areas (relating to people; emotional response; imitation; body use; object use; listening response; fear or nervousness; verbal communication; non-verbal

Results

Autistic children had significantly higher serum osteopontin levels (mean ± SD = 197.10 ± 48.84 ng/ml) than healthy controls (mean ± SD = 122.30 ± 39.16 ng/ml), P < 0.001 (Fig. 1). Increased serum osteopontin levels were detected in 80.95% (34/42) of autistic children.

In addition, children with severe autism had significantly higher levels of serum osteopontin (mean ± SD = 209.70 ± 47.89 ng/ml) than patients with mild to moderate autism (mean ± SD = 174.40 ± 43.21 ng/ml), P = 0.02 (Table 1). Moreover, serum osteopontin levels

Discussion

Osteopontin is a key mediator that may serve to perpetuate and amplify the inflammatory process in many autoimmune disorders. Given the ameliorating effect of anti-osteopontin treatment in experimental autoimmune encephalomyelitis (EAE) in mice and in MS patients, anti-osteopontin antibodies may be an attractive candidate for therapy in autoimmune diseases (Murugaiyan et al., 2008).

In the current study, autistic children had significantly higher serum osteopontin levels than healthy controls, P <

Conflict of interest

All authors declare that there are no conflicts of interest.

Acknowledgment

This work was financially supported by the King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

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