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Opioid Excess Theories
The opioid excess theory of autism says that autistic children are symptomatic due to excess opioid-like substances, whose effects on the brain produce the symptoms of autism.
Opioids and opioid-like substances, especially when in excess, have many effects upon hormones and hormonal regulation.
Among humans, opioids stimulate diminish both ACTH and corticosterone 1. Naloxone, an opiate antagonist, stimulates the release of ACTH. Both types of action are probably mediated within the hypothalamus. Lutenizing Hormone (LH), important in reproduction, is decreased by opioids, while opiate antagonists stimulate LH, both apparently by modulating LHRH release. Opioids affect the regulation of other gonadotropins (sex hormones). Exogenous opiates potently stimulate prolactin and gonadotropin hormone secretion. Opiate antagonists do not affect these hormones.
In rats, opiate antagonists decrease basal and stress-induced secretion of prolactin. Data regarding Thyroid Stimulating Hormone (TSH) are quite contradictory. Both inhibitory and stimulatory effects have been described.
Oxytocin and vasopressin release are inhibited by opioids at the posterior pituitary level. There is good evidence for an opioid inhibition of suckling-induced oxytocin release. Opioids also seem to play a role in the regulation of vasopressin under some conditions of water balance. The pancreatic hormones, insulin and glucagon, are elevated by opioids apparently by an action at the islet cells. Somatostatin, on the contrary, is inhibited. An effect of naloxone on pancreatic hormone release has been observed after meals which contain opiate active substances.
Dr. Alan Friedman, a physical chemist at Johnson and Johnson, has isolated and identified peptides in urine or serum using a single and triple electrospray quadropole mass spectrometer. The “MassSpec” sprays the material into a chamber, where it is spun by electromagnetic forces, and followed sequentially into two more chambers. The materials can then be charted by atomic weight.
Dr. Friedman contrasted the samples of normal children with autistic children. The amount and volume of particles in the autistic children was an order of magnitude more in volume and in number of them. Some of these particles include Casomorphine, A-Glaidin, Desmorphin, Deltophin II, Morphine modulating peptide, Novel Autism Peptide I, and Novel Autism Peptide III. These peptides have interaction with other neuro-peptides. Desmorphin is only found in Autistic Children and on the backs of non-captive poison dart frogs. These opioid-like molecules are thought to cause the symptoms of autism.
Dipeptydal peptidase deficiency:
Alan Friedman and colleagues have pioneered the potential role of DPP IV deficiency in autism. Some have gone so far as to suggest that DPP-IV deficiency may explain all of the abnormalities seen in autism. Dipeptidyl peptidase IV (DPP-IV) is a serine peptidase that removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided the penultimate residue is proline.
The only known enzyme to break down casomorphine, dipeptidyl peptidase IV or DDP-IV, appears to be absent or reduced in autistic children. The gene for this enzyme is distal to other suspected autism genes on 2 and Q of 7 and is expressed in the kidney, the small intestine, the liver, the blood-brain barrier, and has involvement in T-Cell activation. Also found in the urine were undigested food particles, suggesting a leaky gut syndrome.
Mice with the a defective casomorphine enzyme gene will die if not on a gluten free diet. Later we will discuss the possible role of glutein and cassein in autism, and the elimination of these substances from the diet as a treatment. The toxicity of gluten and cassein may result from the lack of DPP IV. Thus, DPP deficiency may be important in explaining opioid excess.
DPP IV has a number of different names. When it is present on the surface of a T-cell it is called CD26.
Dr. Friedman postulates that DPP-IV is either absent via a genetic mechanism (probably through two recessive genes) or that the enzyme has been inactivated, possibly through autoimmune mechanisms (a theory of autism which we will cover later). It has been postulated that people, autistic from birth, produce no DPP-IV, and those who developed normally and then regressed, had their DPP-IV inactivated through an acquired mechanism (such as auto-immunity).
One such compound is dermorphin, a mu-opioid agonist that acts as an hallucinogen. Another is deltorphin II. Some researchers theorize that these compounds appear because the enzyme which cleaves certain peptide bonds (DPP IV) is either missing or inactivated. Gluten and casein are two of the proteins from which these opioids can be produced. There may be additional proteins for which this is true as well.
Theories of Potential Therapies for DPP IV Deficiency [Unevaluated]:
If DPP IV deficiency results in autism, what can be done? If the enzyme is missing, replacing it should solve the deficiency. DPP IV is found on intestinal mucosal cells, epithelial cells in the GU tract, and on the surface of T-cells. It might be possible to hook the DNA sequence coding for DPP IV onto some type of delivery mechanism (such as a plasmid) and infuse the plasmids into the patient so that the desired sequence would be incorporated into the patient’s DNA. Another alternative is stem cell therapy or live cell therapy. Injected cells might produce DPP IV which would migrate to areas in which it is needed.
If the enzyme is inactivated by an autoimmune mechanism, replaced enzyme would probably be inactivated as well.
Here is a the skeleton for a future treatment: Drucker, et al. 2 studied DPP-IV deficicient rats. Administration of GLP-2 to these rats was associated with a markedly increased bioactivity of rat GLP-2 resulting in a significant increase in small bowel weight. A synthetic GLP-2 analog, r[Gly2]GLP-2, with an alanine to glycine substitution at position 2, was resistant to cleavage by both DPP-IV and rat serum in vitro. Treatment of wild-type rats with r[Gly2]GLP-2 produced a statistically significant increase in small bowel mass. DPP-IV-mediated inactivation of GLP-2 is a critical determinant of the growth factor-like properties of GLP-2. The possibility exists that treatment of autistic people with sufficient quantities of GLP-2 or with synthetic r[Gly2]GLP-2 which cannot be cleaved by DPP-IV would alleviate symptoms associated with autism.
Drucker DJ, DeForest L, and Brubaker PL have shown that GLP-2-like compounds have potential use for enhancement of mucosal regeneration in patients with intestinal disease 3. This may relate to autistic children who have gastrointestinal symptoms. Findings such as these may explain the usefulness of hormonal therapies for autistic children’s gut problems.
GLP-2 is part of proglucagon, which also contains GLP-1. Proglucagon is secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 is accounted for in part by dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage are more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease.
Dermorphin and Sauvagine:
The abnormal opioid peptides found in the urine of autistic children are known to have a number of important effects, many of which may relate to the symptoms of autism. Some of these effects may relate to other gut disorders, especially the so-called hollow organ dysmotility syndromes, in which pain arises from uncoordinated electrical activity and peristalsis in the gut, including the production of spasm and chronically elevated gut wall muscle tension. Some of the gastrointestinal disorders of autistic children (especially their abdominal pain) may be explainable on this basis.
Dermorphin consists of the amino acid sequence Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 30. It is a mu-opioid agonist and is displaced by naloxone or morphine; hence, the justification for using naloxone with autistic children to block the effects of dermorphin and its relatives. The D-configuration of the amino acid residue in position 2 is of crucial importance for its binding ability. Replacing the D-Ala2 with L-Ala makes a compound that is only 1/5000th as potent in binding to the receptor.
Shorter dermorphin homologs, dermorphin-(1-4)-NH2 and dermorphin-(1-3)-NH2, are 20 and 40-fold less potent, respectively, than dermorphin. The C-terminal carboxamide function is of significant importance for manifestation of the full intrinsic binding potency of dermorphin. Deamidated dermorphin has 1/5th the potency of the parent peptide. While the whole dermorphin sequence is required for expression of its full binding activity, the N-terminal tripeptide contains the features which allow receptor recognition.
Dermorphin and other opioid-like peptides can affect stomach acid output, and therefore, digestion 31. Intracerebroventricularly (i.c.v.) injected dermorphin suppresses the stimulation of gastric acid output by water distension of the stomach in a dose-dependent manner. Insulin stimulated gastric secretion is also partially blocked. Subcutaneous injections of dermorphin inhibite basal and water distension-induced gastric secretion and are antagonized by subcutaneous naloxone (at a dose of 1 mg/kg).
Injections (i.c.v.) of dermorphin have no effect on histamine-induced gastric secretion, but a close relative, Dermorphin N-terminal-tetrapeptide-amide (NTT), does . NTT also increases pentagastrin-induced gastic acid secretion. The opioid antagonist, N-methyl-levallorphan-methanesulphonate also blocks this effect. Thus, the brain plays a role in regulating gastric secretion.
Can these abnormal peptides explain many of the increased gastrointestinal problems of autistic children, or even of other patients with intestinal motility and spastic disorders? Time will tell, but the presence of increased intestinal permeability may explain how these molecules pass into the bloodstream from the gut to affect adults with gastrointestinal disorders.
In support of these ideas is the finding that a premature phase III of the migrating myoelectric complex (MMC) in the duodeno-jejunum is triggered by NTT 32. The activity of the gastic antrum is not significantly modified. NTT also increased the contractile activity of both proximal and distal portions of the colon, including a long-lasting period of increased muscle tone in the distal colon. Either naloxone or N-methyl-levallorphan-methanesulphonate completely prevented these motor effects of NTT on gastrointestinal tract. This opiate-like activity on gastric acid secretion and intestinal motility of the dog is thought to occur through the activation of peripheral mu opioid receptors.
Certainly justification exists for treatment of autistic children with gastrointestinal disturbances with naloxone.
Intravenous infusion of dermorphin significantly increases plasma levels of prolactin, human growth hormone, thyrotropin stimulating hormone (TSH) and plasma renin activity, but decreased plasma levels of cortisol. Dermorphin produced a small decrease in adrenocorticotropic hormone (ACTH), and a small increase in plasma aldosterone. Pretreatment with the opioid receptor antagonist naloxone suppressed the prolactin and TSH response, blunted the human growth hormone and plasma renin activity increase, completely prevented the plasma cortisol decrease, and enhanced plasma cortisol and ACTH levels.
These actions are thought to be mediated through opioid receptors. Dermorphin is thought to increase plasma renin levels through stimulation of the sympathetic nervous system. Dermorphin does suppress plasma cortisol levels by affecting ACTH secretion, potentially explaining altered pituitary-adrenocortical axis function found among developmental delayed children.
Sauvagine is another opioid-like peptide found in higher concentrations among autistic children. It and dermorphin affect both ACTH and beta-endorphin release from pituitary cells, inhibit prolactin and human growth hormone release. When dermorphin is administered by intracerebroventricular injection, it induces analgesia and catalepsy, along with conspicuous EEG and behavioral changes and a sharp reduction in gastric emptying time and gastric acid output. Prolactin release is stimulated.
Dermorphin and deltorphin are opioid-like substances which elicit acute and chronic activation of of mu- and delta-opioid receptors, thereby affecting the functional activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, both in basal conditions and in response to acute stress.
Acute administration of dermorphin (a mu-receptor agonist) increases basal and stress induced plasma levels of corticosterone and beta-endorphin. These effects are antagonized by pretreatment with naloxone, a specific mu-opioid receptor antagonist, but not by naltrindole, a delta-opioid receptor antagonist. Long-term administration of dermorphin does not alter resting plasma levels of corticosterone and beta-endorphan, but does reduce stress-induced increases of these hormones.
Both the acute and chronic administration of the delta-opioid receptors agonist, failed to modify resting and stress induced hormone levels. Thus, mu-opioid receptors, but not delta-opioid receptors modulate the response of the hypothalamic-pituitary-adrenal axis to acute stress.
Intravenous dermorphin injection decreases the levels of thryotropin releasing hormone in the hypothalamus. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min after the injection. The plasma thyroid hormone levels were not changed significantly. The plasma TRH and TSH responses to cold were inhibited by dermorphin, but the plasma TSH response to TRH was not.
Naloxone partially blocked the inhibitory effect of dermorphin on TSH levels. In the para-chlorophenylalanine or pimozide pretreated groups the inhibitory effect of dermorphin on TSH levels was prevented, but not in the groups pretreated with 5-hydroxytryptophan or L-DOPA. These drugs alone did not affect plasma TSH levels in the dose used. Dermorphin is thought to act on the hypothalamus to inhibit TRH release, its effects being mediated through mu-opioid receptors and modified by central nervous system amines.
Opioids and Secretin:
Opioids decrease gastric acid secretion. One theory as to the apparent “secretin deficiency” seen in many autistic patients is that the pH of the contents in the upper duodenum never gets low enough to cause the mucosal cells to release secretin.
Opioids have been shown to decrease hepatic glutathione. Low levels of glutathione have been demonstrated in autism.
Opioids and immunosuppression:
Many autistic people demonstrate a mild immunosuppression which could be accounted for by the actions of opioids on T-cells. Opioids decrease T-cell proliferation via the mu-receptors.
Gluten/Casein Theories and Relation to Celiac Disease
Dr. Paul Shattock, of Sunderland,England is doing work on the casein free/gluten free diet connections to autism and is studying the development of caso-morphine and gluteo-morphine in autistic children. In some individuals who cannot metabolize gluten, a-gliadin is produced. The body cannot metabolize A-gliadin, which binds to opiod receptors C & D. These receptors are associated with mood and behavior disturbances. A strict gluten and casein-free diet does appear to reduce the level of opioid peptides and improve autism for some people. The earlier the implementation of the diet, the better the chance of recovery.
There are at least 3 different opioid receptors – mu, delta, and kappa. When an opioid molecule attaches to a receptor in which it”fits”, adenylate cyclase is inactivated, leading to a decrease in intracellular cAMP. Cyclic AMP (cAMP) is an important messenger system in the brain and body. Opioid theory. In keeping with the opioid theory of autism, some children are given naltrexone (an opioid antagonist) with reported benefit. An example would be a small dose of 10 mg every 2-3 days
The increase in urinary IAG levels among autistic people observed by Paul Shattock may be explained in this manner. Tryptophan hydroxylase (the rate-limiting step in the conversion of tryptophan to serotonin) must be phosphorylated in order to be active. Cyclic AMP is required for phosphorylation. If intracellular cAMP levels have been lowered because of constant (inappropriate) stimulation of opioid receptors on the cell surface, less tryptophan hydroxylase is phosphorylated, and therefore more of the enzyme is inactive. When this happens, tryptophan is not converted into serotonin, but is shunted down alternate pathways, eventually leading to urinary IAG and 3-indoleacetate.
Another abnormality observed in autism is the accumulation of long-chainand very-long-chain fatty acids in cell membranes. Carnitine palmitolytransferase is essential in the steps responsible for the transport of Long Chain Fatty Acids (LCFA) and Very Long Chain Fatty Acids (VLCFA) across the mitochondrial membrane so these fatty acids can be broken down and metabolized. Carnitine palmitoyltransferase synthesis and half-life are dependent on the presence of cAMP.
There is evidence that cAMP levels may be reduced in autism (see other sections). One theory for the action of secretin is that it raises cAMP levels. Carnitine has also helped some autistic children,and, in fact, there is a glycogen storage disease that is a carnitine deficiency syndrome which presents like autism.
There are 12 types of glycogen storage disease, including carnitine deficiency syndrome, and defects of Acyl-CoA dehydrogenase.
The Cincinnati Children’s Hospital Medical Center’s Department of Enzymology has identified two patients with the”carbohydrate deficient glycoprotein syndrome” through alpha-1-antitrypsin phenotyping. The carbohydrate deficient glycoprotein in the serum of these patients produces a band on polyacrylamide gel isoelectric focusing that moves cathodally of the Z-band. In the area of carnitine deficiency, there is, for example, less than 5% of normal muscle carnitine concentration. After carnitine supplementation, patients unable to talk or walk, with hypotonic musculature and symptoms of autism, can became able to walk with the help of a walker, can stand alone for short periods, and can acquired an interest in their surroundings. The common findings of carnitine deficiency were an impaired ability to walk, muscular hypotonia, reduced muscle carnitine concentration and an improvement in locomotion while on carnitine.
Among a family with recessive X-linked cardiomyopathy, affected patients used to die before age 2 yrs. Early carnitine supplementation has greater improved survival. The clinical picture of this disease resembles Barth Syndrome, the gene for which has a location near the marker DXS52 on the X chromosome (Bolhuis et al., 1991). This carnitine deficiency syndrome is also related to the DXS52 marker (Bione, et al., 1996). The banding pattern of cDNA from a patient’s liver differs from that of normal liver and that sequencing of cDNA from a patient’s heart shows that exon 7 has been eliminated.
Vitamin B12 therapy is based in part upon the role of vitamin B12 in synthesizing essential fatty acids.
Gamma Interferon Theory
Dr. Vijendra Singh has found elevated levels of interleukin-12 and gamma interferon in autistic patients. Opioids can increase levels of gamma interferon.
Free Sulphate Theory
Dr. Rosemary Waring has demonstrated low levels of free sulfate in the plasma of autistic people. Free sulfate homeostasis is regulated by reabsorption in renal tubules primarily. Opioids change sodium, bicarbonate, and chloride reabsorption in the kidney, but no work has been done on sulfate reabsorption.
Waring (1993) has demonstrated deficiencies in the sulphur-transferase capabilities of people with autism. This inadequacy is not the consequence of a missing enzyme (sulphur transferase) but of insufficient sulphate ions for the sulphation to be accomplished.
Sulphur transferase activity is important for many biological reactions in the body, some of which may be relevant to autism. These reactions include the breakdown of bilirubin and biliverdin, which are the breakdown products of haemoglobin; as well as the breakdown and removal of phenolic compounds. The tests used to estimate sulphur-transferase activity rely upon the conversion of paracetamol to its sulphate.
An inadequately functioning sulphur-transferase system will also affect the metabolism of some neurotransmitters. Serotonin (5-HT) metabolism will be affected, and the appearance of unusual metabolites (such as the hallucinogen bufotenin) could be predicted. Himwich (1972) has reported this, but the significance is uncertain.
Foods with high phenolic content should exacerbate symptoms since the overtax the available sulphur resources of the body. Anecdotal reports abound about the adverse effects of apples, oranges and other citrus fruits, chocolate (possibly on account of the phenol flavoring vanillin) and other phenolic foods on behavior in children with autism. Interestingly, two parents (who must remain anonymous). Cranberry juice has been anecdotally reported to reduce or even eliminate these effects. Whether this due to the sulphur content of the juice or some other mechanism including placebo remains to be determined.
Sulphate ions are not absorbed from the gut so this route is not a possibility for replenishment. The main source of free sulphate in the body is the amino acid “cysteine” which is obtained from the breakdown of protein. Some parents have attempted to combat this by feeding their children large doses of cysteine in tablet or powder form with mixed results reported. Other parents have introduced other sulphur containing amino-acids and claim this therapy beneficial. One of the sulphur containing amino-acids used for this purpose is “taurine,” which is reported to have an anti-opioid effect (Braverman 1987).
Parents have also been experimenting with alternative routes of administration. One popular route is percutaneous, in which magnesium sulphate (Epsom Salts) are placed in the bath water in the hope that the sulphate will enter the body through the skin. Anecdotal benefits are claimed from this therapy, though increased irritability has also been reported.
Similar sulphate deficiencies have been reported in people with migraine, rheumatoid arthritis, jaundice and other allergic conditions all of which are anecdotally reported as common in the families of people with autism.
Sulfated glycosoaminoglycans are critical to the formation of the neuromuscular junction and the development of appropriate motor control and function.
Other Sulfation Problems in Autism
®Sulfation problems have been described by Rosemary Waring at the University of Birmingham in autism which could lead to an inability to handle virus infections, with a disruption of cell-mediated immunity® as well as an impairment of natural killer cell function.® Unlike the situation with type I interferons, which are released by infected cells, interferon gamma (a type II interferon) is released by T lymphocytes and natural killer cells, but that happens not when they themselves have been activated, but rather, when they are alerted to the presence of infection by other immune cells or by a superantigen or a chemical mitogen.
Sulfate also plays an important role in initiating interferon gamma’s signal.® [ Reference:® Benito A. Yard, Christian P. Lorentz, Dieter Herr, Fokko Van Der Woude.® Sulfation-dependent Down-Regulation of Interferon-gamma-induced Major Histocompatibility Complex I and II Intercellular Adhesion Molecule-1 Expression on Tubular and Endothelial Cells by Glycosaminoglycans.® Transplantation Vol.66(9), November 15, 1998, pp. 1244-1250]. Glycosaminoglycans (GAG) are sulfated sugars, involved with great deal of the action on the cell surface.® They also have activity in their “shed” form, where they act in the extracellular matrix, external to the cell.® All cells make GAGs, and shed GAGs continuously, but to properly assemble these sulfated GAGs, each cell has to be supplied with adequate sulfate, which is low in autism.® When these sugars are not sufficiently populated with sulfate, they will not behave normally, and their interaction with other chemistry can be hampered.® If sulfated GAGs are required for the proper action of interferon gamma, then a problem with sulfation may indeed be able to explain why so many autistic children have a hampered cell-mediated immunity and poor natural killer cell function.
Sulfated GAGs on the cell surface appear necessary for interferon gamma to generate a signal through its receptors on the cell surface.® More highly sulfated GAGs do indeed bind interferon and prevent it from binding to its receptors and generating its signal into the cell.® This varies in a dose-dependent manner.
Sulfated cell surface GAGs are required to dimerize, or assemble, two different components of receptors. Also, in the extracellular matrix around the cell, sulfated GAGs have been found to provide an escort for the GAG-binding chemical to get to the cell surface, actually protecting it from degradation as it wends its way to its cell-bound GAG/receptor complex.® Another example of this process is seen in chylomicron metabolism, where sulfated GAGs in most pathways are necessary for helping the cells in the liver to “eat” and process cholesterol-laden fatty particles.
There is another article from the May 1994 Scientific American: “How Interferons Fight Disease”, by Howard M. Johnson et al., that gives a particularly valuable review of what a problem with the interferon gamma signal would be expected to produce.® Even though this article does not even mention GAGs, it does say that in order to activate its receptor, some part of the interferon gamma molecule which is coming from the outside of the cell has to associate with a part of its receptor that is actually underneath the cell membrane and in the cytosol, so the authors speculate that the whole complex has to at least be partially endocytosed (taken inside the cell) before this could happen.® That may be where these GAGs are functioning, as they are recognized in the liver also as being involved with the endocytosis of ligand/receptor complexes.
But, if this process were inhibited by poor sulfation what would be the consequences?
“Interferons activate pathways that cause cells to transcribe, or copy, certain genes into molecules of messenger RNA.® The RNA transcripts, in turn are translated into proteins that interfere with viral replication or produce other effects…
Interference with viral protein translation:
For example, one of the best-studied proteins (the eIF-2-alpha protein kinase) interferes with the cellular machinery that viruses exploit in order to reproduce themselves.® Viruses trick the protein-making machinery of host cells into translating viral messenger RNA into the proteins needed to make new infectious particles.® Messenger RNA, viral or otherwise, is translated by ribosomes.® These structures travel down the length of the RNA strand, linking one specified amino after another to a growing protein chain. First, however, each ribosome has to be built.® Several molecules join together to form the smaller of two ribosomal subunits, and then the larger subunit comes on board.
All three interferons can precipitate the production of the eIF-2-alpha protein kinase, the active form of which phosphorylates one component required for forming the smaller ribosomal unit.® Such phosphorylation blocks further construction of the subunit and thus stalls protein synthesis.® The newly made kinase becomes active only when it encounters double-stranded RNA.® Such RNA appears in a cell only when a virus replicates its genetic material.® Consequently, the enzyme blocks protein synthesis in infected cells but not in healthy ones.
Destruction of viral RNA:
Among other groups of proteins induced by both type I and type II interferons is the family consisting of the 2′,5′-oligo (A) synthetases. These enzymes, too, interfere with the production of viral proteins, but they do so by activating enzymes that break down RNA before it can be translated into protein. …
Enhancement of macrophage function:
Interferon gamma can induce macrophages to kill tumor cells and cells infected by parasites, bacteria or viruses.® It can also prod macrophages ot destroy pathogens that have colonized the scavengers themselves.® And interferon gamma stimulates macrophages to produce what are called class II MHC (major histocompatibility complex) molecules.® After macrophages ingest pathogens, they break up several of the microbes and fit the fragments into grooves on the MHC molecules, which are then transported to the cell surface.® There they display the antigenic fragments to what are called CD4 T cells.® (These lymphocytes can “see” antigens only if the foreign fragments are complexed with a class II MHC molecule.)® Having recognized particular antigens, the CD4 cells proliferate and release chemicals that help other immune system cells to fight off infection..
Interferon gamma…serves as a kind of immunologic switch.® The protein helps to turn on the cell-mediated arm of the immune system, consisting of macrophages, various kinds of T cells and other cells that respond to microbes inside the cells of other tissues.® At the same time, interferon gamma may dampen the production of antibodies.® Antibodies are better suited to eradicating pathogens that establish colonies outside of cells.”
The article does not really talk about natural killer cells, but it would make sense if they are the other cell type besides macrophages that release interferon gamma, that their effectiveness would be greatly reduced if their signal from interferon was lost because of poor reception by the recipient cell.
All in all, these two articles go far in explaining the possible cause of the particular weaknesses we’ve found in some children’s immune system with both poor cell-mediated immunity and impaired function of natural killer cells that go along with their sulfation problems.
Cholecystokinin and Autism
Rats born without a functional CCKA receptor developed a type II (adult onset) like diabetes (insulin resistant type). Insulin and insulin-like growth factor, can both engage each other’s receptors, so a process affecting the function of one, may influence the other. IGF (insulin-like growth factor) is important for cell growth. IGF also regulates the sulfate uptake in glycosaminoglycans in cartilage and potentially other tissues.
Oxytocin and Vasopressin in Autism
Oxytocin is produced through the influence of the cholecystokinin-A (CCKA) receptor, which requires its substrate, cholecystokinin, to be sulfated (see the free sulfate theory of autism). If there is insufficient ability to sulfate compounds (a finding in some autistic people), the receptor will not work well, and many CCKA mediated functions will be afffected.
There is an argument that pitocin (oxytocin) might cause some cases of autism since so many mothers of autistic children had to have pitocin to induce labor. Others have suggested that the association was more likely caused by the mother/childunit having sulfation problems which made it difficult for mom’s oxytocin to be produced in sufficient quantity to move labor along, necessitating a jumpstart with exogenous oxytocin (pitocin). The theory is that mothers with sulfation problems would have a higher likelihood for delayed or desultory labor.
A literature is developing to support a role for oxytocin in autism 4.
Coexisting with oxytocin or vasopressin in the cell bodies and nerve terminals of the hypothalamic-neurohypophysial system are smaller amounts of other peptides 5. For a number of these ”copeptides” there is strong evidence of corelease with the major magnocellular hormones. The effects on secretion of oxytocin and vasopressin of three copeptides, dynorphin, cholecystokinin (CCK), and corticotropin releasing hormone (CRH), has been studied. Dynorphin is coreleased with vasopressin from neural lobe nerve terminals and acts on neural lobe kappa-opiate receptors to inhibit the electrically stimulated secretion of oxytocin. Naloxone augments oxytocin release from the neural lobe in a manner directly proportional to the amount of vasopressin (and presumably dynorphin) released.
Cholecystokinin, coreleased with oxytocin by neural lobe (NL) terminals, has been shown to have high-affinity receptors located in the NL and to stimulate secretion of both oxytocin and vasopressin. CCK’s secretagogue effect is independent of electrical stimulation and extracellular Ca2+ and is blocked by an inhibitor of protein kinase C.
CRH, coreleased with oxytocin from the neural lobe, has receptors in the intermediate lobe of the pituitary, but not in the neural lobe itself. CRH stimulates the secretion of oxytocin and vasopressin from combined neurointermediate lobes but not from isolated neural lobes. Intermediate lobe peptides, alpha and gamma melanocyte stimulating hormone, induces secretion of oxytocin and vasopressin from isolated neural lobes. Their effect is, like that of CCK, independent of electrical stimulation and extracellular Ca2+ and is blocked by an inhibitor of protein kinase C.
Among the CRH-producing parvocellular neurons of the paraventricular nucleus, in the normal rat, approximately half also produce and store vasopressin. After removal of glucocorticoid influence by adrenalectomy, virtually all of the CRH neurons contain vasopressin.
The two subtypes of CRH neurosecretory cells found in the normal rat possess different topographical distributions in the paraventricular nucleus, suggesting the possibility of differential innervation. Stress selectively activates the vasopressin containing subpopulation of CRH neurons, indicating that there are separate channels of regulatory input controlling the two components of the parvocellular CRH neurosecretory system.
The presence of opioid peptides and opiate receptors in the hypothalamo-neurohypophysial system, as well as the inhibitory effects of enkephalins and beta-endorphin on release of oxytocin and vasopressin has been well documented 6. Opioid peptides inhibit oxytocin release and thereby promote the preferential secretion of vasopressin when it is of functional importance to maintain homeostasis during dehydration and hemorrhage. Both neuromodulators and a neurohormones co-exist in the same neuron, as demonstrated for vasopressin with dynorphin or leucine-enkephalin, which serves to regulate the differential release of two biologically different, yet evolutionarily-related, neurohormones, e.g. oxytocin and vasopressin, from the same neuroendocrine system.
Autism and Amino Acids
Many autistic people have low levels of specific amino acids, despite a diet sufficient to support normal levels. DPP IV is found on epithelial cells in the kidney and is responsible for breaking down peptides into amino acids which are then reabsorbed. An absent or non-functioning enzyme could explain lowered levels of amino acids.
Methylation Theory of Autism
Methylation is an important metabolic process, possibly defective in autism, and pertaining to the control of histamine excess, protection of DNA, promotion of serotonin production, and other brain functions. A number of experiments have suggested a relationship between methyl group metabolism and the exocrine secretion of the pancreas 32.
These included nutritional studies which showed that ethionine, the ethyl analog of methionine which inhibits cellular methylation reactions, is a specific pancreatic toxin. Other studies indicated that protein carboxymethylation might be involved. Capdevila, et al. 32 showed that in vivo ethionine inhibits amylase secretion from freshly isolated rat pancreatic acini, while in vitro ethionine inhibits amylase secretion from the AR42J pancreatic cell line.
S-Adenosylhomocysteine (SAH) is an inhibitor of all methyltransferase reactions involving S-adenosylmethionine (SAMe). Treatments that elevate cellular levels of SAH such as inhibition of S-adenosylhomocysteine hydrolase and the in vitro addition of adenosine and homocysteine result in the inhibition of amylase secretion in both isolated pancreatic acini and AR42J cells. Measurement of SAMe and SAH levels in AR42J cells shows that inhibition of secretion is more closely related to elevation of SAH levels than to a decrease in the SAMe/SAH ratio.
Small G-proteins are carboxymethylated on the C-terminal byprenylcysteine, and inhibitors of membrane-associated prenylcysteine methyltransferase, N-acetylfarnesylcysteine, N-acetylgeranylgeranylcysteine, and farnesylthioacetic acid (FTA), block secretion in AR42J cells. N-Acetylgeranylcysteine is not an inhibitor of the methyltransferase and does not inhibit amylase secretion. FTA inhibits membrane-associated prenylcysteine methyltransferase from AR42J cells.
These results suggest that a methylation event is needed for pancreatic exocrine secretion which may be the reversible methylation of a G-protein involved in signal transduction or membrane trafficking. One theory of action of secretin revolves around restoration of normal methylation in the pancreas, and thereby normalizing pancreatic exocrine secretion. Pancreatic exocrine secretion is blocked by inhibitors of methylation.
Stress and Immunity
The experience of stress affects cellular immunity, an important aspect of many medical problems, including controlling/curing cancer and the immunobiology of autism. Treating disease with immunological components means also treating and managing psychological stress.
Human immune function is mediated by the release of cytokines, nonantibody messenger molecules, from a variety of cells of the immune system, and from other cells, such as endothelial cells. There are Th1 and Th2 cytokines. Autoimmune and allergic diseases involve a shift in the balance of cytokines toward Th2. The autoimmune aspect of autism has been related to excessive Th2 cytokines resulting, in part, from vaccination. Gulf War syndrome and asthma have been similarly linked to excess immunization in the presence of increased environmental toxins and pollutants (high antigenic load).
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