On "Bettelheiming"

 

I began working with children with autism back in 1995, and most of the history of autism before the mid 2000s has been erased (enabling new narratives to be presented and accepted) so I want to add some of it back here. Bettelheim was a complete fraud and charlatan. He fabricated any credentials and expertise he claimed to have, and wrote his book "The Empty Fortress" based entirely on conjecture. Despite this, his book and theory (the notorious "refrigerator mother" theory) were unquestioningly accepted by mainstream medicine and for decades all treatment of autism was based entirely on his "work"- no research or independent inquiry was done at all. What this meant was that children with autism and their mothers were sent to psychiatrists who interpreted everything the child did as a sign of alienation by the mother (for example, a child who had a stim of knocking on things was said to be "knocking on his mother's emotions, asking to be let in"). No attempt was made to try to understand the person with autism or help them or teach them or ease their distress. The mothers were told that they had caused their child's autism (remember that at this time, autism meant the form that we now call "profound" or "level 3" autism only) and were shunned. Often they were made to wait outside because they were told they were so heinous for what they had done that they weren't worthy or deserving of human treatment. There were times when a child died in an accident (remember, we're talking about level 3 autism in a world with zero accommodations or awareness) and the mothers were told that the child had intentionally unalived themselves to get away from them. There were mass self-unalivings of mothers at this time because society trusted and believed what the doctors said without question (until Bernie Rimland came along, who has also largely been erased, and who finally did some research and created the beginnings of the concept of autism we have now of it being a neurodevelopmental disorder), and the weight of that blame and self-blame was more than many could cope with.

When people say that the history of autism treatment is filled with "snake oil salesmen" this began with western medicine. The word "quackery" referring to doctors was first coined to describe AMA doctors when they were new on the scene. They never acknowledged or apologized for the harm they did by embracing Bettelheim with such anti-scientific fervor. "Bettelheiming" is much more than not being believed- it's being scapegoated, bullied into silence, blame-shifted and victim-blamed and it was often deadly. If you listen to what families of people with Level 3 autism have been saying this past month, things haven't gotten much better, only now it's parts of the autism community itself who have been co-opted into this bullying. This is why history matters. This is what can happen when it gets erased. This is the tip of the iceberg of just the history of autism, let alone all the other history that has been erased in America.

Mast Cells Function as Sensors of Food Quality

IgE-Mast cell mediated allergy: a sensor of food quality
“allergic sensitization triggers the formation of avoidance behavior”, food can contain toxic noxious substances in different amounts and our bodies have ways of directly sensing it and responding to protect itself, including extra mucous production, nausea, vomiting, diarrhea, malabsorption, increased peristalsis.  These protective responses can be in response to our bodies sensing the toxicity via smell, taste, chemosensors in the gut.  This is a system that senses food quality and is more general and doesn’t adapt over time.

“Type 1 allergic reactions can induce similar symptoms as already known sensors of food quality. This similarity suggested that type 1 allergic reactions may also act as a ‘food quality control system” that allows learning and behaviour adaptation.³ The great advantage of involving the immune system would be its ability to recognize a nearly infinite number of distinct substances in a very specific manner, which is an original property of the adaptive immune system.” , “early type 1 allergic reactions trigger persistent allergen-specific avoidance behavior” , mice that were deficient in IgE and/or mast cells didn’t develop avoidance behavior.  “Type 1 allergic reactions promote protective antigen avoidance behaviour via IgE armed mast cells.”

“In response to allergic stimulation, cytokines from Tfh cells promote antibody class switch and antibody secretion by B cells, which yield antibodies of various isotypes, including IgE and IgG. IgE arms mast cells with an antigen-specific receptor.”, “during the early preclinical allergic response, mast cells are sufficiently activated to release leukotrienes, which triggers long-lasting allergen-specific avoidance behavior.”  If the exposure to the allergen persists IgE levels may increase and it increases its affinity to the allergen and “trigger strong mast cell activation and allergic disease.”

“In the absence of IgE or mast cells, allergen ingestion is increased, eventually leading to severe immunopathology.”

“IgE production is dependent on IL-4 from T follicular helper (Tfh) cells. This cytokine is sufficient to induce low affinity IgE, which however does not induce severe allergic symptoms, while additional cytokines from Tfh13 cells, including IL-13 and IL-21, are required for the development of high affinity IgE and anaphylaxis”

“High affinity IgE-mediated mast cell activation is the major mechanism for the induction of severe type-1 allergic reactions.” “murine IgG1 (human IgG4) antibodies which are also induced by IL-4, can trigger anaphylaxis too, though only in the presence of higher amounts of antigen” 

“Antibodies of the subclasses IgG2 and IgG3 are not IL-4 dependent, may not contribute to the pathology of type 1 allergic reactions, but can mediate severe inflammation via the activation of the complement system and various innate effector cells.”

“most allergic symptoms are absent in IgE deficient mice, even after forced uptake of high amounts of allergen, they still develop severe anaphylaxis, probably involving antibodies of other subclasses.”

“This work reveals a protective role of IgE-mediated mast cell activation, acting via modification of behavior.”

“even early allergic symptoms are associated with the activation of areas of the brain involved in the response to aversive stimuli.” 

“the induction of allergen avoidance behavior required only mild allergic reactions mediated by IgE, which precede the development of gut allergic inflammation. Evidence was provided, that activated mast cells affect behavior through the release of cysteinyl leukotrienes and the induction of growth and differentiation factor 15 by colonic epithelial cells, eventually sensed by the nervous system.”

“early IgE-mediated allergic reaction triggers avoidance behaviour while chronic allergen ingestion results in IgE-mediated disease.”

“The ratios between the levels of allergen specific IgE and the levels of allergen specific antibodies of other subclasses, correlate better with the development of severe allergic symptoms than the levels of IgE alone.”

“This reflects the fact that antibodies of other subclasses such as IgG1 or IgA can inhibit the severe allergic reactions induced by high-affinity IgE.”

“this mechanism may also be relevant in non-allergic individuals, who nevertheless produce subclinical quantities of IgE, potentially sufficient to cause mild mast cell activation and behavioural change, but without triggering allergic pathology.”

Immune sensing of food allergens promotes avoidance behaviour
https://www.nature.com/articles/s41586-023-06362-4

Mast cells link immune sensing to antigen-avoidance behaviour
https://www.nature.com/articles/s41586-023-06188-0

Food allergy as a biological food quality control system
https://www.cell.com/cell/fulltext/S0092-8674(20)31677-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420316779%3Fshowall%3Dtrue

Identification of a T follicular helper cell subset that drives anaphylactic IgE
https://www.science.org/doi/10.1126/science.aaw6433

B-cell receptor physical properties affect relative IgG1 and IgE responses in mouse egg allergy
https://www.mucosalimmunology.org/article/S1933-0219(22)01761-5/fulltext

T follicular helper cells
https://www.immunology.org/public-information/bitesized-immunology/cells/t-follicular-helper-cells

Eosinophilic GI Disease

 Eosinophilic GI Disease (EGID) is a group of conditions that occur when there are elevated levels of eosinophils in segments of the GI tract, either the esophagus, stomach, small intestines or colon.  These conditions are called Eosinophilic Esophagitis (EoE), Eosinophilic Gastritis or Gastroenteritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EC or EoC).  I have heard reference to Eosinophilic Duodenitis Eosinophilic Rectitis but I don't think either are official conditions.  The esophagus is the one part of the GI tract that doesn't normally have eosinophils, whereas the rest of the GI tract does.  This has led some to speculate that EoE is a different entity than the other EGIDs.  

EGIDs are diagnosed by biopsy.  Tissue samples are collected during endoscopy or colonoscopy, and then sent to a pathologist who looks at the samples under a microscope to identify the presence of eosinophils.  If the numbers are too high, a diagnosis is made.  Symptoms vary depending on the form of EGID a person has, and can be mild to severe.  In EoE, a common symptom, the one that often leads to diagnosis, are food impactions in the esophagus that require medical care to remove.  Symptoms of lower EGIDs tend to be vague such as cramping and pain, vomiting, nausea, diarrhea, food intolerances and a severely restricted diet, malnutrition, and bone pain (usually in the legs).  

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis

Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Molecular analysis of duodenal eosinophilia

Elimination diets are often used by doctors to identify problem foods, as there are no tests to identify eosinophilic triggers.  Treatment often begins by having the patient avoid identified (or suspected) triggers.  If this doesn't adequately control symptoms, various medications can be used, including topical steroids such as Budesonide or Fluticasone (steroids that is swallowed), a PPI (Protono Pump Inhibitor), Singulair, or oral steroids to control flares.  A type of medication called biologics are starting to be used for some EGIDs, in particular Dupilumab (brand name Dupixent).  Eosinophils are the same cells that tend to be responsible for asthma so many of the same medications are used.  Some people describe EGIDs as "like asthma but in your GI tract".  If those treatments fail, it is not uncommon for people with EGIDs to require artificial nutrition such as elemental formula, a feeding tube, or even TPN (IV nutrition).  People with EoE can develop strictures in the esophagus, areas where the tissue has scarring which narrows the width of the esophagus.  This can be treated with dilations, a procedure in which the area is mechanically stretched.

Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics

The leading center for diagnosis and treatment of EGIDs, especially EoE, is Cincinnati Children's Hospital (they also work with adults with EGIDs) 

Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE

Food-specific IgG4 is associated with eosinophilic esophagitis

Common and disparate clinical presentations and mechanisms in different eosinophilic gastrointestinal diseases

Histopathology of Eosinophilic Gastrointestinal Diseases Beyond Eosinophilic Esophagitis
"EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and TH2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs. The level of expression of certain genes associated with TH2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC. Current immune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease."

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders—A Comprehensive Review
"Eosinophils, a specific type of leukocyte derived from CD34+ CD125+ stem cells in the bone marrow, are crucial in defending against pathogens, such as bacteria and parasites. Additionally, they play a pivotal role in modulating humoral immune IgA and cellular T-cell responses, and in maintaining tissue homeostasis.

In the context of EGIDs, the abnormal accumulation of eosinophils is primarily driven by interleukin-5 (IL-5), interleukin-4 (IL-4), and interleukin-13 (IL-13). These cytokines are primarily produced by type 2 helper lymphocytes (Th2) in response to exposure to aeroallergens and food allergens. The overproduction of interleukins is further amplified by dysregulated cells in the innate immune system, including Group 2 innate lymphoid cells (ILC2s) that mature directly in tissues like the GI tract or lungs, plasma cells, and mast cells.  Pathogenesis of Th2 inflammatory drive in Eosinophilic Gastrointestinal Disorders (EGIDs), especially EoE. Exposure to initial food antigens triggers lymphocyte-Th2 activation, resulting in the accumulation of eosinophils in the esophagus. Following stimulation with Eotaxin 3, eosinophil degranulation promotes acute damage to the esophageal epithelium, followed by subsequent chronic fibrotic remodeling of the esophagus, which is dependent on TGF-beta.

Th2 cytokines, particularly IL-13, along with other inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and other chemokines, play a direct role in the activation and degranulation of eosinophils. Eotaxin-3 serves as the primary chemokine involved in these processes and contributes significantly to eosinophilic chemotaxis and accumulation in GI tissues. The release of proteins from eosinophilic granules, including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and major basic protein (MBP), leads to acute cytotoxic and oxidative damage to the tissue. This acute damage results in compromised barrier function through the downregulation of Desmoglein 1 (DSG1), Filaggrin (FGN), and the Epidermal Differentiation Complex (EDC).
The course of acute eosinophilic Th2 inflammation is typically self-sustained and progressive, often leading to chronic damage. This chronic state is often driven by T regulatory lymphocytes’ activation, accompanied by the recruitment of other cell types, including mast cells and basophils [26]. The persistent inflammatory insult can result in sub-mucosal fibrotic tissue deposition and muscular hypertrophy, primarily induced by Transforming Growth Factor beta (TGF-beta). 

A recent study on colonic biopsies conducted by Shoda et al. revealed that EoC is distinct from other EGIDs, with pathophysiological mechanisms that are not completely dependent on allergic inflammatory reactions [186]. The study identified 987 differentially expressed genes that were overexpressed in EoC tissues, thereby defining the “EoC transcriptome”.  Interestingly, the pathogenesis of EoC seems to have only a weak correlation with Th2-related allergic pathogenesis.  (A)dults typically experience chronic abdominal pain and watery diarrhea [25,179,180]. Additional symptoms can include nausea, vomiting, and weight loss. The presence of atopy history in EoC patients often complicates the clinical picture with conditions like asthma, food allergies, rhinitis, or eczema.

The depth of eosinophilic infiltration in the colonic wall allows for the identification of three disease patterns [147].

The mucosal involvement (type 1), defined as eosinophil infiltration of the mucosa, is the most common. This type often follows a continuous disease course (>6 months) without remission, with patients exhibiting symptoms such as bloody diarrhea, microcytic iron-deficiency anemia, and protein-losing enteropathy [5].

Transmural involvement (type 2) occurs when eosinophils infiltrate the muscular layer. It is associated with symptoms like abdominal spasms, pain, and a possible impact on intestinal motility. Complications such as intestinal obstructions, strictures, volvulus, and perforations may occur. The course of the disease in this form is typically recurrent [5].

The serosal subtype (type 3) is the rarest and occurs when eosinophilic infiltration reaches the serosa. This form can be associated with more severe symptoms, including eosinophilic ascites and intense abdominal pain [5].

Radiological signs include intestinal wall and mucosal fold thickening and submucosal edema [150,153]. Mucosal thickening, stenosis, and sub-mucosal edema form the basis of the “halo sign,” characteristic of EoC. The “arachnoid limb-like sign” may also be observed via radiological imaging [150]. In cases of transmural involvement, stenosis, particularly at the cecum, may be observed.

 

In approximately 70% of EoC cases, no alterations in the colonic mucosa are observed during endoscopic evaluation [183,187,188]. However, when abnormalities are present, they typically involve the colon segmentally, with only about 10% of patients presenting with pancolitis [14,25,183]. The endoscopic findings of EoC are often non-specific and do not correlate with the severity of symptoms [7].

 

Drug-induced colitis, triggered by antiplatelet drugs (clopidogrel, aspirin, and ticlopidine), Non-Steroidal Anti-Inflammatory Drug (NSAIDs) (especially ibuprofen), and estrogenic-progestogen agents is another cause of colonic hypereosinophilia [194,195].  Among connective tissue diseases, rheumatoid arthritis uniquely exhibits patterns of colonic eosinophilia [200]. 

 

In addition to hypereosinophilia, other microscopic characteristics that typify EoC histology include extensive degranulation, eosinophilic micro-abscesses, architectural distortion, fibrosis with mucosal atrophy, loss of mucin, and follicular lymphoid hyperplasia, often accompanied by lymphocytes and plasma cells [187,188].

 

According to the strongest evidence, a PEC with more than 50 eosinophils per HPF in the right colon, more than 35 eos/HPF in the transverse colon, or more than 25 eos/HPF in the left colon, along with a consistent clinical and symptomatic profile, indicates a diagnosis of EoC [14] 

 

adults typically receive steroid anti-inflammatory therapy, such as prednisone or budesonide, as the initial treatment [170,180]. If adults experience a relapse after discontinuing prednisone, indicating steroid-dependent disease, Budesonide Controlled Ileal Release (CIR) can be an effective maintenance therapy. Budesonide CIR has the advantage of primarily topical activity, minimizing the long-term adverse effects associated with steroids [202].

Immunomodulators like azathioprine and methotrexate also represent alternatives to maintenance therapy for EoC. Additionally, Montelukast, a leukotriene receptor antagonist, is beneficial in maintenance therapy due to its ability to block eosinophil homeostasis and prevent their infiltration into the intestinal wall [131]. Fecal microbiota transplantation has been suggested as a rescue strategy in EoC, though this evidence is limited to case reports [203]. Emerging therapies for EoC have mainly been tested in animal models. Studies evaluating the efficacy of anti-Siglec-F antibodies (targeting a sialic acid-binding immunoglobulin superfamily receptor) and anti-CCR3 (cysteine–cysteine chemokine receptor 3) antibodies have shown promising results [204,205]. Future therapeutic options are anticipated with the validation of biological drugs like dupilumab, reslizumab, and mepolizumab, which are currently undergoing testing.

 

 

 

 

Yale Study About Post-Vaccine Syndrome

(This is a pre-print, I will update this post as more information becomes available)

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination
"To explore potential pathobiological features associated with PVS (Post-Vaccine Syndrome), we conducted a decentralized, cross-sectional study involving 42 PVS participants and 22 healthy controls enrolled in the Yale LISTEN study. Compared with controls, PVS participants exhibited differences in immune profiles, including reduced circulating memory and effector CD4 T cells (type 1 and type 2) and an increase in TNFα+ CD8 T cells. PVS participants also had lower anti-spike antibody titers, primarily due to fewer vaccine doses. Serological evidence of recent Epstein-Barr virus (EBV) reactivation was observed more frequently in PVS participants. Further, individuals with PVS exhibited elevated levels of circulating spike protein compared to healthy controls. These findings reveal potential immune differences in individuals with PVS that merit further investigation to better understand this condition and inform future research into diagnostic and therapeutic approaches."

Protocol for Vaccine Injury Management (from Dr Been, based on Yale study)

Dr Been's video about this study

New and Experimental Treatments for Mast Cell Disease and Allergy

Nanoparticles Targeting Mast Cells Prevent Allergic Reactions in Mice
Researchers at Northwestern University successfully used a new treatment to prevent anaphylaxis in allergic mice using nanoparticles that targeted the mice' mast cells.  These nanoparticles were coated with molecules meant to function as allergens, and another molecule- called Siglec-6 that- that signals mast cells not to react.  The result was that the targeted mast cells were deactivated, which protected the mice and kept them from experiencing anaphylaxis.  "In one final experiment, mice sensitized to an IgE allergen were given the nanoparticle infusions with the two antibodies, and exposed to their allergen. None experienced signs of an allergic reaction."

Mast Cells, MCAS, and Psychiatric Symptoms

Brain mast cells link the immune system to anxiety-like behavior
"Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior."

"Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links."

Mast Cell Activation & Inflammation in Brain Disorders: How to Calm Things Down
"Though our culture is only starting to consider psychiatric conditions as inflammation of the brain, if you or someone you know has panic attacks, depression, mood swings, ADHD, brain fog, chronic fatigue, PTSD, autism, cognitive issues or even dementia, then you know the destruction neuroinflammation plays in people’s lives.

Tweaking neurotransmitter functioning, the primary role of modern conventional psychiatry, isn’t the same as treating inflammation in the brain.  While psychotropic medications may help lessen symptoms (and can be life saving), they don’t address root causes including inflammation. In those with high immune reactivity, they may even trigger an inflammatory response themselves."

Brain inflammation has a lot to do with the interactions between mast cells, microglial cells, and CRH (corticotropin releasing hormone), which both triggers these cells and is released by them under stress.  This can be either physiological or emotional stress.  Examples of things can alter our stress response and contribute to chronic inflammation in the brain include toxic metals, chronic infections such as viruses and yeast overgrowth, mold exposure, trauma, and early disruption of healthy attachment.  Stress calls for cortisol, so CRH is released to signal the adrenal glands to release mroe cortisol, which also activates mast cells and microglial cells, leading to chronic brain inflammation, which in turn can damage the brain and lead to neurodegeneration.  

Research is also showing the role of mast cells in traumatic brain injury, multiple sclerosis, Parkinson’s disease, dementia, Alzheimer’s disease, stress conditions, sleep disorders, migraine, pain, ADHD and autism.  When mast cells are stimulated they disrupt and release mediators that increase the permeability of what we call the Blood Brain Barrier (BBB) and Gut Blood Barrier (GBB).  If microglia are overstimulated, "they will release their own inflammatory mediators causing local inflammation and disrupted connections between neurons.  If this goes on too long, nearby neurons will die which leads to neurodegeneration which can equate to the beginning of dementia."

Mast Cells, Stress, Fear and Autism Spectrum Disorder
“Prenatal stress has been associated with higher risk of developing ASD in the offspring. Moreover, children with ASD cannot handle anxiety and respond disproportionately even to otherwise benign triggers. Stress and environmental stimuli trigger the unique immune cells, mast cells, which could then trigger microglia leading to abnormal synaptic pruning and dysfunctional neuronal connectivity. This process could alter the “fear threshold” in the amygdala and lead to an exaggerated “fight-or-flight” reaction. The combination of corticotropin-releasing hormone (CRH), secreted under stress, together with environmental stimuli could be major contributors to the pathogenesis of ASD. Recognizing these associations and preventing stimulation of mast cells and/or microglia could greatly benefit ASD patients.”

Mast Cells and Stress- a psychoneuroimmunological perspective

Mast cells regulate blood-brain-barrier permeability from acute stress 

Mast cells can cause permeability of the blood-brain-barrier and contribute to neurological disorders  

Microglia and mast cells: two tracks on the road to neuroinflammation.

Neural circuitry engaged by prostaglandins during the sickness syndrome

Mast cell activation disease: an underappreciated cause of neurologic and psychiatric symptoms and diseases

 
Mast cell disease causes neurological and psychiatric symptoms and diseases

 

Mast Cells Affect Brain Physiology and Behavior

 
Mast Cell Disease can manifest as Mixed Organic Brain Syndrome (psychiatric symptoms)

 
Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series

 
The Role of Mast Cells in Alzheimer's Disease.

 
Mast cells and migraine pathways