Since its first use in the early 1900s to describe a cluster of abnormal symptoms observed in a group of schizophrenics, and later similar symptoms in children, there have been significant advances in the understanding and treatment of ASD. There are still, however, many unanswered questions concerning the etiology of ASD as genetic variability among autistic individuals coupled with diverse phenotypic presentations have complicated the identification of a single causative agent. Nevertheless, researchers have made significant progress and have identified several genes differentially expressed in autistic individuals. Although these genes are not sufficient to cause ASD, they may provide a way to identify genetically susceptible individuals, or aid in the diagnosis of this disorder. Recently, maternal infection and fetal exposure to maternal cytokines, primarily IL-6, have been identified as potential environmental ‘trigger’, which, when coupled with certain genetic polymorphism, may lead to the development of ASD. Although the exact mechanism by which IL-6 elicits these events is unknown, its identification provides a potential diagnostic marker and therapeutic intervention point for ASD.
These advancements are promising; however, several unanswered questions still remain, prompting the need for more research. The identification of IL-6 as a potential trigger, for example, has raised questions concerning the ability of cytokines to traverse the placental barrier, and whether or not this passage is confined to certain developmental time points. Also unknown is whether or not the placenta itself contributes to the increase in fetal cytokine expression, as this has been observed in the absence of maternal cytokine migration. Researchers are also faced with the question concerning the mechanism by which IL-6 induces the abnormalities observed clinically in autism and whether or not inhibition of pathological IL-6 is sufficient to attenuate these abnormalities. It is also unclear as to whether or not maternally derived IL-6 is sufficient to promote the development of ASD or whether certain genetic polymorphisms are needed. Although animal models of MIA suggest that IL-6 is sufficient to induce the behavioral, immunological and neurological abnormalities observed in ASD, it is still unclear whether these findings completely mirror clinical observations. The role of genetics in the etiology of ASD also poses several questions including why some people, exposed prenatally to maternal cytokines may develop ASD while others do not.
As we investigate the etiology of this disorder, there are also important questions that arise concerning the diagnosis of this disorder. Although it is well accepted that autism is a part of a spectrum of disorders collectively referred to as ASD, there are some within the research and clinical community that would classify it as a syndrome, a singular manifestation of different disorders. This approach may explain the difficulty in determining the exact etiology of the disorder as well as the diversity of phenotypes presented clinically. Proponents of the syndrome approach argue that the term spectrum suggests a singular disorder with clinical symptoms varying within a given phenotypic range or spectrum. As a syndrome, researchers such as Mary Coleman and Christopher Gillberg suggest that autism is a singular phenotypic presentation of different diseases with varying etiologies [172
]. This approach suggests that autism may be a phenotype manifested as a result of different diseases and etiologies acting singularly or synergistically to produce the behavioral symptoms manifested clinically. Although Coleman's and Gillberg's suggestions differ from current norms within the ASD community, they do acknowledge the diagnostic importance of investigating autism as a spectrum disorder as it is necessary in the initial diagnosis. It is for the investigation of etiologies and the provision of therapeutics that these authors propose newer approaches, as the treatment of autism as a product of its etiology may be advantageous in providing more patient-tailored treatments. Whether a syndrome or a spectrum, it is evident that autism or ASD is the result of several etiologies. It is also evident that environmental triggers, when coupled with genetic polymorphisms, may lead to diverse phenotypic presentations. What is not known is how these factors, genetics and environment, interact in a given individual to precipitate this disorder.
These are just a few of the questions facing researchers today, and although significant advancements have been made, these advancements have also created more questions. Nevertheless, the identification of IL-6, among other discoveries, has paved the way for improved diagnostic criteria in addition to new therapeutic intervention points. The potential for IL-6 as an intervention point is also promising as it provides a measurable diagnostic marker in addition to potential therapeutic target. With these advancements, early therapeutic intervention, with the goal of significantly attenuating or alleviating the symptoms of ASD, may eventually become a treatment option as opposed to strictly palliative therapy.