Exorphins derived from cow’s milk casein elicit pseudo-allergic wheal-and-flare reactions in healthy children
"Intracutaneous skin tests were performed with-ß-casomorphin-7, alpha-casein (90-95) and cow's milk extract in 25 children without any clinical indication of cow's milk allergy or intolerance. Immediate wheal reactions were measured and compared with skin reactions to histamine and codeine. Tests were repeated after pretreatment with 10mg cetirizine, a H1-antagonist . The opioid peptides induced wheat-and-flare reactions in all children. Beta-Casomorphin-7 and alpha-casein (90-95) caused pseudo-allergic immediate type reactions, apparently by direct histamine release.
In a previous study, we found that beta-caso-morphin-7 induces histamine release from peripheral blood leukocytes in vitro and provokes immediate wheal-and-flare skin reactions in healthy adult volunteers without cow's milk allergy. The present study extends this finding to children, and shows that also alpha-casein (90-95) induces such reactions.
These findings give evidence that beta casomorphin-7 is a histamine releasing agent, whose action is via opioid receptors and probably also mechanisms not related to opioid receptors. Presumably skin reactions to alpha-casein (90-95) are also due to direct mediator release, as a biopsy taken from the skin injected with this peptide showed mast cell degranulation. This was additionally demonstrated in one adult healthy volunteer (male, 40 years old,no cow's milk allergy or intolerance)."
Bovine Beta Casein Variants Implications to Human Nutrition and Health
Correlation between A1 beta casein supply per capita in 1990 and ischaemic heart disease in 1995 in 20 countries; r = 0.76 (95% confidence interval: 0.48–0.90; p ≤ 0.0001).
"A2 is the original form of the beta casein protein when cows were domesticated thousands of years ago, the A1 type arose and spread with breeding and migration of man. A2 is more comparable to the human beta casein than A1 in terms of digestive breakdown. Casein proteins make up 80% of the total protein in milk and comprise three classes; alpha, beta and kappa which aggregate to form micelles which reflect light to give milk its white colour. A1 and A2 beta casein differ in their protein structure by a substitution of the amino acid at position 67. A1 beta casein contains a histidine residue at this position, to yield the peptide β-casomorphin-7 (BCM-7), A2 beta casein contains a proline residue.
Only A1 beta casein yields β-casomorphin-7 (BCM-7), an exogenous opioid peptide (exorphin) that can potently activate opioid receptors throughout the body, with greatest affinity for μ opioid receptors. Levels of μ opioid receptors are highest in the hypothalamus, cerebral cortex, and spleen, moderate in the cerebellum, intestine, kidney, adrenal, and reproductive organs, and lowest in the lung and liver. μ opioid receptors are not expressed in the stomach, heart, or endothelium. Opioid receptors are also expressed on inflammatory cells, including lymphocytes and leukocytes."
The affinity of bovine BCM-7 to opioid receptors is approximately 10 times greater than that of human BCM-7, as it requires a 10-fold greater naloxone concentration to prevent receptor binding.
"A1 beta casein and BCM-7 are also implicated in the pathogenesis of type 1 diabetes via two mechanisms. In the first, consumption of A1 beta casein induces the production of autoantibodies that ultimately cause autoimmune-mediated killing of pancreatic β cells... These immunomodulatory and pro-atherogenic effects of A1 beta casein may be responsible for the increased risk of increased risk of heart disease and type 1 diabetes in populations associated with high per capita A1 beta casein consumption. The consumption of beta casein has also been linked with the aggravation of symptoms associated with autism and schizophrenia. These effects were attributed to the opioid activities of BCM-7 and to oxidative stress, causing neurological deficits that manifested as symptoms of schizophrenia and autism.
Experimental studies have shown that BCM peptides and analogues may be able to cross the blood–brain barrier. This was particularly evident in regions with ‘leaky’ capillaries, such as the pineal gland, the neurohypophysis, and the choroid plexus... a clinical study detected BCM-8 in the cerebrospinal fluid of pregnant and lactating women. Therefore, BCM peptides may influence central signalling pathways after crossing the blood–brain barrier. Excessive exposure to A1 beta casein or BCM-7 is implicated adverse response, including interference with gastrointestinal function and symptoms of intolerance reactions.
Studies have shown direct effects of BCM-7 on several gastrointestinal functions. For example, BCM-7 has been reported to reduce the frequency and amplitude of intestinal contractions, thus slowing gastrointestinal motility, and to stimulate mucus release. BCM-7 also inhibits lamina propria lymphocyte proliferation, which may affect susceptibility to infection. Recent studies in rodents report that A1 consumption promotes significant intestinal inflammation and immune activity relative to A2. BCM-7 also has immunomodulatory effects... pro-atherogenic effects, promoting low-density lipoprotein (LDL) oxidation and the generation of autoantibodies to oxidized LDL, both of which might contribute to the progression of atherosclerosis."