Ways to Address Perinatal Mast Cell Activation and Focal Brain Inflammation, including Response to SARS-CoV-2, in Autism Spectrum Disorder

Abstract

The prevalence of autism spectrum disorder (ASD) continues to increase, but no distinct pathogenesis or effective treatment are known yet. The presence of many comorbidities further complicates matters, making a personalized approach necessary. An increasing number of reports indicate that inflammation of the brain leads to neurodegenerative changes, especially during perinatal life, “short-circuiting the electrical system” in the amygdala that is essential for our ability to feel emotions, but also regulates fear. Inflammation of the brain can result from the stimulation of mast cells—found in all tissues including the brain—by neuropeptides, stress, toxins, and viruses such as SARS-CoV-2, leading to the activation of microglia. These resident brain defenders then release even more inflammatory molecules and stop “pruning” nerve connections, disrupting neuronal connectivity, lowering the fear threshold, and derailing the expression of emotions, as seen in ASD. Many epidemiological studies have reported a strong association between ASD and atopic dermatitis (eczema), asthma, and food allergies/intolerance, all of which involve activated mast cells. Mast cells can be triggered by allergens, neuropeptides, stress, and toxins, leading to disruption of the blood–brain barrier (BBB) and activation of microglia. Moreover, many epidemiological studies have reported a strong association between stress and atopic dermatitis (eczema) during gestation, which involves activated mast cells. Both mast cells and microglia can also be activated by SARS-CoV-2 in affected mothers during pregnancy. We showed increased expression of the proinflammatory cytokine IL-18 and its receptor, but decreased expression of the anti-inflammatory cytokine IL-38 and its receptor IL-36R, only in the amygdala of deceased children with ASD. We further showed that the natural flavonoid luteolin is a potent inhibitor of the activation of both mast cells and microglia, but also blocks SARS-CoV-2 binding to its receptor angiotensin-converting enzyme 2 (ACE2). A treatment approach should be tailored to each individual patient and should address hyperactivity/stress, allergies, or food intolerance, with the introduction of natural molecules or drugs to inhibit mast cells and microglia, such as liposomal luteolin.

Nutraceuticals in Personalized and Precision Medicine – a preliminary scoping review indicates efficacy for disease treatment, general wellbeing, and defense against Covid-19

“…We then manually searched PubMed for articles within our 598 that were related to Covid-19, and found 15 relevant papers (Table 4). Six of them are reviews [37][38][39][40][41][42], two studies provide perhaps the clearest evidence on the subject [43,44]; one is a comparative study that perhaps provides the clearest evidence on the subject [44]. It is a retrospective report on 311 patients with severe Covid-19, treated in February of 2020 at the Wuhan Union Hospital, China.…”

A Personalized Approach to Evaluating and Treating Autism Spectrum Disorder

“…Other phenotypes such as those with immune deficiencies as well as those with autoimmune encephalopathies are also described. In another article, the importance of mast cell activation in activating microglia resulting in focal brain inflammation and disrupted synaptic pruning is discussed [11]. Similar to EDS/HSD, aberrant mast cell activation and related symptomatology are common in cohorts with ASD and may designate endophenotypes of diseases.…”

“…Two papers discuss potential treatments for immune dysfunction in ASD. Using a systematic review and meta-analysis approach, evidence for the effectiveness of intravenous immunoglobulin (IVIG) in ASD is presented [10], while another study discusses approaches to treating mast cell disorders with an emphasis on luteolin [11].…”

“…Perhaps most apparent, these articles underline the primacy of mitochondria in ASD, including oxidative stress and redox regulation, which are themselves major functions of mitochondria. Although the connection between ASD and this important cellular organelle is hardly new, this collection of papers serves to demonstrate the ubiquitous nature of the connection, which ranges from mitochondrial aspects in the prenatal and environmental risk factors/exposures [2,3,8] to biomarkers/metabolites [5,8,[12][13][14][15][16], enzymology [12], and the positive response to therapy, at least in part targeting the mitochondria [8,11,12,15,16,18,19].…”

“…Many papers also relate to another potential etiology of ASD, particularly the immune system, in which multiple interactive domains are highlighted, including innate immunity, immune deficiency, autoimmunity, inflammation, and mast cell activation [7,8,10,11,15,16]. However, similarly to neurons, leukocytes are highly dependent on energy metabolism, and the connections between energy and immunity are many and important.…”