Some extracts from this review:
'Environmental factors have been implicated (in the development of autism) for prenatal rubella infection, anticonvulsants and antiemetics taken during pregnancy, perinatal hypoxia, post-natal infections such as encephalitis and in metabolic disorders....within the general population there appears to be no bias or selective pressure against ASD traits, where arguably from the evolutionary viewpoint due to impairments in social interactions and in some cases, lifelong dependency, one would anticipate selective pressure would exist...in autism there are multiple weak gene interactions. Indeed, many candidate genes that determine disease susceptibility or severity or disease course have been implicated or studied in autism...however, unequivocal evidence for a genetic association with ASD has so far not been established.'
'The lack of association between ASD and social class, immigrant status and geographical location may suggest that a biological, i.e. not solely genetic cause plays a leading role in the etiology of autism.'
'There is a growing awareness of an immunological involvement in children with ASD. Systematic immunologic aberrations in ASD have been linked with both autoimmunity...and secondly with dysfunctional immunity such as abnormalities or defects of function in immune cell subsets, leading to an inappropriate or ineffective immune response to pathogen challenge. Indeed, in general the links between the immune and neurological systems are becoming increasingly well known.'
'Products of the immune system may play an important role in early neuro-development and can influence patterns of behaviour. ..recent data have suggested that the brain is an immunologically active organ and that immune reactions do occur within the CNS (central nervous system)...various immune abnormalities have been described by an increasing number of laboratories worldwide showing both the involvement of auto-immune processes and the dysregulation of the immune response in children with autism. Many autistic children suffer prolonged and recurrent infections. Evidence for an increased inappropriate innate immune response was shown by the over-production of pro-inflammatory cytokines...the presence of antibodies directed against components of the CNS in the sera of autistic children is indicative that a possible autoimmune process may be involved in the pathology of ASD.'
'Many infectious agents including rubella, measles, human herpes virus 6, influenza and cytomegalovirus have been associated with the etiology of autism..these associations...may highlight an underlying inability of ASD children to fully eradicate viral insults. As such, viruses and viral products may persist in children with ASD.'
'Gastrointestinal symptoms have been described in a number of ASD patients..the precise number of children with ASD who have gastrointestinal symptoms is not currently known but some studies have estimated this to be between 18-40%....increased intestinal permeability in ASD is suggestive of an inflammatory process that may perturb the intestinal barrier function.'
'Patients with ASD have an altered or inappropriate response to viruses, the nature, extent and involvement of autoimmune processes in disease and the importance of mucosal inflammation co-morbidity in some children. Little is truly known about the response of children with ASD to foreign antigens...exposure of the developing neuronal system to enhanced or abherrant immune responses during critical periods of development may not be uniform and may lead to the expression of different phenotypes in autistic patients.'
Source: Clinical and Developmental Immunology, June 2004, Vol 11 (2), pp.165-174.
A Review of Autism and the Immune Response
Recent studies in the medical literature have confirmed that gastrointestinal symptoms are common in autism. In two prospective studies, GI symptoms were present in 80% and 70% of autistic children respectively. In contrast with the ASD group in the latter study, GI symptoms were only reported in 28% of neuro-typical controls.
Physical symptoms in ASD children are often misinterpreted as just autistic behaviours. In our experience, what turns out to be GI distress often present as inexplicible irritability, aggressive or auto-aggressive (self-injurious) behaviours, discomfort, sleep disorders and other behavioural disturbances. The problem of physical symptoms such as abdominal pain being interpreted simply as aberrant behaviours is particularly problematic in children who are non-verbal and who have serious difficulties expressing themselves. Detailed case histories often provide evidence of abdominal colic and sleep disorders during the nursing stage and frequent infections of the upper respiratory tract and GI tract caused by bacterial, viral, parasitic or yeast infections.
Affected children are often hypersensitive to sounds, light, flavours, smells and clothing labels. In addition, there is often a history of intolerance to certain foods containing gluten and casein as well as indicators of food allergies....diarrhoea and constipation are common..the extra intestinal problems experienced by our ASD children with GI symptoms include respiratory, neurological and dermatological disorders.
One explanation might be that part of the neurological disability in children results from absorption across an inflammed intestinal lining of molecules that are toxic to the developing brain.
Inflammation of the intestinal wall can be induced by..food allergies, use of antibiotics and non-steroidal anti-inflammatory drugs, infection, enzymatic insufficiency, mycotoxins from yeast/fungi, gluten, casein, chemical additives, colourings, preservatives, malabsorption of proteins, heavy metal intoxications and pesticides. Possibly due to GI inflammation and abnormal immune function, children with autism may have increased levels of harmful bowel organisms. Frequent antibiotic use in the first years of life can contribute to the chronic inbalance.
In our study of 45 ASD children and 57 developmentally normal controls presenting for GI assessment, chronic inflammation... was present in 100% of the autistic cases compared with 66.66% of the controls, reflecting a high background rate of infectious entercolitis in Venezuelan children. Since then other studies carried out in the United States, Brazil, Italy and Venezuela have confirmed the finding of inflammation and LNH in ASD.'
Gastrointestinal Pathology in Autism Spectrum Disorders
TO THE EDITOR: Although the causes of autism are largely unknown, this life-long developmental disorder is now showing a strong increase of prevalence (1/500). Intestinal disease was first described in 1998 in these patients (1) although there have been indications of impaired gastrointestinal function in the past (2).
(Article only available by payment).
The American Journal of Gastroenterology 100, 979-981 (April 2005) | doi:10.1111/j.1572-0241.2005.41202_4.x
Although the causes of autism are largely unknown, this long-life developmental disorder is now recognised to affect as many as 1 to 500 children. An upper and lower intestinal disease has been recently described in these patients (pts) in spite of gastrointestinal symptoms have been reported by the parents back more many years. This disorder comprising ileo-colonic lymphoid nodular hyperplasia (LNH) and chronic inflammatory colonic disease was called autistic enterocolitis:
an association between autism and bowel disease was then proposed.
Patients and Methods
Nine consecutive male pts (mean age 18 years, range 7-30 years) with a diagnosis of autism according to ICD-10 criteria that showed chronic intestinal symptoms (abdominal pain, bloating, constipation and/or diarrhoea) were enrolled. After routinely blood and stool tests, gastroscopy and colonoscopy with multiple biopsies were performed under sedation. A wireless enteroscopy capsule was also performed in 3 adult pts.
Anemia and fecal blood positive test were found in 2 pts and 3 pts,
respectively. Gastroscopy revealed mucosal gastritis in 4 pts, esophagitis in 1 and duodenitis in 1 pts. Histological findings showed a chronic inflammation of the stomach and duodenum in 6 pts (65%) but inconsistent with celiac disease. Macroscopic mucosal abnormalities (aphtoid ulcerations and loss of vascular pattern) were found in 1 pts at colonoscopy and a LNH in the terminal ileum in 4pts. Microscopic colitis with intraepithelial lymphocytes and eosinophils
infiltrations, mucosal atrophy and follicular hyperplasia was histologically present in all the pts (100%) whereas a chronic inflammation with iperemia and villous shortening of the terminal ileum was shown in 6 (65%) pts. The wireless capsule revealed areas of bleeding or patchy erythema, mucosal erosions and ulcers in both jejunum and ileum in 1 patients whereas a particular chronic jejunum and ileal erosive pattern was evident in the other two.
These preliminary data are strongly consistent with previous descriptions of autistic enterocolitis and supported a not-coincidental occurrence. Moreover, they showed for the first time a small intestinal involvement, suggesting a panenteric localisation of this new IBD. The treatment to gain clinical
remission has still to be tried and it will be extremely important to ameliorate the quality of life of such pts who are likely to be overlooked because of their long-life problems in the communication of symptoms.
Source: The American Journal of Gastroenterology 100 (4) Pg 979 - April 2005
Panenteric IBD-Like Disease in a Patient with Regressive Autism Shown for the First Time by the Wireless Capsule Enteroscopy: Another Piece in the Jigsaw of this Gut-Brain Syndrome?
Federico Balzola, M.D. Valeria Barbon, M.D. Alessandro Repici, M.D. Mario Rizzetto, M.D. Daniela Clauser, M.D. Marina Gandione, M.D. Anna Sapino, M.D.
Background: Children with developmental disorders experience chronic gastrointestinal symptoms.
Aims: To examine the nature of these gastrointestinal symptoms and histologic findings in children with autism spectrum/developmental disorders and ileocolonic disease.
Methods: Chart review. 143 autism spectrum/developmental disorder patients, with chronic gastrointestinal symptoms, undergoing diagnostic ileocolonoscopy.
Results: Diarrhea was present in 78%, abdominal pain in 59% and constipation in 36%. Ileal and/or colonic lymphonodular hyperplasia (LNH), defined as the presence of an increased number of enlarged lymphoid follicles, often with hyperactive germinal centers, was present in 73.2%. Terminal ileum LNH presented visually in 67% and histologically in 73%. Colonic LNH was multifocal and presented histologically in 32%. Ileal and/or colonic inflammation presented in 74%, consisting primarily of active or chronic colitis (69%). Ileal inflammation presented in 35%. Presence of LNH significantly predicted mucosal inflammation. Patients with ileal and/or colonic LNH had lower mean/median age than those without; patients with ileal and/or colonic inflammation had lower mean/median age than those without. There was a significant association between ileo and/or colonic inflammation or LNH, and onset of developmental disorder; plateaued or regressive onset conferred greater risk than early onset.
Conclusions: Patients with autism or related disorders exhibiting chronic gastrointestinal symptoms demonstrate ileal or colonic inflammation upon light microscopic examination of biopsy tissue. Further work is needed to determine whether resolution of histopathology with appropriate therapy is accompanied by GI symptomatic and cognitive/behavioral improvement.
Source: Autism Insights 2010:2 1-11
Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms.
Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension.
Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function. Seventy-five percent of the autistic children (27/36) had an increased pancreatico-biliary fluid output after intravenous secretin administration. Nineteen of the 21 patients with diarrhea had significantly higher fluid output than those without diarrhea.
Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggests an upregulation of secretin receptors in the pancreas and liver. Further studies are required to determine the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder.
Source: J Pediatr. 1999 Nov;135(5):559-63.
Autism spectrum disorder refers to syndromes of varying severity, typified by impaired social interactions, communicative delays and restricted, repetitive behaviours and interests. The prevalence of autism spectrum disorders has been on the rise, while the etiology remains unclear and most likely multifactorial. There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora. Two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopic findings are described, followed by a review of this controversial topic.
Source: Can J Gastroenterol. 2009 Feb;23(2):95-8.
Unrecognized gastrointestinal disorders may contribute to the behavioral problems in non-verbal patients, but they are often overlooked since the clinical symptoms are nonspecific. Eosinophilic esophagitis (EE) is a chronic inflammatory disorder manifesting itself predominantly in reflux-type symptoms that do not respond to standard anti-reflux pharmacotherapy. Here we report the first case of EE in an autistic patient with feeding difficulties caused by exacerbated EE symptoms.
Source: J Autism Dev Disord. 2011 Mar;41(3):372-4. doi: 10.1007/s10803-010-1059-y.
We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.
Source: J Neuroimmunol. 2001 Nov 1;120(1-2):170-9.
Among patients with autism spectrum disorders (ASD) evaluated in our clinic, there appears to be a subset that can be clinically distinguished from other ASD children because of frequent infections (usually viral) accompanied by worsening behavioural symptoms and/or loss/decrease in acquired skills. This study assessed whether these clinical features of this ASD subset are associated with atopy, asthma, food allergy (FA), primary immunodeficiency (PID), or innate immune responses important in viral infections.
This study included the ASD children described above (ASD test, N = 26) and the following controls: ASD controls (N = 107), non-ASD controls with FA (N = 24), non-ASD controls with chronic rhinosinusitis/recurrent otitis media (CRS/ROM; N = 38), and normal controls (N = 43). We assessed prevalence of atopy, asthma, FA, CRS/ROM, and PID. Innate immune responses were assessed by measuring production of proinflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in response to agonists of Toll-like receptors (TLRs), with or without pre-treatment of lipopolysaccharide (LPS), a TLR4 agonist.
Non-IgE mediated FA was equally prevalent in both ASD test and ASD control groups, occurring at higher frequency than in the non-ASD controls. Allergic rhinitis, atopic/non-atopic asthma, and atopic dermatitis were equally prevalent among the study groups except for the CRS/ROM group in which non-atopic asthma was more prevalent (52.6%). CRS/ROM and specific polysaccharide antibody deficiency (SPAD) were more prevalent in the ASD test group than in the ASD control, FA, and normal control groups: 23.1% vs. < 5% for CRS/ROS and 19.2% vs. < 1% for SPAD. However, CRS/ROM patients had the highest prevalence of SPAD (34.2%). When compared to ASD and normal case controls, PBMCs from 19 non-SPAD, ASD test group children produced: 1) less IL-1beta with a TLR7/8 agonist, less IL-10 with a TLR2/6 agonist, and more IL-23 with a TLR4 agonist without LPS pre-treatment, and 2) less IL-1beta with TLR4/7/8 agonists with LPS pre-treatment. These are cytokines associated with the neuro-immune network.
Clinical features of the ASD test group were not associated with atopy, asthma, FA, or PID in our study but may be associated with altered TLR responses mediating neuro-immune interactions.
Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures.
This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production.
ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens.
Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities.
Source: Neuropsychobiology. 2005;51(2):77-85.
Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms.
We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses.
ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs.
Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria.
Source: Neuropsychobiology. 2002;46(2):76-84
Recent reports have given a central role to environmental factors in the etiology of autism spectrum disorders (ASD). However, most proposed perinatal factors seem to converge into the activation of the immune system, suggesting that an early inflammatory response could be a unifying factor in the etiology ASD. Here I review the evidence of early immune activation in individuals with ASD, and the chronic peripheral and central alterations observed in the inflammatory response in ASD. This evidence shows that ASD is associated with altered neuroinflammatory processes and abnormal immune responses in adulthood. How these immune alterations can affect developmental programming of adult behavior or directly affect behavior later in life is discussed in the context of both clinical and animal models of research. Recent studies in rodents clearly support a role of elevated cytokines in the behavioral symptoms of ASD, both during development and in adulthood.
Source: Mol Cell Neurosci. 2013 Mar;53:69-76. doi: 10.1016/j.mcn.2012.10.003. Epub 2012 Oct 13
Autism spectrum disorder (ASD) is a highly heterogeneous disorder diagnosed based on the presence and severity of core abnormalities in social communication and repetitive behavior, yet several studies converge on immune dysregulation as a feature of ASD. Widespread alterations in immune molecules and responses are seen in the brains and periphery of ASD individuals, and early life immune disruptions are associated with ASD. This chapter discusses immune-related environmental and genetic risk factors for ASD, emphasizing population-wide studies and animal research that reveal potential mechanistic pathways involved in the development of ASD-related symptoms. It further reviews immunologic pathologies seen in ASD individuals and how such abnormalities can impact neurodevelopment and behavior. Finally, it evaluates emerging evidence for an immune contribution to the pathogenesis of ASD and a potential role for immunomodulatory effects in current treatments for ASD.
Source: Int Rev Neurobiol. 2013;113:269-302. doi: 10.1016/B978-0-12-418700-9.00009-5.
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with "allergic-like" problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut-blood-brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation.
Source: Biochim Biophys Acta. 2012 Jan;1822(1):34-41. doi: 10.1016/j.bbadis.2010.12.017. Epub 2010 Dec 28
Many children with Autism Spectrum Diseases (ASD) present with seizure activity, but the pathogenesis is not understood. Recent evidence indicates that neuro-inflammation could contribute to seizures. We hypothesize that brain mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures. Treating neuro-inflammation may be useful when anti-seizure medications are ineffective.
Source: J Neuroinflammation. 2011 Nov 30;8:168. doi: 10.1186/1742-2094-8-168
Autism spectrum disorders (ASDs) are characterized by deficits in social communication and language and the presence of repetitive behaviors that affect as many as 1 in 50 US children. Perinatal stress and environmental factors appear to play a significant role in increasing the risk for ASDs. There is no definitive pathogenesis, which therefore significantly hinders the development of a cure.
We aimed to identify publications using basic or clinical data that suggest a possible association between atopic symptoms and ASDs, as well as evidence of how such an association could lead to brain disease, that may explain the pathogenesis of ASD.
PubMed was searched for articles published since 1995 that reported any association between autism and/or ASDs and any one of the following terms: allergy, atopy, brain, corticotropin-releasing hormone, cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, mast cells, mitochondria, neurotensin, phenotype, stress, subtype, or treatment.
Children with ASD respond disproportionally to stress and also present with food and skin allergies that involve mast cells. Brain mast cells are found primarily in the hypothalamus, which participates in the regulation of behavior and language. Corticotropin-releasing hormone is secreted from the hypothalamus under stress and, together with neurotensin, stimulates brain mast cells that could result in focal brain allergy and neurotoxicity. Neurotensin is significantly increased in serum of children with ASD and stimulates mast cell secretion of mitochondrial adenosine triphosphate and DNA, which is increased in these children; these mitochondrial components are misconstrued as innate pathogens, triggering an autoallergic response in the brain. Gene mutations associated with higher risk of ASD have been linked to reduction of the phosphatase and tensin homolog, which inhibits the mammalian target of rapamycin (mTOR). These same mutations also lead to mast cell activation and proliferation. Corticotropin-releasing hormone, neurotensin, and environmental toxins could further trigger the already activated mTOR, leading to superstimulation of brain mast cells in those areas responsible for ASD symptoms. Preliminary evidence indicates that the flavonoid luteolin is a stronger inhibitor of mTOR than rapamycin and is a potent mast cell blocker.
Activation of brain mast cells by allergic, environmental, immune, neurohormonal, stress, and toxic triggers, especially in those areas associated with behavior and language, lead to focal brain allergies and subsequent focal encephalitis. This possibility is more likely in the subgroup of patients with ASD susceptibility genes that also involve mast cell activation.
Source: Clin Ther. 2013 May;35(5):584-91. doi: 10.1016/j.clinthera.2013.04.009.
Autoimmune diseases continue to increase, but the reason(s) remain obscure and infections have not proven to be major contributors. Mast cells are tissue immune cells responsible for allergies, but have been increasingly shown to be involved in innate and acquired immunity, as well as inflammation. This involvement is possible because of their ability to release multiple mediators in response to a great variety of triggers. We recently published that activation of mast cells is accompanied by mitochondrial fission and translocation to the cell surface from where they secrete at least ATP and DNA outside the cell without cell damage. These extracellular mitochondrial components are misconstrued by the body as "innate pathogens" leading to powerful autocrine and paracrine auto-immune/auto-inflammatory responses. We also showed that mitochondrial DNA is increased in the serum of young children with autism spectrum disorders (ASD), a condition that could involve "focal brain allergy/encephalitits". Blocking the secretion of extracellular mitochondrial components could present unique possibilities for the therapy of ASD and other autoimmune diseases. Unique formulation of the flavonoid luteolin offers unique advantages.
Source: Autoimmun Rev. 2013 Oct;12(12):1136-42. doi: 10.1016/j.autrev.2013.06.018. Epub 2013 Jul 3.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations. Therefore, ASD has traditionally been framed as a behavioral disorder. However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation. While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals. A majority of these brain tissue studies have been published since 2010. The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination. This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD.
Source: Front Physiol. 2014 Apr 22;5:150. doi: 10.3389/fphys.2014.00150. eCollection 2014.
Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD.
Source: Brain Behav Immun. 2012 Mar;26(3):383-92. doi: 10.1016/j.bbi.2011.08.007. Epub 2011 Aug 28.
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders defined behaviorally by abnormalities in social, verbal, and nonverbal communication. The etiologies of ASD are unknown, likely to be the result of a variety of numerous genetic, neurological, environmental, and immunological interactions that lead to a general behavioral phenotype defined as ASD. This review will focus on the various immune system anomalies, in particular, autoantibodies, which have been reported in subjects with ASD. In addition, we will discuss recent studies performed by our group concerning the presence of autoantibodies directed against neural antigens, which are observed in patients with ASD.
Source: Ann N Y Acad Sci. 2007 Jun;1107:79-91.
Millions of children are infected by enteroviruses each year, usually exhibiting only mild symptoms. Nevertheless, these viruses are also associated with severe and life-threatening infections, such as meningitis and encephalitis. We describe a 32-month-old patient with enteroviral encephalitis confirmed by polymerase chain reaction in cerebrospinal fluid, with unfavorable clinical course with marked developmental regression, autistic features, persistent stereotypes and aphasia. She experienced slow clinical improvement, with mild residual neurologic and developmental deficits at follow-up. Viral central nervous system infections in early childhood have been associated with autism spectrum disorders but the underlying mechanisms are still poorly understood. This case report is significant in presenting a case of developmental regression with autistic features and loss of language improving on follow-up. To our knowledge, this is the first published report of enterovirus encephalitis leading to an autism spectrum disorder.
Source: J Child Neurol. 2014 May;29(5):708-14. doi: 10.1177/0883073813508314.
Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P <or= 0.0001). Furthermore, immunoblotting of measles vaccine virus revealed that the antibody was directed against a protein of approximately 74 kd molecular weight. The antibody to this antigen was found in 83% of autistic children but not in normal children or siblings of autistic children. Thus autistic children have a hyperimmune response to measles virus, which in the absence of a wild type of measles infection might be a sign of an abnormal immune reaction to the vaccine strain or virus reactivation.
Source: Pediatr Neurol. 2003 Apr;28(4):292-4.
Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.
Source: J Biomed Sci. 2002 Jul-Aug;9(4):359-64
Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism.
Source: Clin Immunol Immunopathol. 1998 Oct;89(1):105-8
To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD).
Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy.
PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable.
A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.
Source: J Pediatr. 2005 May;146(5):605-10.
This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.
Source: J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36.
In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.
Source: J Child Neurol. 2000 Jul;15(7):429-35.
Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.
Source: Clin Infect Dis. 2002 Sep 1;35(Suppl 1):S6-S16
Autism causes incapacitating neurologic problems in children that last a lifetime. The author of this article previously hypothesized that autism may be caused by autoimmunity to the brain, possibly triggered by a viral infection. This article is a summary of laboratory findings to date plus new data in support of an autoimmune pathogenesis for autism.
Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay.
Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)--salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants--a marker of systemic inflammation.
The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy. The author has advanced a speculative neuroautoimmune (NAI) model for autism, in which virus-induced autoimmunity is a key player. The latter should be targeted by immunotherapy to help children with autism.
Source: Ann Clin Psychiatry. 2009 Jul-Sep;21(3):148-61.
The immunopathogenesis of autism is presented schematically in Fig. 1. Two main immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the MHC region, as this is an immunologic gene cluster whose gene products are Class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The antigen in virus infection initiated by the virus particle itself while the cytokine production and inflammatory mediators are due to the response to the putative antigen in question. The cell-mediated immunity is impaired as evidenced by low numbers of CD4 cells and a concomitant T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2. Impaired humoral immunity on the other hand is evidenced by decreased IgA causing poor gut protection. Studies showing elevated brain specific antibodies in autism support an autoimmune mechanism. Viruses may initiate the process but the subsequent activation of cytokines is the damaging factor associated with autism. Virus specific antibodies associated with measles virus have been demonstrated in autistic subjects. Environmental exposure to mercury is believed to harm human health possibly through modulation of immune homeostasis. A mercury link with the immune system has been postulated due to the involvement of postnatal exposure to thimerosal, a preservative added in the MMR vaccines. The occupational hazard exposure to mercury causes edema in astrocytes and, at the molecular level, the CD95/Fas apoptotic signaling pathway is disrupted by Hg2+. Inflammatory mediators in autism usually involve activation of astrocytes and microglial cells. Proinflammatory chemokines (MCP-1 and TARC), and an anti-inflammatory and modulatory cytokine, TGF-beta1, are consistently elevated in autistic brains. In measles virus infection, it has been postulated that there is immune suppression by inhibiting T-cell proliferation and maturation and downregulation MHC class II expression. Cytokine alteration of TNF-alpha is increased in autistic populations. Toll-like-receptors are also involved in autistic development. High NO levels are associated with autism. Maternal antibodies may trigger autism as a mechanism of autoimmunity. MMR vaccination may increase risk for autism via an autoimmune mechanism in autism. MMR antibodies are significantly higher in autistic children as compared to normal children, supporting a role of MMR in autism. Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) are significantly increased in autistic patients (Singh et al., 1997). Increase in Th2 may explain the increased autoimmunity, such as the findings of antibodies to MBP and neuronal axonal filaments in the brain. There is further evidence that there are other participants in the autoimmune phenomenon. (Kozlovskaia et al., 2000). The possibility of its involvement in autism cannot be ruled out. Further investigations at immunological, cellular, molecular, and genetic levels will allow researchers to continue to unravel the immunopathogenic mechanisms' associated with autistic processes in the developing brain. This may open up new avenues for prevention and/or cure of this devastating neurodevelopmental disorder.
Electrophysiological findings implicate site-specific impairment of the nucleus tractus solitarius (NTS) in autism. This invites hypothetical consideration of a large role for this small brainstem structure as the basis for seemingly disjointed behavioral and somatic features of autism. The NTS is the brain's point of entry for visceral afference, its relay for vagal reflexes, and its integration center for autonomic control of circulatory, immunological, gastrointestinal, and laryngeal function. The NTS facilitates normal cerebrovascular perfusion, and is the seminal point for an ascending noradrenergic system that modulates many complex behaviors. Microvascular configuration predisposes the NTS to focal hypoxia. A subregion--the "pNTS"--permits exposure to all blood-borne neurotoxins, including those that do not readily transit the blood-brain barrier. Impairment of acetylcholinesterase (mercury and cadmium cations, nitrates/nitrites, organophosphates, monosodium glutamate), competition for hemoglobin (carbon monoxide, nitrates/nitrites), and higher blood viscosity (net systemic oxidative stress) are suggested to potentiate microcirculatory insufficiency of the NTS, and thus autism.
Source: Int J Environ Res Public Health. 2013 Dec 11;10(12):6955-7000. doi: 10.3390/ijerph10126955.
This is the text-only version of this page. Click here to see this page with graphics.
Edit this page | Manage website
Make Your Own Website: 2-Minute-Website.com