Autism shown to not be a purely genetic disorder

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Abstract
Alterations and maladaptations of the immune system remain some of the most controversial concepts in autism spectrum disorder (ASD). Nonetheless, intensifying evidence confirms that much of what ASD involves is related not to a static encephalopathy-based model of autism but rather to the consequences of environmental insult and complex and dynamic psychological and physiological processes involving the interdependence of the nervous, immune, and host microbiome. This narrative review provides a conceptual framework, focuses on clinical research, and is written for specialists and non-specialists. To provide access to multi- and interdisciplinary perspectives with wide-ranging cutting-edge implications for all people with ASD. Beginning with historical, epidemiological, and etiological underpinnings, we elaborate on a contemporary understanding of the immune system in the pathophysiology of ASD. Theoretical and scientific discourse on the relationship of the immune system with the nervous system and host microbiota in homeostasis/allostasis, neurodevelopment, and psychological and physiological health and disease is also provided. As a basis for conceptual advances detailing the interconnection, interdependence, and interference with or subjugation (as would be the case for autoinflammatory and autoimmune conditions) of the nervous system and host microbiota by the immune system, and the role of these interactions in the pathogenesis of ASD. This gives us a platform for not only examining the role of the immune system in the etiology, pathogenesis, and pathophysiology of ASD but also understanding social and higher-level processes of consciousness for individuals on the spectrum. Finally, taking a neuroimmunological perspective, we highlight the need for a multi-scale, holistic approach to understanding and developing future therapeutic modalities to address the core symptoms of ASD that go beyond the current reductionist and “magic-bullet” medical paradigm.

Concluding Remarks
The explicit role of environmental (xenobiotic) insult in the etiology and pathogenesis of ASD has been speculated upon for over half a century and highlighted here. Chronic or acute xenobiotic activation of the immune system would trigger self-reinforcing disease processes through failed shut-off of stress-responsiveness. ASD, therefore, is an example of a situation that emerges as things “go beyond the tipping point” at various vulnerable states of neurological and immunological development. As highlighted by this review, the complex pathophysiology and heterogeneous ASD phenotype are hypothesized, for some individuals with ASD, to be related to the deregulation of the immune system. This raises the question for some individuals diagnosed with ASD of whether the manifestation of immune cell pathology and immune system dysregulation is truly involved in the pathogenesis, or whether they are epiphenomena of the disorder; and whether their brain is truly and intrinsically electrochemically “defective” or instead biochemically “obstructed”? In support of the latter model, recently D´Adamo et al. [104] provided a case report of the reversal of autism symptoms in one of two dizygotic twins, each living with a different parent, where reversal occurred only in the child who received a personalized lifestyle and environmental modification approach. These findings and other published cases of ASD reversal are encouraging. We would endorse more dialogue between parents, clinicians, and academics, with further documentation of regression and recovery. In addition, we would also endorse more research to take a “bottom-up/middle-out/top-down” approach to address the problem of how to explain the transmission of immune/biochemical/metabolic/bioenergetic perturbations (bottom) into neuro-immuno-biochemical-metabolic-bioenergetic synchronization and coherence (middle) and thence into neurocognition/behavior/social functioning (top) for individuals with ASD. A crossover of ASD pathophysiology with autoinflammatory and autoimmune conditions further provides a novel hypothesis for understanding the pathogenesis of ASD. Moreover, omics and immunomics could provide game-changing platforms to elucidate the complex interactions between genes, environment, disease pathology, and the immune system, leading to ASD phenotypes and the development of safe and effective personalized therapeutic solutions that address the core symptoms of ASD. Indeed, a key takeaway of this study would be to highlight the primary need for a multiscale, multisystem, individualized intervention approach to helping people with ASD. In addition, as such a program begins to mature, we would also endorse the design and implementation of collaborative research infrastructures to capture cognitive/emotional/social/consciousness outcomes and account for the full range of hierarchical levels of biological resolution in the people receiving these integrated treatments.

In 2009, Plotkin, Gerber, and Offit made the bold statement that: “Autism is not an immune-mediated disease. Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism” [428]. Perspectives, theories, and scientific and clinical research provided in this study are in stark contradiction to the statement expressed above. In addition, after reviewing the incredibly complex neuro-immuno-microbiota interactions implicated in clinical research, we believe that only once we understand that ASD is not genetically inevitable or a genetic tragedy but an environmental and physiological catastrophe, will we truly be able to grasp and address the root causes of the dramatic rise in its prevalence. Indeed, scientific evidence presented here would suggest that people with ASD are the “canaries in the coal mine” – that is, they are the most susceptible among us who are affected first by problems that might eventually reach us all [383]. Moreover, it is quite plausible that this catastrophe goes beyond ASD. The rise of ASD may well to a significant extent evolve, or emerge, from overlapping vulnerability pathways associated with systemic problems of other chronic diseases [572]. The point henceforward becomes not just to support and seek full recovery for those diagnosed with ASD, but also to forthrightly address how we as individuals, families, communities, and society in the contemporary era can most effectively protect future generations.

Let's hope that they never come up with genetic utero testing for autism.