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Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page i THE PLOT AGAINST ASTHMA AND ALLERGY PATIENTS Asthma, Allergies, Migraine, and Chronic Fatigue Syndrome are Curable, but the Cure Is Hidden from the Patients Felix Ravikovich, M.D. As featured on CBC’s fifth estate KOS Publishing BOOKS ON MEDICINE THAT WORKS Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page ii ACKNOWLEDGMENTS This book is my first and only literary child. It took nine long years to carry it, and I would not have been able to deliver it without the support of several people. I want to pay tribute to the late Drs. Bayard Horton and Kenneth Melmon for their fascination with histamine, their devotion to it, their research and their belief that one day histamine will serve patients. This book would not be possible without my wife Galina who is, actually, my co-author. She conceived the idea and for two years, while I was fighting in the courts, she worked on it alone, researched the medical sources collected by me and began to put my ideas on paper. When I joined her, she became my sounding board, the only knowledgeable person with whom I could share my astonishing, at times dramatic discoveries made during my detective search of medical literature. The situation forced her to immerse herself so deeply into some of the most serious fields of medicine and science that by the end, she became, albeit unofficially, the equivalent of a professional in clinical immunology. Her background as a university professor enabled her to work out how to present the most complicated material in the way digestible not only for those who have a medical or biological education, but also for intellectuals with little or no such experience. I express my love to my son Alex who was a comforting friend, whose advice I sought in many critical situations during the process, and who patiently corrected my imperfect English. I would like to express my special thanks to Klemmens Fass, my unofficial lawyer, who remained faithful to me when my other lawyers be; trayed me. He Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page iii Acknowledgments refused outright to be paid for the long hours of discussions during the years of my prosecution by the College. He also became my behind-the-stages law teacher, and his advice helped me to go through all the stages of the legal proceedings as well as the writing of this book. I am grateful to Denise Crawford for her willingness to help with the numerous technical and linguistic problems that I encountered through the years of writing. I appreciate the enormous work done by Isidor Zelinkovsky at the early stages of my prosecution by the College of Physicians and Surgeons of Ontario. He managed to get the Canadian Broadcasting Corporation interested in the histamine affair and persuaded them to give the opportunity to my patients to tell their stories of their almost miraculous improvement and outright recoveries with histamine therapy and the despair over losing it. The program aired in Canada and in parts of U.S. created the necessary publicity, which, in my opinion, contributed to my having not lost my license outright; I was given a reprimand and forbidden to use histamine. I am thankful to Ed Sprague, a patient who has become a close friend and as such accompanied me to all of my meetings with the lawyers and through the many stages of my trial as a silent witness. The numerous improprieties he saw have changed his views on our justice system forever. Later on, he was the most active organizer of press releases sent to the medical institutions, media and government bodies of Ontario. I cannot overestimate the tremendous support of Elizabeth and Daniel Gamper that enabled me to go on with my work and book writing. My gratitude goes to Tom Hirsch, my first literary agent, who became a passionate advocate of histamine therapy and was willing to give up his fees just to see this book published. Last, but not the least, I thank Helke Ferrie who has dared to publish this book. The people of Ontario should be grateful to her for the courage to fight the medical regulatory authorities and for regularly publishing the facts about the crimes committed by them against patients and doctors. I am thankful to those of my patients who organized PRET (Patients’ Rights for Effective Treatment), a group that arranged the meeting at CBC’s fifth estate television studio, demonstrated in front of the building which houses the College of Physicians and Surgeons of Ontario, published and distributed information on histamine therapy, attended the legal proceedings and kept writing letters of support. iii Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page iv Copyright © 2003 by Felix Ravikovich All Rights reserved. No part of this book may be reproduced in any manner whatsoever without prior written permission from the publisher except in the case of brief quotations embodied in review. National Library of Canada Cataloguing in Publication Ravikovich, Felix, 1938– The plot against asthma and allergy patients: asthma, allergies, migraine, chronic fatigue syndrome are curable, but the cure is hidden from patients / Felix Ravikovich. Includes bibliographical references and index. ISBN 0-9731945-1-0 1. Allergy—Treatment. 2. Asthma—Treatment. 3. Medicine—Research. I. Title. RC584.R39 2003 616.97'06 C2003-906757-2 Cover and text design/layout: Heidy Lawrance Associates Printed in Canada on recycled paper Published and distributed by KOS Publishing Inc. 1997 Beechgrove Road, Alton, ON Canada L0N 1A0 Tel: (519) 927-1049 Fax: (519) 927-9542 Quantity discounts available Plot/Allergies•i-xii•1-317 11/21/03 1:55 PM Page v TABLE OF CONTENTS Acknowledgements ii Introduction by Helke Ferrie vii PART 1 Immune Mechanisms 1 PART 2 Causes and Triggers in Allergy 69 PART 3 Allergic Inflammation 98 PART 4 “Histaminegate” 106 PART 5 Medications 173 PART 6 Allergy Skin Testing and Immunotherapy 203 PART 7 Bronchial Asthma 238 PART 8 Diseases of Hypersensitivity 318 A. Chronic Rhinitis B. Skin Allergies C. Hay Fever PART 9 Functional Encephalopathies 344 A. Vascular Headache B. Chronic Fatigue and Immune Dysfunction Syndrome C. Depression D. Attention Deficit and Hyperactivity Disorder E. Irritable Bowel Syndrome F. Other Histamine-Related Encephalopathies Epilogue “Eppur Si Mouve!” 387 Bibliography 390 Appendix 396 • Abstracts presented by Dr. F. Ravikovich at international conferences and his article • Letter by Dr. K. Melmon to Dr. F. Ravikovich • Press release by the patients’ committee, PRET • Notice to the reader Index 408 Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page vi Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page vii Introduction: Renovating Medicine “Practicing medicine without knowledge of biochemistry and physiology is merely pop-gun pharmacy.” Sir William Osler, 18901 “Far too large a section of the treatment of disease is today controlled by the big manufacturing pharmacists, who have enslaved us in a plausible pseudo-science.” Sir William Osler, 1909 As the publisher and editor of this book it is an exceptional pleasure to be asked to write an introduction to this most unusual work. Many readers who know me from my regular articles on the politics of medicine published in Vitality Magazine, Alive and others, share my conviction that the greatest problem modern medicine faces in our time is the perverting influence of political and corporate power on good medical practice and medical research. To make medicine once again patient-centered, not patent-centered, and to free medical research from corporate priorities, is the task of our time as surely as it was the task in the 18th century to remove political power from kings and put it into the hands of the people. Indeed, the most profound insight I have experienced first as a medical science writer, and now as a publisher of “Books on Medicine that Works,” is the discovery that in virtually all areas of medicine the basic scientific breakthroughs achieved in the leading research institutions are rarely communicated to people, are very often not even taught to medical students, and are not readily available to practicing doctors. Plot/Allergies•i-xii•1-317 11/21/03 2:19 PM Page viii viii THE PLOT AGAINST ALLERGY PATIENTS What IS readily available to everybody is information on yet another supposedly miraculous drug which promises to alleviate the symptoms of any known disease. Pick up any recent edition of Macleans Magazine, for example, and attached to its outside you will find, courtesy of GlaxoSmithKline, in dramatically colored red, white, and black a folder stating: “IMPORTANT INFORMATION FOR PEOPLE WITH ASTHMA ENCLOSED.” A handy little quiz inside allows the reader to be sure in seconds that he or she may suffer from asthma more seriously than previously thought and that their “asthma is not under control.” This message comes to you courtesy of GlaxoSmithKline, the world’s largest producer of steroid puffers. You are holding in your hands a book that, unlike the above advertisement, really does contain important information for people suffering from asthma. Dr. Ravikovich is fully familiar with the world-wide basic science research on allergic diseases, successfully used a cure and reported on his results at international conferences. He also tells you why that cure is not generally known or available. Here is the story of a doctor who fought for his patients. This book provides the reader with a political revelation, a medical tour de force, and a scientific detective story. It will take you into the world of the immune system and its biochemistry and you will become thoroughly familiar with the world’s leading medical journals and the medical research into the bio-chemistry of the causes of asthma and allergic disease. But this is also a shocking detective story: you will learn how those very same medical researchers, who to this day are celebrated leaders in the community of immunologists, mysteriously disavowed their own findings and effectively betrayed patients worldwide as they bowed to corporate agendas—for reasons best known to themselves. Although this seems unbelievable at first, it is not without precedent. The same developments have been published with regard to cancer and psychiatric illnesses. There, too, some of the leading researchers who had discovered the underlying mechanisms of both areas of illness with the potential cures for both, and had published their findings in the world’s most prestigious science journals, What is significant here is to understand clearly, that none of that research in allergy, cancer and psychiatry was superceded by new findings, or in any way proven incorrect, or found to be a dead end for scientific research. The astonishing revelations contained in this book are supported by what happened in cancer and psychiatric research because in those areas, the revival of all that useful medical research is beginning to Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page ix Introduction happen now. It is my fervent hope that this outstanding book will start the same process of revival for asthma and allergy. Today, the sell-out of medical practice to agendas that have nothing to do with curing the sick, is nearly total. Patients are now referred to as “consumers” who are encouraged to believe that they have “choices” of treatment offered in that enormous market of modern medicine run as a business. It is as if illness has become an accepted life-style choice—right after the car industry. After all, Pfizer is not only the world’s largest pharmaceutical corporation, but also the world’s second largest corporation. The representatives of the drug companies are accepted as “stake-holders” in medicine to the point where they are part of determining standards of practice, sit on the councils of the medical licensing authorities, virtually control all medical research in the absence of publicly funded research (but not in most of continental Europe), and act as policy and fundraising staff for our political leaders.2 As for the business mantra of “consumer choice,” for the asthma and allergy patient it’s basically steroids or steroids or steroids: mint flavored syrups for kids, or laced with antibiotics (to cover all bases), or as shots, as creams, and usually as the ever present puffer shaped as a toy for kids, handy and pretty like a lipstick for the ladies. As for the cure, “profits can only be harvested from chronic disease” a CEO of a pharmaceutical giant observed in a recent shareholder’s meeting.3 But whose responsibility is it to fix this situation? Consider this then: The world’s most prestigious science journal, Nature (March 28, 2002), ran an article entitled “Can you believe what you read?” showing how the editors of the most respected medical journals have begun to do some radical housecleaning when it became overwhelmingly apparent that published research too often reflects corporate interests to the point of distorting the observed facts. On June 27th 2002 Nature reported that even medical bio-ethicists are now “being offered stock board positions, consulting contracts, research grants, and even stock options” by pharmaceutical companies—and they accept these goodies! Two international conferences were held in 2002 on conflicts of interest in medicine (Atlanta and Warsaw). The former editor of the New England Journal of Medicine, Marcia Angell, justly famous for her fearless scrutiny of corruption in medicine, now works closely with the Center for Science in the Public Interest (www.csip.org), a watchdog exposing unethical behavior of doctors selling out to industry and industry’s false or self-servingly incomplete product claims. ix Plot/Allergies•i-xii•1-317 x 11/24/03 11:20 AM Page x THE PLOT AGAINST ALLERGY PATIENTS Just how bad things have become can be measured by the fact that on February 5 2002 the prestigious journal, Annals of Internal Medicine (vol. 136, no. 3) and the UK’s famous Lancet simultaneously published the “Physicians Charter” as a new manifesto to guide medicine (www.professionalism.org). The charter asserts that it is time doctors get back to the basics. The Charter reads like the Hippocratic Oath of 2,500 years ago translated in modern English. The message is simple and blunt: don’t abuse your patients financially or sexually, don’t hurt them, let them chose among available treatments, and treat them properly even if they are black, Jews, poor, retarded, dying, just plain old, or don’t have any money, and don’t blab about them to others without their consent. Central among all these ancient basics of medical ethics was the admonishment that a doctor must not lie when you do research because somebody offers to pay you for it. (The immunologists whose work is discussed in this book would do well to read this Charter.) Wow! This document was prepared by an international team of medical ethicists for the international effort called the “Medical Professionalism Project.” It states at the outset: “We share the view that medicine’s commitment to the patient is being challenged by external forces of change” which “tempt physicians to forsake their traditional commitment to the primacy of patients’ interests.” So, that is what the international medical community admits, Dr. Ravikovich provides in this book evidence in support of this urgent need for a major renovation of the House of Medicine and why that renovation must start with doctors, after which the pharmaceutical industry is easily tamed. This book is not simple. But neither is living with asthma, hives, irritable bowel syndrome, chronic fatigue, constantly itchy skin, the annual round of hay fever, or potentially fatal food allergies. The information in it is not “alternative”—the research is entirely mainstream. Here you will learn why you are sick, why your standard treatments don’t work very well and make you sicker through so-called side effects, how you could become healthy, or at the very least greatly improved and get off drugs, and what you can do to help make this healing treatment available. This is no ordinary self-help book—indeed I wish it was. This book is a crash course in asthma and allergy medicine designed to empower you with knowledge and hopefully inspire you with a holy rage and the determination to help bring out these facts so they become generally known to doctors and patients alike. Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page xi Introduction A good book like this does not need my recommendation, but a quick guided tour might help the reader who is new to this material. Thus, Part 1 provides the technical detail of how the immune system works, as is generally agreed upon by scientists in this field. For the beginner Part 2 may serve as a useful beginning; Part 5 will help patients understand why they are not improving and what is known in mainstream pharmacology about these drugs and their serious limitations and dangers. Part 4 has the provocative title “Histaminegate” which refers intentionally to the Watergate scandal of the 1970s. This chapter deserves the reader’s closest attention and is worth reading with the greatest attention to detail. The remaining chapters provide information on the various allergic diseases which will be of special interest to different readers. The Epilogue is something of a bombshell because it describes the most recent publication on allergy research that came out only two weeks before this book was submitted in its manuscript form to me. This research paper fully validates everything you read in this book and returns to the research that was more and more successfully hidden over the past two decades. The politically significant fact of this development is that this was published by the Swiss government’s research institution funded by tax money, not drug companies. The equally important medical historical facts are that now “the truth which was denied entrance through the door has forced its way in by the window”—as the Russian proverb puts it and as Dr. Ravikovich is fond of reminding us. The Appendix contains documentation on the terrible struggle Dr. Ravikovich became involved in when his life-saving treatment was attacked by the medical licensing authorities, and suggestions are included on what you, as the reader or friend of an asthma and allergy patient, can do to change the current situation. Treating asthma, allergy and related diseases successfully, at a fraction of the current cost of mere limited symptom control, is an art and a science easily learned by any interested doctor. There is currently a great deal of interest in therapies that cure and are not merely symptom control methods generally employed by the majority of physicians. What suffering patients often don’t realize is how terrible the frustration of doctors is who wish to help but often are prevented by the regulatory systems from employing new methods. xi Plot/Allergies•i-xii•1-317 xii 11/21/03 2:06 PM Page xii THE PLOT AGAINST ALLERGY PATIENTS If doctors want this scientifically validated treatment approach to use, it could be learned within a week or two. It is founded on basic science and as a treatment validated through experience. However, here in Ontario the use of histamine to treat asthma is literally forbidden since 1996 even though blocking medical innovation and overruling patient choice is contrary to the Medicine Act of Ontario and the Helsinki Accord on Human Rights which Canada signed in 1988. This ban was ordered without a single item of supporting scientific evidence and bypassed all mandatory debate required for the formulation of medical standards of practice. You can change that. Read this book and consider the information given in the Appendix and exercise your rights as a citizen and as a patient. Helke Ferrie 1. Michael Bliss, William Osler: A Life in Medicine, University of Toronto Press 1999 2. See The Olivieri Report, published by the Canadian Association of University teachers, Lorimer, 2002. For cancer see S. Epstein, The Politics of Cancer Revisited, 1998, East Ridge Press. Epstein is one of the world’s leading oncologists known especially for his success in getting DDT banned and refocusing cancer research onto the science of carcinogens. He is responsible for laws protecting workers from asbestos, pesticides, radiation etc. throughout North America and the European Union. For psychiatry see the new book by the world-renowned pharmacology scientists and corporate whistleblower David Healey, Let Them Eat Prozac, Lorimer 2003, published by the Canadian Association of University Teachers. 3. J. Robinson, Prescription Games: Money, Ego and Power Inside the Global Pharmaceutical Industry, McClelland & Stewart, 2001. Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 1 PART ONE IMMUNE MECHANISMS CELLS Almost a century and a half ago, a German scientist, Rudolf Virchow, made a revolutionary discovery: the body is actually a “state” consisting of “citizens”—live cells, each of which is a perfectly balanced unit. A deviation from the cellular balance is a disease, that is, lack of ease. Cells are our invisible natural workforce and best health guardians. Therefore it is important to understand what can go wrong with their complicated functioning, how to help them restore their rhythmical work, and how to achieve this with minimal introduction of suppressive medications. What is a cell? It is a tiny basic operative unit of a live body. If we accept Virchow’s view of our body as a “state,” then it is populated with over 100 trillion “citizens” working in coordination with each other. Our health and quality of life depend totally on how our cells function. Cells have different colours, sizes, and shapes and can be stationary or in motion. Under the membrane of each cell, there is a chemical lab, and the chemicals it generates determine the cellular function. Similar cells unite in teams to form tissues and organs. Cellular teams work in unison, no matter where in the body they reside, and produce the same chemicals at any given moment. A cell contains over a billion molecules, and each carries specific chemical messages. Cells communicate with each other in a cell-to-cell talk through these chemicals, just as we communicate with words, spoken or written. The more chemicals a cell is able to manufacture, the more “verbal” it is. Some cells perform limited local functions only, and their inner labs are fairly simple. Others are complex pharma- Plot/Allergies•i-xii•1-317 2 11/21/03 12:38 PM Page 2 THE PLOT AGAINST ALLERGY PATIENTS ceuticals able to produce as many as 300,000 different proteins: these cells perform numerous complex functions. The possibility of cloning an animal from just one cell makes it clear how intricate its lab can be. Cells are very “friendly” with one another. They lie in close proximity, and if something is wrong with one group, and it changes its chemistry, the neighbors express their “sympathy” by changing their chemistry as well. You definitely experienced it many times: your boss yells at you, and your legs give way, your pulse accelerates, your stomach turns into a knot, and you are ready to rush to the washroom. All this happens because the cells in your nerves, muscles, intestines, vascular wall and endocrine glands identify with your hurt feelings regulated by the brain cells. The opposite happens when your satisfied or elated brain cells start to release endorphins, natural narcotics, and the cells all over the body respond by participating in the joy. You feel as if you can fly, able to lift heavy objects and solve most difficult problems. This is what the unity of the different departments of the body means. ur body consists of cells, which are tiny chemical labs of various complexities. The chemicals released by cells are the language of their communication. They listen attentively to each other’s talk, and therefore, the work of different groups of cells is interrelated. This makes the functioning of the organs comprised of these cells also interrelated. O GENES All cells comprise the same set of over 30,000 minuscule particles within its nucleus. They are called genes. A gene is a biological unit of heredity that passes certain physical characteristics from parents to their children. Genes determine everything from such evident things as the eye colour, the voice timbre or the height, to such imperceptible minutiae as actual operations of a cellular lab. Every cellular chemical has its gene that governs its function. Genes are behind each cellular operation and secretion. In their chemical language, they instruct the cells what proteins and in what amount to produce in particular situations. A cell’s performance depends on the performance of the genes. The same genes work synchronically in all cells and send the messages from within, and the genetic instructions influence the lab’s activity qualitatively and quantitatively. If there is no genetic error or mutation affecting the functioning of our cells, our health is good. Nature is not faultless. Our dissatisfaction with something in our appearance is actually a reflection of how we perceive our visible genetic imperfec- Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 3 Immune Mechanisms tions. Health problems often reveal genetic imperfections hidden from the eye. We may be born with genetic errors or may acquire them inexplicably in the course of life or through exposure to a harmful factor—such as radiation, toxic environment, etc. The term for genetic changes—mutation—comes from the Latin mutare—to change. Defective genes send flawed messages to the cellular lab, leading to the inappropriate production of the corresponding chemicals. The resulting imbalanced chemistry means a disease in the organ or system comprised of cells that produce this substance. Several genes or even a group of them may be responsible for each disease. Changes in DNA, the nucleic acid which is the iny particles inside carrier or genetic code, can be structural and funccells called genes are tional. The latter means that the genes are, in princarriers of our heredity. ciple, structurally normal, but have some “variations” The genes govern in their activity. This is of key importance for clinical cellular functioning, and medicine, since if only the genes’ functioning is hence, chronic diseases impaired, attempts to correct it can be successful. Not are mainly the result of by deleting and replacing them, as is planned in the incorrect messages sent current trend towards potentially dangerous genetic to the cellular lab by engineering, but by tuning them up instead. faulty genes. Genetic Once initiated, a genetic change is potentially changes occur spontatransmissible, and may be passed by parents to their neously or through the children, grandchildren, etc. Genetic errors leading to impact of external health problems may be so subtle that their existence factors and may be remains unnoticed for years until time and/or strong passed to future effect deepen the hidden flaw. Doctors often see generations. If the parents that are taken aback when their child is diaggenetic faults are of a nosed with asthma or other allergic disease that functional, rather than neither of them seems to have; it is the combination of structural nature, mediparents’ genes that has amplified their own noncine has a chance to apparent genetic errors in their offspring. attempt a correction. T THE INTERRELATED FUNCTIONING OF GENES AND CELLS Each gene performs the same operation again and again. It is like a tiny perpetual motor operating in a sophisticated machinery that includes the interdependent work between the genes and the cells. The relationship of the chemical lab and the genes that lie at the heart of each cell is not unilateral, as 3 Plot/Allergies•i-xii•1-317 4 11/21/03 12:38 PM Page 4 THE PLOT AGAINST ALLERGY PATIENTS it may seem. It is not simply a matter of the genes governing and the lab obeying. Genes need “fuel” or “feedback” for their functioning, and certain chemicals generated by the cellular lab itself play this role as do some chemicals coming from outside. Some activate the genes’ functioning, others inhibit it. Genes can give proper instructions to the cells only when they get an adequate “fuel supply.” Indeed, as Dr. Craig Venter, one of the two leaders of the Genome Project, said on April 23, 2002 at the Gairdner Foundation International Awards event, “proteins are the building structure of life, not genes.” The understanding of the reciprocity in the functioning of the genes and cells may turn the dream of medicine—safe and efficient genetic engineering —into reality. Use of proper substances may gently correct the functioning of the genes and hence, rectify their messages to the cells. These substances would be genomodulators, and their effect upon the genes he activity of the would be genomodulation. To modulate means to adjust. cellular lab and the The Latin root modulare means to bring out characterisfunctioning of the genes tics peculiar to a definite region; thus, genomodulation are interdependent. would mean a repair of genetic functioning to the Moreover, cellular normal level. Such type of “genetic engineering” would production at large can be non-invasive and safe. Since medicine does not use affect the genes’ this sort of genomodulation, one would think that such activity. Medicine can proteins-modulators are not known or are commeruse this fact as the key cially unavailable. Wrong. This book will discuss later to access the genes if two powerful genomodulators that work in harmony their defects are only with each other like a unit. functional, not struc1. One is a chemical generated by the cells and tural, and thus realize released into extracellular space, also existing safe “genetic engiin a form of a drug. neering.” The use of a 2. The other is an intracellular enzyme. well known synthetic Both have been known for decades as messengers version of a body’s informing the cellular lab. If their harmonious work is chemical triggers the impaired, we may use a synthetic version of the first in response of an intracelinjections, and it will naturally engage the other. lular enzyme and Numerous chronic conditions can improve or be cured enables the latter to by this. The improvement means that the genetic funcrestore the functioning tioning in the patients treated this way was corrected of impaired genes. temporarily or for good. T Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 5 Immune Mechanisms IMMUNITY ur immunity consists Everybody knows that immunity is the body’s defence of highly complex against disease, but, among laymen, few are aware that groups of cells called it is, actually, a defence realized by cells called immuno- immunocompetent cells. competent. These cells are competent in recognizing the They work in coordinaenemy and producing the chemistry that protects the tion with each other and host. We are born only with the seeds of immunity. The specialise to fight fighting ability of immunocompetent cells is dormant different diseases. These for the first several months of life. Exposure to an cells start to malfuncenemy “wakes them up.” Each exposure provides a chal- tion if the genes lenge for them to specialize—to become competent in governing the immune fighting a particular enemy. Some cells neutralize viruses response are mutated. and bacteria, some fight cancer, others react to allergens in those who are prone to allergic reactions. Each category of the specialized cells performs its specific function. Thus, many groups of cells are united under the concept of immunocompetence. Their coordinated work can be compared to a well-rehearsed orchestra, and the released chemistry is the music. Immunocompetent cells are located throughout the body. Certain genes govern all aspects of their functioning. As was recognized a century ago, immune diseases are the result of changes of the genes that govern all the activity of the immune cells. The instructions of defective genes are, naturally, defective, so are the kinds and the amounts of the chemicals liberated by these cells. An error may turn the cellular music into a cacophony the way a poorly tuned piano key can turn a concerto into a disaster. The uncoordinated music of the immunocompetent orchestra means a poor defence against diseases, no defence at all, or a distorted defence/reaction. O ENEMIES OF THE IMMUNE SYSTEM We live in a world full of microorganisms that try to invade the body mainly through our respiratory and gastrointestinal tracts and skin. These organisms may cause a disease, but may also play a positive role in challenging our immune system, causing the cells to produce defensive proteins and thus, couching them how to defend us. We also have our inner “enemies” such as excessive stress, hormonal changes due to puberty, pregnancy, menstrual period, extreme temperature swings, etc., which require extra effort for the body to adjust. When not in excess, an adjustment strengthens our immune system, since the cells learn in the process what substances to produce and in 5 Plot/Allergies•i-xii•1-317 6 11/21/03 12:38 PM Page 6 THE PLOT AGAINST ALLERGY PATIENTS what amounts to deliver them. For example, the longer life span among women compared to men is considered to be due to the frequent hormonal challenges that strengthen their immune system. However, our society has created numerous challenges that exceed the ability of our immune system to resist them with success. Our food is full of colorants and preservatives, some indicated on labels, others hidden. We breathe toxic fumes and drink contaminated water. We feed the cattle and chicken with antibiotics and hormones that speed their growth. We enes malfunction even legalize the hazardous effects of these drugs by due to inborn errors allowing their “permissible” amount in meat and or those acquired in the poultry. Cattle are fed grass and grain treated with fertilprocesses of life. Their izers, and we allow a certain amount of these poisons in functioning may also canned goods that use dairy and meat products. To change under the influcompound our problems, we often take medications ence of extreme envibecause we do not want to tolerate a slight discomfort, ronmental factors. even for a short period of time, and easily find a doctor Genetic changes are willing to write out a prescription. The respect of the called mutations. society to drugs is so high that we write them with capital Mutations create a letters. We are forced into vaccinating our children predisposition to cellular although the generally accepted “hygiene” theory by S. malfunctioning, since Romagnani recognizes that the increased exposure to flawed genes send vaccinations is among the factors contributing to the wrong signals to the spread of allergies and asthma.1 cells they govern. Social pressures in our competitive society are also important health hazards. Our biological evolution has not caught up with the fast pace of “civilization” and its stressful and sustained emotional factors that contribute to the destruction of our great defender—the immune system. This destruction starts with the genes that govern the “pharmaceutical lab” of immunocompetent cells. Apart from accumulating unfavourable external conditions that affect our genes, their malfunctioning and/or mutation may occur spontaneously in the course of life, without any obvious reason. G ALLERGY AS A CELLULAR OVERREACTION The very term allergy indicates that a patient’s body functions differently from a normal body: Greek allos means other, while ergon means work. Like an abused child who snaps at suspects an enemy even in a friendly stranger, Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 7 Immune Mechanisms an immune system governed by impaired genes sees enemies not only in viruses, bacteria or cancer cells but in the things and events which would leave a healthy immune system undisturbed. It may “snap” mmunocompetent at a pollen particle, fur/dander of a pet, a favorite cells genetically food, the texture of fancy underwear, a pleasant scent of a perfume, a weather change, a mood fluctu- predisposed to malfuncation or a natural rise or fall in one’s own hormonal tioning are hypersensilevels. The cells may also “overreact” without any tive and may overreact challenge, that is, spontaneously, which means that spontaneously without they start releasing certain chemicals in disproportional a trigger, or react to a amounts. Such chemical overreaction of immuno- friendly environment by competent cells is called hypersensitivity or hyper- releasing wrong chemistry. This brings on releasability. Allergies are genetically predetermined. They start allergy symptoms. Only with the malfunctioning of the regulatory genes those people whose responsible for the balanced work of the allergy depart- genes are mutated have ment of the immune system. Genetic predisposition is chronic allergic the primary dominant factor in the production of diseases. Exposure to a allergic diseases, while the environment may become a harmful environment complimentary factor. In the absence of genetic muta- may only augment the tion, the effect of the environment is mostly temporary genetic defect and and leads to acute reactions and temporary symptoms, through this lead to not to chronic allergic diseases. This explains why hyperreleasability of the some people develop lasting allergy symptoms upon immunocompetent cells. a certain exposure, while others get away with an acute episode. A slight genetic defect, mostly inherited, occasionally acquired, may remain unnoticed for years. However, time itself and/or cumulative effects of the hazards may “break the back of the camel.” In other words, the initial small defect in the genes may become magnified, and as a result, the operation guided by these genes may cause the cells to respond with a pathological reaction to what they would have perceived as harmless before. Since the language of the cells is their dynamic chemistry, the malfunctioning immunocompetent cells speak in chemically improper syntax and thus produce the signs of disease. Conventional allergy dwells on the environment as allergy cause and rarely spells out the fact that a trigger may provoke a recurrent allergic disease only in people with the underlying genetic defects or predisposition. Allergic I 7 Plot/Allergies•i-xii•1-317 8 11/21/03 12:38 PM Page 8 THE PLOT AGAINST ALLERGY PATIENTS reactions without any trigger are also left unexplained. This deflects attention from primary errors to secondary events. IS TREATMENT OF ALLERGIES ON THE GENETIC LEVEL FEASIBLE? Knowledge of the alphabet is not sufficient to enable one to combine the letters into words, and words into sentences. In a similar way, we cannot say that the current listing of about 30,000 genes gives us the knowledge of their functions and, most importantly, their interrelations, not to mention, the patterns of their manipulations. The understanding that genetic malfunctioning lies at the core of allergies means that its correction would be the best possible treatment for diseases of hypersensitivities. The interrelationship of genes responsible for one single disease, as well as their interrelationship with the rest of the genome, are extremely complex processes and may never be fully understood. Besides, the procedure of correcting or replacing flawed genes is technically very complicated, and is, therefore, as the leading geneticists say, many years away. Francis Collins, head of the Human Genome Project of the National Institutes of Health, predicts, that by 2010, we may have about 25 tests for genetic predisposition to about 25 major causes of diseases and death. Diagnostic tests, not therapies! One ought to think also about the many possible physiological, moral, and ethical issues involved in such therapies. There is another obstacle. Rationing of knowledge is common in modern medicine, and drug companies have already started battling over patenting the genome discoveries. Drugs or new methods of genetic therapy can rightly be considered discoveries, but the industry wants to patent that knowledge! Imagine what would have happened if the inventors of alphabets had decided to patent the letters. If the industry finds support for this plan from our corrupt governments, the possibility of genetic cures will be moved to still further into the future. Another problem is related to the enormous amount of money needed to fund the development of procedures for the intricate process of penetrating genes. Thus, as an every day treatment, genetic engineering is not feasible, even theoretically, in the near future. Fortunately, allergies and asthma, although multigenic and multifactorial diseases, arise mostly not from structurally defective genes but from deviations in the genes’ functioning. This means that in order to reverse an allergic disease, we need only to “tune up” these genes. The fact that in allergies, the performance of the Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 9 Immune Mechanisms governing genes is correctable should make medicine happy. More so because the prevalence of allergy and asthma grows rapidly. HOMEOSTASIS To understand how medicine can “tune up” the body and help it to reverse allergies on its own, we must understand a basic law of nature—homeostasis. The word consists of two roots: home(o)—sameness and stasis—standing, and thus, the term denotes the tendency to preserve a balance. Nature strives for harmony and endowed us with delicate self-regulatory systems. Whenever unfavourable forces affect our body, these systems are challenged and, without our awareness, adjust to the changes, thus protecting us. For example, exposure to cold causes shivering, which is he body functions the body’s way of warming up, while exposure to hot normally when all the weather automatically causes profuse sweating that cellular substances are prevents overheating. Both the warming and the produced in balanced cooling are achieved through spontaneous changes in amounts. A healthy body the cellular chemistry. possesses regulatory Look how clever the body deals with dieting: after tools through which it an initial weight loss, the metabolism slows down to corrects imbalances. make better use of the smaller amount of food the The main condition dieter consumes. In fact, weight loss may practically under which the immune stop despite the reduced food intake. While this may system functions upset dieters, our metabolism is “computerized” to normally is a homeohelp the body to survive during food-deficient times. static production of all Another example: if you eat a lot of sweets, the chemicals by the high level of blood sugar mimics the condition of immunocompetent cells. diabetes and may lead to metabolic changes. To prevent complications, the body has a mechanism to cope with the dangerous excess: the insulin-producing gland gets the instruction to increase its output to metabolize the sugar. Any deviation from the norm, be it a deficit or a surplus, may be equally harmful, and these examples show that a healthy body self-rectifies such changes through its protective autoregulatory switches governing all functions. The tendency towards maintaining equilibrium, no matter whether it is body temperature, blood pressure or hormone production or, in fact, production of any chemical, is an inborn feature that keeps the body alive and is a part of the universal law of homeostasis. T 9 Plot/Allergies•i-xii•1-317 10 11/21/03 12:38 PM Page 10 THE PLOT AGAINST ALLERGY PATIENTS Homeostasis is the core of immune system functioning. Health is balanced cellular production of all chemicals, or harmonious cellular functioning. Each time our immune system fights an invader, its only task is to restore the balanced production of chemicals by immunocompetent cells. Unlike other immune-related chronic diseases, allergies and asthma are much more easily reversible because permanent changes in the tissues’ interior occur only in the very advanced stages. The spontaneity of relapses and remissions in allergies and asthma indicates that it is possible to restore the functioning of the immunocompetent cells involved in them because the mutation of the underlying genes is only functional. CELLULAR RECEPTORS What are the tools through which a healthy body regulates the production of all of its substances? Knowing them in general, we could probably find the ailing regulatory tools in allergy patients, repair them and help these people. The instruments through which the body establishes homeostatic amounts of cellular secretions are cellular receptors, which all cells have either on the surface of the cell membrane, or inside the cell itself. Receptors are molecules of protein that work like antenna, each very selective in their response to the surrounding environment. Each type of receptor is tuned to a certain signal. Some discern a signal of pain, others of temperature, sound, color, a specific chemical substance, etc. Signals come in the form of chemicals, the language of the cells. Each receptor selectively binds to a specific substance, or picks up the information contained in a physical stimulus, and then dispatches the obtained information to the cellular lab. The received signals affect the manufacturing process in the inner cellular lab. The information travels with a lightning-like speed. The more complex the cellular lab, the more varied its receptors are. Different groups of cells may have the same type of receptors and hence, respond to the same signal by changing their chemistry in tandem. Intracellular signaling followed by chemical effects is called signal transduction, while cell-to-cell talk is signal transmission. The development and activity of all cellular receptors are determined by genes. ells have various receptors, and each kind senses specific stimuli and/or chemical messages. The receptors then change chemically in response to the stimulus or bind to the substances that carry these messages and pass the “digested” information to the inner lab for production of certain chemicals and hence, physiological effects. C Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 11 Immune Mechanisms A cell with its receptors can be compared to an insect whose antenna detect signals from its peers or the environment. In response to a stimulus, a signal, the insect’s body produces certain chemicals, and that changed chemistry conveys a message for action. The signal may prompt the insect’s body to exude venom to repel/kill an enemy or to secrete pheromones specific to the situation: to alert its peers of a danger, to attract an insect of the opposite sex, to call for help. Similarly, receptors are conductors of such cellular messages. Imagine an insect with its antennas severed: all its communication with the peer community and the environment are is cut off, and the insect is doomed to die. Similarly, the cell’s ability to synthesize and release chemicals depends on its receptor functioning and our health depends on proper receptor functioning. RECEPTORS AS SWITCHES A cell is a generator of chemicals, and like any generator, it is supposed to have switches to turn the he body corrects any processes on or off. An immunocompetent cell unbalanced cellular synthesizes numerous chemicals and has switches for production through each of the chemicals it generates. Cellular receptors receptors that work like play the roles of switches that intensify or temper the turn-on and turn-off cellular production process. To make sure that the switches. Every cellular cell produces just the right amount of a particular chemical is regulated by substance, there are receptors that switch on its its specific receptors, release and other receptors that switch it off. Each and like switches, they cellular switch works within a range. The regulation adjust production to is implemented the same way the temperature of an cellular norm. Only propiron is increased or reduced by turning the lever, erly working on/off depending on the type of the fabric being pressed. switches provide the Proper control over the synthesis and release of correct release of each chemicals is vital because both excess and deficit can cellular chemical. lead to disease, as is, for instance, the case of a coma resulting from blood sugar excess or its shortage. Each receptor type is tuned to a certain chemical. Cells “measure” the amount of this chemical in the surrounding space with their receptors in the same way that an insect’s antenna senses the environment for specific signals and then passes its message to the inner lab. The lab responds accordingly either with intensification or inhibition of the release. This receptor-mediated process goes on incessantly. T 11 Plot/Allergies•i-xii•1-317 12 11/21/03 12:38 PM Page 12 THE PLOT AGAINST ALLERGY PATIENTS nly well developed receptors are able to sense and correct the release of cellular chemicals by increasing or decreasing their production. If one kind of receptor is inefficient, the cells release the chemicals according to the signals of its opposite. Thus, the inefficiency of a turn-off receptor type leads to the predominance of the chemistry generated by its rival turn-on receptor. None of the current allergy medications repairs the prime defect—inefficient receptors—they do not restore the protective ability of the immune system. Instead, all of them block the activity of the efficient receptors. O If a certain receptor type, say an off switch, is inefficient, its counterpart, the on switch, works unopposed. This can make the cell generate so much of a chemical that it inundates the tissues and leads to disease. Only efficient on/off receptors can provide balanced output. RECEPTOR EFFICIENCY DETERMINS PROPER CELLULAR WORK In the same way a high grade TV antenna determines the number of stations and the quality of the image, cellular receptors provide a proper message transmission. For adequate cellular functioning, both the quantity and the quality of receptors are important: the cells should have enough cellular receptors, and these should be well developed. Scarce, underdeveloped or inefficient receptors cannot adequately discern signals, nor can they transmit coherent information to the interior of the cellular lab. As was said, the operation of any on-switch must be counterbalanced by the off-switch. An example is a warm shower: only functional taps can provide one. Otherwise, we would have either cold or hot water only. In every-day life, nobody tries to resolve the problem of a broken cold water tap by reducing the flow from the hot tap. It is the broken tap that needs to be repaired. Every-day logic that prompts us to fix the broken tap, fails when it comes to fixing our health. Here is proof. The immune system is designed as a self-regulatory machinery, and allergies are among self-regulatory diseases. This knowledge allows us to develop medications that will stimulate or block receptors depending on the purpose. Medications can relieve the symptoms either by blocking the active healthy receptors or by stimulating the inactive ones. Activation of the inefficient tool is preferable since it not only rectifies the primary defect but also preserves the integrity of the rest of functioning system. Strangely, drugs designed to stimulate deficient responses are a rarity in medicine in general and are Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 13 Immune Mechanisms absent in allergy, but allergy therapy concentrates primarily on blocking the active, normal (!) responses. Logically, help should come in the form of facilitating the repair of the primary defect. But conventional allergy practice completely disregards this simple logic and uses only suppressors. CONVENTIONAL TREATMENT OF ALLERGIES Each organ with unhealthy immunocompetent cells expresses its malfunctioning through the symptoms typical of its specific nature. Thus, the lower respiratory tract expresses its disease through cough and bronchial obstruction; a runny/stuffy nose is a sign of the affliction of the nasal lining, while itch and rash indicate the involvement of the skin. Two kinds of medications are used to treat allergies. The purpose of both is symptomatic relief, not cure. These are symptomatic drugs that target the end organ—bronchi, nasal passages, skin, etc. They are supposed to block the release of the “bad” chemistry that causes the symptoms and thus to relieve bronchial obstruction, an itch or a nasal congestion. Actually, the “bad” chemistry is secondary to the primary cause which is the deficient turn-off receptors, but unfortunately the restoration of their activity with proper stimulants never becomes the treatment target. Given the fact of the mutated genes causing the harmful functioning of the flawed receptors, allergy patients are doomed to perpetual medicalization and regular visits to medical offices. Moreover, the suppression of the excessive release fails too often, and then other drugs are prescribed. These not only attempt to reduce the effect of the “bad” chemistry, but suppress all the processes in the cellular lab, bad and good, and that is why they are called immunosuppressants. Worse yet, even at the cost of cellular suppression, these medications provide only temporary relief, because they do not eliminate the cause of the malfunction in the cells, but merely suppress all the work of the cellular lab. This suppression covers all immunocompetent cells, and their protective functions are also shut down. These medications suppress the functioning of the cells far beyond the immune system, and thus, these side effects greatly overshadow even their apparent shortterm benefits once taken for a long period. Of course, allergy is a chronic disease, and so these medications are often taken daily, which undermines the body’s entire immunity in addition to all those side effects. The immunocompetent cells, already compromised by the pre-existing genetic malfunctioning, lose their innate ability to produce their protective chemistry. This deprives the patient consuming the drug of most immune defences and, hence, severely affects the course of the allergic illness for which the drugs are prescribed. 13 Plot/Allergies•i-xii•1-317 14 11/21/03 12:38 PM Page 14 THE PLOT AGAINST ALLERGY PATIENTS odern allergy therapy focuses on the end organ by blocking the natural on-receptors responsible for the overproduction of those substances which, in excess, cause the symptoms. Most commonly, and especially in asthma, it uses immunosuppressive medications that allegedly target the “bad” chemistry, but in reality suppress the work of all immunocompetent cells. Blocking is too often inefficient. Suppression destroys the cellular ability to produce protective chemistry, which results in the generally undermined immunity, and, in the long run, worsening of the primary disease and/or other side effects of various kinds and severity. Neither approach aims to restore the functioning of the immune system and by that, resolve the allergy problem. M In general, we often learn about drugs’ side effects only when the fatalities from their consumption rise too high to be ignored. Such drugs are taken off pharmacy shelves, replaced by others, allegedly safer products, and only time exposes the adverse effects of those newer products. In allergies and especially in asthma, immunosuppressive medications are, however, the only effective ones, and allergists try to reduce the side effects of these widely prescribed drugs. Adverse effects are rarely discussed in medical sources and are usually missing from medical textbooks as well. No wonder, that in the long run, the course of the disease, for which these medications are prescribed, becomes worse. Napoleon Bonaparte is said to have remarked: “Doctors will have more lives to answer for in the next world than even we generals.” T-CELLS Any discussion of a self-regulatory disease should start with the commanders of the immune cells. They are the T-cells or T-lymphocytes. These cells are a nature’s masterpiece. The verbs used to define the T-cells’ role in immune response and function affirm that they initiate, propagate and orchestrate all immune reactions. T-cells mainly direct the battles by telling other immunocompetent cells what chemicals to generate and in what amounts. They also most actively participate in all processes where their subordinates are involved, and immediately respond to the messages coming from other cells. Various chemicals signal these commands and responses. T-cells possess a unique ability to learn how to participate in immune reactions and govern them. At first, these cells are “naïve.” In a medical context this word is used to describe the fact that an immune cell has not yet been exposed to invaders and, therefore, has not yet had a chance to express its fighting potential. Exposure to a virus, microbe, or any other Plot/Allergies•i-xii•1-317 11/21/03 2:19 PM Page 15 Immune Mechanisms intruder provides the cell with information that causes it to become “educated.” This activation signifies the beginning of their specialization in the corresponding field. The process continues with repeated exposure to the trigger in a way similar to muscle training when exercise results in a corresponding muscle development. Allergy is a deviation from the norm. T-cells are supposed to be our protectors, but in the allergic patient they lack their regulatory ability. This creates the background for an exaggerated activity of -cells are central to the subordinate immune cells, now promoting disease. immunity. They In allergy-prone people, any foreign substance or any specialize in fighting unspecified event may become a trigger of a diseasepromoting immune response. T-cells called different diseases. After T-helpers (TH1 and TH2) now unfortunately “help” to an encounter with an invader, which they produce chemicals promoting the allergic response. The only other subdivision of T-cells that never perceive as an enemy, fails us and stays in the disease fighting mode are the they retain memory of T-suppressors. T-suppressors get activated simulta- what chemicals to neously and in response to the activity of all other produce for any future helper cells. In the ’70s, the term was introduced that fight. In allergy, there labeled suppressors as T-suppressor regulatory cells are two natural opposing denoting that they regulate all responses, especially in subdivisions of T-cells— allergies.2 Suppressors moderate not only the host- helpers that are mainly hostile activity of helpers, but also the disease- on the diseasepromoting activity of other immunocompetent cells. promoting side, and In the process of maturation, all T-cells, T-suppressors suppressors that funcand both kinds of T helpers, become memory T-cells. tion to promote health This means, that like the brain, they remember how to and also control the participate in the fight by releasing certain chemicals work of T-helpers. Both characteristic for their and activities in promoting or kinds of cells, once specialised, become suppressing disease. memory cells and remember how to fight T-SUPPRESSORS T-suppressors are our protectors in the immune for or against the system’s war we call allergy. Their overall activity disease. T determines whether allergy will or will not take place. The conclusion is that if one has allergy symptoms, T-suppressors are for some reason insufficient. Interestingly, since 1991, discussion of these cells, central for 15 Plot/Allergies•i-xii•1-317 16 11/21/03 2:19 PM Page 16 THE PLOT AGAINST ALLERGY PATIENTS allergic processes, has disappeared from medical sources on allergy, even though, of course, these cells are still present and doing their work as they always have done. At the same time, the same publications describe in detail helpers, TH1 and TH2, which are subordinate to T-suppressors. A legitimate question is: why? There can be only one logical explanation for this: by removing the protectors, T-suppressors, from the stage, the discussion now centers only on the diseasepromoting T-helpers. By not discussing the role of T-suppressors, which restore the body’s disease-fighting ability, the unlimited use of various medications is justified. By acting as if T-suppressors are not significant, the human body is portrayed by medical science as if it was unable to regain its disease-fighting ability. This, view justifies the unlimited use of various medications, including very potent ones. The most frightening fact is that, along with controlling the disease-promoting activity of the immune cells, these drugs collaterally also crush the activity of our saviours, T-suppressors. While the symptoms may temporarily be controlled, the price for this temporary relief may be the obliteration of our T-suppressors and thus also their ability to fight for us against disease. The fact that T-suppressors are ignored in medical discussion is, from a scientific point of view, incomprehensible; it was science that discovered them and elucidated their activity. Ignoring T-suppressors also contradicts the laws of homeostasis upon which a functioning immune system depends, namely that disease-promoting action always also stimulates the disease-fighting forces, in order to defend the host. -suppressors are controllers of all allergy-related immune responses, and their activity and memory are the keys to the normal functioning of all participating cells. Inability of T-suppressors to control T-helpers and organize the defence against them explains allergy symptoms. Inexplicably, during the ’90s, these cells have practically disappeared from all allergy-related scientific publications, which creates the false view of our immunity as a system ruled and operated totally by negative forces. T MAST CELLS Among the closest subordinates of T-cells, two kinds play a special part in allergic reactions. They are sister cells—stationary mast cells and mobile basophils. Mast cells reside in tissues, while basophils flow with blood. Due to the similarity of their functions, when speaking about mast cells, we imply basophils as well, even though they enter an allergic reaction at different stages. Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 17 Immune Mechanisms If T-cells are the conductors of the orchestra of allergy-participating cells, mast cells are the lead instrument. Their leading role indicates that all the properties of mast cells and basophils are realized in allergy as in no other disease. They start and maintain allergic reactions. Mast cells are major generators of chemicals in allergic reactions. The word mast comes from the German verb to feed, thereby indicating that these cells “feed” the immune processes with their abundant chemistry, which then provides for the various immune reactions. The most important and prolific chemical among them is histamine. Although histamine has been known for almost a century as a cellular chemical, in 1952, it was discovered to be a product of the mast cells. Since then, it has always been emphasized in all textbooks and medical dictionaries as the most distinctive feature of these cells and allergic diseases. Each mast cell contains 50–200 histamine granules densely packed under the cellular membrane. Mast cells are very “touchy” in general, but especially in allergy patients: upon certain chemical changes in the surrounding space, the granules crack like fragile egg shells and leak out histamine. This act is called degranulation. Histamine leaks abundantly in many diseases where there is an infectious or immune-related inflammation, or an injury. However, in allergies, mast cell release of histamine is especially profuse, and, therefore, histamine release is accepted as the start and the hallmark of allergic reactions. In humans, histamine is the only pre-stored mediator that participates in allergic reactions; it causes initial activation of all immune cells participating in allergy, and it changes their chemistry. Because mast cells concentrate in the skin, air passages, brain, gastrointestinal tract, histamine spill occurs predominantly in these areas. Mast cells initiate allergic reactions by overspilling histamine, while their sister cells, basophils, take over at a delayed stage and maintain the process. Their histamine production constitutes about 90% of all histamine released. While mast cells can produce numerous mediators of allergy, apart from histamine, basophils produce mainly histamine. The hyperresponsiveness of mast cells and basophils, and their exaggerated release of histamine, as the major driving force, allows us to call allergies diseases of hypersensitivity. The mast cells’ hyperactivity in releasing histamine is a sign of the person’s inborn predisposition to allergy, which means that certain genes governing the function of these cells are faulty. In his work on mast cells and basophils, Dr. L. Lichtenstein, the pioneer of histamine research, and the 1994 president of the American Academy of 17 Plot/Allergies•i-xii•1-317 18 11/21/03 12:38 PM Page 18 THE PLOT AGAINST ALLERGY PATIENTS ast cells and basophils are the cells that unleash and maintain allergic reactions. Their central feature is the presence of histamine granules under the membrane. In allergy patients, these cells are abnormally sensitive and may release excessive amounts of histamine in response to virtually any trigger and do so spontaneously. The histamine spill ignites allergic reactions. Uncontrollable release of histamine from these cells is a genetically predetermined feature and is a major indicator that the host has allergies. The exaggerated histamine release from mast cells and basophils is the key event in allergy, which clinical and even theoretical allergy medicine now basically ignores. M Allergy and Immunology (AAAI), reaffirmed this idea in his presidential address published in the most prestigious immunological periodical.3 To the present day, this concept has not been rejected or even questioned. However, in the latest medical sources histamine leakage at early and late stages of allergic reaction is described solely under the unrevealing mast cell releasability or mast cell degranulation, activation, or recruitment, with the word histamine always omitted. At the same time, the names of other, qualitatively and quantitatively inferior mediators of allergy are emphasized. In this way, the impression is created that mast cells are disconnected from their central product, histamine, and, thereby, their role in allergic reactions appears as seemingly insignificant. Instead, what is put forward as significant are other cells that neither initiate allergic reactions nor keep the allergic response going, or/and enter the game only in response to a histamine spill at much later stages. This conceals the inseparability of mast cells and basophils from histamine granules as their most characteristic feature, and deflects attention from the fact that a massive histamine spill signals the onset of allergic symptoms and maintains these at later stages. DENDRITIC CELLS The third type of cells important in allergies is the dendritic cell. The name dendritic comes from the Greek tree. Indeed, threadlike extensions of dendritic cells resemble a branched tree—the image that inspired their name. These cells’ “secretory products are more diverse than those known for any other cells of the immune system,” states the leading medical textbook on internal medicine.4 There are several types of dendritic cells, and they densely populate the skin, the lungs, the lymph nodes, and the nasal mucosa. One kind is of particular interest for us because of its regulatory activity in immune processes, its ability to affect the performance of T-cells, and its cardinal role in skin allergies and related skin conditions. These are Langer- Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 19 Immune Mechanisms hans cells, or simply LCs. These cells are a repository of numerous chemicals, histamine among them. They bind to the intruder and present it to T-cells for identification and action. LCs also possess the unique migratory ability of traveling from the skin to the regional lymph nodes and inform T-cells of the presence of intruders encountered on the skin or in the air passages. In addition, the changing chemistry of LCs following their encounter mong immunocomwith an intruder, can directly involve other immunopetent cells, there is competent cells. LCs have another unique feature— affinity with nerve cells, which also belong to the family the family of dendritic of dendrites. The extensions from LCs stretch to the cells. One type, dendrites of nerve cells, thus forming their continua- Langerhans cell or LCs, tion. These connections, as well as the cells’ reciprocal are especially important chemistry, become the bridges for their communica- in allergy. They densely tion. The involvement of LCs on the skin inevitably populate the skin, while leads to the involvement of the nerve cells and vice versa. other members of the Skin diseases of neurological origin, such as psoriasis or dendrite family reside neurodermatitis, are the best examples of the ties and all over the body. Upon interdependent functioning of the immune and an encounter with an enemy, LCs bind to it nervous systems in the body. and present it to T-cells, thus activating them. HISTAMINE Since all allergic reactions start and continue with a Dendritic cells have a histamine spill, histamine will become central to this special affinity to nerve book. Practically speaking, allergies and asthma are cells, which are also diseases of one substance—histamine. When a person dendrites, hence the does not have allergies, histamine release in that easy involvement of person’s immunocompetent cells is balanced. That is both in each other’s activities. why it is so important to clarify what histamine is. A The word histamine is made up of two Greek roots: histios meaning pertaining to tissue and amino denoting a chemical group, an integral constituent of all proteins. Histamine is a compound found in different concentrations in all body tissues. It is an active participant in all health-promoting as well as all disease-promoting processes. Its precursor is histidine, one of the nine essential amino acids. The term essential in regard to amino acids denotes that it is one of the nine compounds without which there is no life. Being similar to all essential amino acids, histidine cannot be synthesized by humans and is obtained only from food. In the 19 Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 20 20 THE PLOT AGAINST ALLERGY PATIENTS body, it naturally transforms into histamine. Numerous food proteins contain a different inherent amount of this histamine’s predecessor. Especially rich are seafood, certain fish and meats (mackerel, sole, pork), cheeses, red wines, chocolate, citrus fruits, nuts, beer. Consumption of such foods leads to increased formation of histamine, and therefore, hypersensitive people often have an allergic reaction after eating them. Like everything in the body, the innate histamine concentration in tissues is genetically predetermined. This is highly individual and also fluctuates depending on the physiologic state of the body at any given moment. The increasing histamine concentration in tissues may occur due to the overreaction of its main repository—the mast cells—to their internal environment. That is why allergy symptoms may instantaneously flare up upon the slightest change in the body’s chemistry. Such changes may occur when a person sleeps less or more than usual, gets warm or cold, or even when a sudden mood change takes place. Sometimes, histamine overspill may occur without any trigger at all, simply spontaneously. WHAT HISTAMINE DOES IN THE BODY In normal body functioning, although pre-stored mainly in mast cells and basophils, all immunocompetent cells contain histamine. Moreover, they start to synthesize it de novo upon activation, and this makes histamine the most important messenger in immune processes or, as science calls it, a mediator, in all aspects of immune function. Nerve cells and endocrine cells also synthesize histamine. In the nervous system, where it passes on its most important messages, histamine is called a neurotransmitter. Each cell in the body is connected to nerve cells; therefore histamine messages reach each cell and affect its functioning. Every substance in the body carries its own specific information. For instance, adrenalin mobilizes defensive mechanisms of the body, while insulin is responsible for the carbohydrate metabolism. Histamine’s scope of activity is inconceivably wide. Indeed, histamine “regulates (!) various activities of the brain, such as the arousal state, brain energy metabolism, locomotor activity, neuro-endocrine, autonomic and vestibular functions, feeding, drinking, sexual behaviour and analgesia (pain).” 5 This means that when we sleep or wake up, move, think, feel pain, eat, make love, etc. histamine is active passing its messages, which will vary depending on the organ’s or tissue’s function. Plot/Allergies•i-xii•1-317 11/21/03 12:38 PM Page 21 Immune Mechanisms Another theoretical work that covers the multiple areas of histamine activity emphasizes that “histamine proved to be important for the immune homeostasis.”6 Since balanced immunity signifies health, this knowledge from the basic sciences confirms that not only the allergy-related functions of the immune system depend on histamine, but also its general functioning. It logically follows, that an imbalanced production of histamine must inevitably affect the above-named functions, and such symptoms as insomnia, or excessive fatigue, joint and muscle pains, poor vascular tone, low libido, and even general weakening of the immunity are a possibility. Basic science teaches that histamine not only participates in numerous functions, but regulates many of them. If we develop this idea further, it logically follows that by blocking its activity with medications such as the antihistamines or the highly popular antacids (which are antihistamines for gastrointestinal disorders), we inevitably disrupt all the above-listed functions. Did you know that? I bet you didn’t even though you may have consumed some of these drugs and possibly also experienced their side effects. Your doctor may not know about the regulatory properties of histamine because he or she was not taught about the scope of histamine activity, but was taught simply to prescribe antihistamines and antacids. Doctors generally know histamine only as an “evil” mediator of allergy, which, being spilled from mast cells, initiates and conducts pro-disease messages among the cells participating in allergic reactions. They also know that histamine excess leads to excessive secretion of gastric acid. Therefore, for doctors who are taught this limited view, histamine suppression seems the right thing to do. HISTAMINE IS AN AUTACOID The word autacoid comes from the Greek autos—self and akos—remedy or medicine. There are several autacoids, such as adrenalin, a powerful hormone that increases blood pressure, accelerates the heart rate, etc. Then there is serotonin, familiar to migraine and depression sufferers, since its imbalance leads to these conditions. Too much adrenalin can be fatal; at the same time, synthetic adrenalin saves lives in critical situations. Autacoids are substances of bifocal activity: too much can be harmful, as can be too little. Not all medical dictionaries list the word autacoid, but if you are lucky to find it, you will read that histamine is an autacoid as well. Strangely, in the same dictionaries, the entry for the word histamine will not mention its remedial properties. 21 Plot/Allergies•i-xii•1-317 11/21/03 2:19 PM Page 22 22 THE PLOT AGAINST ALLERGY PATIENTS In a few old textbooks this positive aspect of histamine is mentioned. Today, most textbooks emphasize only its disease-promoting activity in allergies, migraine headaches or production of gastric acidity istamine is a and the need to suppress this activity. This is so despite substance produced the fact that histamine is a substance of dual effect, by all of the body’s cells. as is, for instance, adrenalin also. It participates in Something is wrong: Why does standard medicine numerous functions and fight histamine’s excessive activity with drugs? Why regulates many. does it pretend that the only role for histamine is a Histamine transmits negative one when, in fact, it belongs to the family of numerous vital messages, autacoids? How can the substance contained in all cells without which our body of healthy (!) people be considered so hazardous to the would not be able to body? What is wrong with Mother Natures’ design? function. It is crucial for the proper work of the HISTAMINE HOMEOSTASIS immune and nervous Allergy and related diseases are conditions caused by systems that regulate the the initiation of inappropriate histamine release and functioning of the rest of activity. This does not make histamine a harmful the body. Despite this chemical, since it is an inherent part of life and organ fact, medical textbooks functioning. It is the imbalanced release and unconmostly avoid mentioning trolled activity of this substance that become harmful. histamine, and when they The overspill means that the switches that control do present it, they dwell histamine release are inefficient. solely on its allergyThe existence of such switches is evident from the contributing properties. way a healthy body extinguishes an acute allergic reacThis justifies the use of tion. Here is an example of how it happens. Exposure to numerous medications an allergenic food or a strong smell may occasionally that block its activity provokes mast cells’ degranulation in a healthy host. which results in the The tissues full of these cells are the first to respond disruption of numerous with symptoms—hives, itchy eyes, a congested nose, vital functions. etc. This signals that the impact was too strong even for H the healthy self-regulatory switches, and they were unable to turn off the histamine leakage. However, the disruption of their otherwise normal functioning is brief, the body’s chemistry shifts to a diseasecontributing mode only for a short period. If the patient does not want to put up with these temporary symptoms, he may take an antihistamine. At some point, the receptors regain their ability to turn off the flood, and the Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 23 Immune Mechanisms symptoms stop. The body was able to reverse the disease on its own. Things are different in a hypersensitive patient. There is no effective turn-off, therefore the reaction lingers and may progress due to a shift towards pro-disease chemistry. Something is permanently wrong with the protective regulatory mechanisms in the immune system, and this defect maintains the symptoms. Now the patient may be forced to turn to a never-ending, pill-swallowing regime. It is clear that in allergy patients, histamine turnoff receptors need help to be able to establish homeostatic production. Only the restoration of receptor functioning may end allergy symptoms and save the patient from daily medications. Despite the fact that receptor repair would be of much more benefit, allergy medicine recognizes only the blocking approach: it either inhibits the functioning of the healthy receptors, or suppresses the activity of the cells totally. In either case, the effect is temporary, since it does not correct the prime defect. 23 istamine is a substance of dual activity. It does cause allergy as well as some other disorders, but only when it is released excessively. More important is the fact that histamine is responsible for messages of health among the cells. By originally including histamine into the group of autacoids, science recognized its healing properties. By excluding it now, the medical profession has distorted scientific fact. Silence about the vital role of histamine for the functioning of the whole body and its curative ability is of special concern in clinical immunology and allergy where histamine is of overwhelming importance. H HISTAMINE RECEPTORS Histamine-synthesizing cells have not one but several kinds of histamine receptors that regulate its synthesis and release. They are marked by the letter H that stands for histamine and numbers that denote their type. We will speak mostly about three kinds of histamine receptors and just mention the forth, although science has identified more. All four receptors—H1, H2, H3, H4— are important in passing numerous histamine messages. Since H receptors operate with the substance that participates and regulates numerous immune and neurological functions, these functions depend on the efficiency of these receptors. In allergy, H1 receptors are turn-on switches for histamine synthesis and release. H2 and H3 receptors are off switches. Only when H2/3 receptors are deficient, the normal H1 receptors become disease-promoting tools because they contribute to the histamine Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 24 24 THE PLOT AGAINST ALLERGY PATIENTS release. In the areas other than allergies, the application of these receptors is different and is not discussed in this book. H4 receptor generates and activates immunocompetent cells in allergy and other diseases. The H1 receptor type was discovered over half a century ago. The role of these receptors in the excessive production of histamine has been studied thoroughly and described in all textbooks. H2 receptors were discovered by James Black, a Nobel Prize winner. These receptors are fairly well described by basic science, but practicing physicians are only taught their role in excessive gastric acid production, while their central immunoregulatory role in allergies, asthma and other immune-related diseases is almost always excluded from the program. H3 receptors were discovered on nerve cells in 1983 by the French neurophysiologist J. Arrang and a team of European scientists. Later on, these receptors were identified on other cells, including immunocompentent cells. I doubt that the neuro- and immunoregulatory role of these receptors is known to most practicing physicians. The H4 receptor was first described by D. G. Raible and his colleagues in 1994. This receptor plays a major role in bone marrow activity. The H4 receptor is vital for the production of immunocompetent cells and hence, the functioning of the immune system. Standard medical textbooks generally do not contain any information on this receptor. A Canadian research team working in the Winnipeg cancer institute discovered another class, namely the intracellular receptor H1C that delivers histamine messages to the heart of each cell’s genetic material.7 From a paper sent to me by a renowned American immunologist, I learned about the existence of yet another type, Hx receptor. With time, still more histamine receptors may be identified. The existence of multiple histamine receptors, each of which mediates different cellular functions, indicates the ike any substance, histamine overproduction is controlled in a healthy body by certain turn-off receptors. If these receptors are inefficient, the exaggerated histamine release leads to the prevalence of histamine-induced disease-promoting chemistry, and hence, allergy symptoms characteristic for the tissues and organs in which the flood occurs. The two options an allergy patient has are: a) medications that either inactivate the work of the healthy turn-on receptors or suppress all the activity of the cellular lab; b) repair of the inefficient turn-off receptors in order to enable them to control the leakage. Conventional allergy medicine prefers the blocking approach with its temporary effect. L Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 25 Immune Mechanisms importance of the substance whose messages they conduct. All immunocompetent and nerve cells, those of the vascular walls and the endocrine glands, indeed, the cells of all regulatory systems, synthesize histamine, and thus they have histamine receptors. The distribution and functional activity of all H receptors are the central factor that determines the release of histamine by different cells. This release affects the work of numerous organs and systems, and when impaired, manifests in various physiological and clinical effects. 25 istamine production and activity are regulated by stimulatory and inhibitory receptors marked with the letter H. By now, several kinds of H receptors have been discovered and their mode of action established as different in different organs. The fact is that clinical textbooks tend only to contain information that leads to the production of medications that block stimulatory H1 H H1-SWITCH VS. H2/3 SWITCH All H receptors are meant to respond primarily to histamine. In allergy, H1-receptors are responsible for the symptoms. They are activated by the histamine present in the extracellular space and signal the cellular lab to generate histamine. The body moder- receptors; they do not ates histamine release through H2/3 receptors. Their contain information on messages are opposite to the H1-receptor messages. the healthy regulatory When the messages of H1 receptors are counterbal- effects on the nervous anced by the messages of H2/3 receptors, histamine is and immune systems produced in the amount needed for the normal func- through the role of the tioning of the tissues, such as cellular growth, wound H2/3 receptors. healing, muscular and vascular tone, pain reduction, proper hormone production, etc. If H2 and H3 receptors are inefficient, as it is in allergy, histamine liberation becomes excessive. This results in the prevalence of disease-promoting chemistry, and the areas especially rich in mast cells—the lungs, skin, gut and brain—respond with symptoms specific to them. Histamine overactivity involves all cells possessing histamine receptors. The more histamine receptors the cell has, the greater its involvement. Histamine surplus has a negative effect on neighboring cells, and they start to generate disease-oriented chemistry. This amplifies the pathological process, and creates a situation where the strong H1-receptor messages prevail, and thereby maintain allergy symptoms. The inactivity of H2/3 receptors turns normal H1 receptors into the target for the main allergy medications, antihistamines. Substances that inactivate Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 26 26 THE PLOT AGAINST ALLERGY PATIENTS receptor response are called antagonists, and antihistamines are H1-receptor antagonists. Antihistamines immobilize H1 receptors for the period they circulate in the body; that is, until excreted, and then, another dose of the drug is needed to keep H1 receptors under control. A negative side of antihistamines is that, while they circulate in the bloodstream, all the health-promoting histamine messages are inhibited: wound healing slows down, vascular tone weakens, the brain loses its clarity, etc. Two questions arise: 1. Why are H2/3 receptors weak and unable to provide the balanced release of histamine? 2. Is it possible to boost the efficiency of these receptors? I will try to answer both. istamine release is induced through H1 TWO WAYS TO CONTROL ALLERGY receptors, while H2 and Nature programmed the body, and especially the H3 receptors inhibit its immune system, to function in such a way that any negarelease. Thus, in allergy, tive effect could be easily counteracted. In relation to H1 are on-switches, and histamine balance, this is so unless there is an inherited H2/3 are off-switches. or acquired error in the genes responsible for the formaAllergy symptoms occur tion and/or activity of H2/3 receptors. Due to an error, when the off-switches these receptors may be underdeveloped, inefficient are unable to turn off and/or scarce. If the error is minor, histamine release will the histamine release, be slightly in excess, and the bearers of the deficient and the leakage receptors may experience negligible symptoms. At some continues unabated. point, a seemingly irrelevant event or simply a time factor may reinforce the genetic defect and make it obvious through a full-blown allergic condition. Medicine knows that the blocking effect of H1-antihistamines is, at best short-lived and that they are required on a regular basis. Medicine also knows that suppression of any cellular functioning for extended periods of time is highly undesirable because of the potential health hazards. Logic tells us that the only effective and safe way to control histamine release is to activate the H2/3 receptors, and enable them to perform their natural function. Moreover, basic science provides us with the additional knowledge that the H1 receptor, proclaimed as “bad” in allergy, is not solely allergy-oriented, but is also protective: it assists the H2 receptor in its protective activity. This confirms the opinion of a number of research teams who found that H1-antihistamines, designed to block the receptor’s activity, “might not be ideal therapeutic strategy” since they also inhibit normal histamine metabolism.8 H Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 27 Immune Mechanisms Can we correct the receptor functioning with the presence of the faulty genes that govern it? Can we do this without invasive genetic interference? Yes, we can. Let us see how it can be done. 27 hen the off receptors, H2 and H3, are W genetically defective and/or scarce, there is little or no opposition to the normal H1 receptors, and histamine release turns into a flood. Histamine excess causes the production of prodisease chemistry by the participating cells. The tissues full of histamine-induced chemistry respond with corresponding allergy symptoms. The two ways to treat patients are: 1) temporarily control histamine release by blocking H1 receptors and provide symptomatic relief; 2) activate H2 and H3 receptors and fix the problem. Continual blocking disrupts normal functioning of the tissues with H1-receptor-bearing CELLULAR AND SYNTHETIC HISTAMINE Exercise develops muscles, and similarly, activation strengthens receptors. The scientific term for substance that activates receptors is agonist. In nature, strengthening of the inefficient H2/3 receptors occurs through histamine. Its synthetic version has been available for almost a century. Can it be used for activation? Yes, it can. In this connection, questions arise: ■ If extracellular histamine keeps H1 receptors active all the time, why can’t it activate H2/3 receptors? ■ If synthetic histamine can activate the inefficient H2/3 receptors, what is the difference between synthetic histamine and our body’s histamine? Let us start by looking at the difference between histamine found in our cells and the one in the commercially available form. To establish the potency of a drug, one measures its level in the blood and tissues. All substances in the body start to break down and are metabolized after a certain amount of time. The time it takes for half of the drug to be metabolized is known as its half-life. So, the half-life of an antihistamine determines how many hours apart a tablet should be taken. The difference between the half-life of natural histamine in our cells and its drug version is cells, and this makes the most important distinguishing fact between them. Unfortunately, medical textbooks almost never activation of the weak explain the difference between the two. In fact, although receptor more logical. both are called histamine, they are far from being identical in terms of their action in the body. Intracellular histamine is stored in the granules of mast cells and basophils for about three weeks. Being released into extracellular space, it disintegrates within few minutes. In a healthy body, histamine release is smooth, and its much-needed messages spread all over the Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 28 28 THE PLOT AGAINST ALLERGY PATIENTS body. In a sick person, it leaks excessively, which leads to an allergic reaction. Although the spilled histamine is metabolized within minutes, the constantly cracking granules of mast cells and basophils maintain its high levels in the tissues. Moreover, this exaggerated leakage provokes the manufacture, or synthesis, of additional histamine, particularly by other immunocompetent cells, T-cells which begin to make ynthetic histamine more and more of it as well. This increases the amount differs fundamentally of histamine in the extracellular space and thereby from the cellular chemcauses a whole cascade of illness-contributing chemical. It has a short halfistry. This is like gasoline being poured over a smollife, its concentration is dering fire—it “inflames” the affected tissues. Indeed, very low, and it is indethe term that describes the process is inflammation. pendent of the diseaseSuch inflammation has nothing to do with an infection; promoting chemistry. it is a tissue reaction to the cascade of pro-disease Injected histamine chemicals. cannot produce and Synthetic histamine differs from its natural cellular maintain the state of chemical counterpart in several aspects. First, mandisease the way cellular made histamine is usually employed in a diluted form histamine can. and can, therefore, be much less concentrated than the natural substance. Second, injected histamine is an “uncombined” isolated substance, which means it is a foreigner in the chemical soup simmering in the tissues. It is like a new log thrown into a fire, and time is required for it to start burning. But, actually, there is no time for that: although the half-life of both cellular and synthetic histamine is only a few minutes the injected drug breaks down completely, whereas the immensely exaggerated liberation of cellular histamine goes on due to the continuous degranulation. Just compare the impact of a few minutes of man-made lowdose histamine with the incessant oozing of histamine from mast cells/basophils. These qualitative and quantitative aspects explain why the synthetic chemical cannot lead to a disease the way the body’s histamine can. S H1- AND H2/3 -RECEPTOR RESPONSE TO CELLULAR AND SYNTHETIC HISTAMINE Synthetic histamine cannot lead to disease, but can it lead to recovery? Yes. Receptors respond differently to cellular and injected histamine. Theoretically, both kinds should activate all histamine receptors—H1, H2 and H3, but this is not the case. When H2/3 receptors are deficient, the pro-inflammatory chemistry Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 29 Immune Mechanisms is too overwhelming for them. However, they discern the isolated mild signal of the injected histamine amid the frenzy of the pro-disease signals and respond to it by getting more active. A signal enables them to turn off the H1-tap. We may compare the weak H2/3 receptors with a child who passes by a huge rock that looks like a mountain for him, but picks up a small stone. The healthy H1 receptors “feel comfortable” within the milieu full of histamine and histaminetriggered pro-inflammatory mediators; a small dose of the injected histamine will not be strong enough to incite them to adverse activity. This is why we achieve the H2/3 effect by injecting small doses of histamine. To see how both kinds of histamine work, let us take asthma as an example. The lung tissue, if spread out, would occupy an area the size of a tennis court. The lungs have the largest number of mast cells and basophils, the main producers of histamine. Add to this the disease-promoting chemistry induced by the initial spill. Now, compare this “ocean” with a small amount of histamine in a syringe. Not only the small dose of diluted synthetic histamine is too mild to activate H1 receptors, but its half-life is only a few minutes—time not sufficient to unleash, not to say sustain, a disease process. However, the time and the dose are enough to activate H2/3 receptors and hence, lead to the production of pro-health chemistry by all participating cells. The protective H2/3 effect opposes the H1 effect exactly in the way a healthy body does. Even though medicine operates mostly by measuring and crunching numbers to establish what is less than normal, and what is beyond the range of the normal, qualitative effects may be more important in regulatory diseases than mere measured quantities. In allergy, it is not so much the amount of the opposing chemistry that reverses the disease process, but the regulatory potency of the newly introduced mediators. For an asthma patient, it means relief of the symptoms. The degree of the improvement varies and depends on the functional resilience of these receptors and the degree of their original deficiency. The exact concentrations of histamine which activate only H2 receptors and control H1-receptor activation (from 10–9 M to l0–4M) have been scientifically established.9 The H2/3 receptors react synergistically, which means they are more effective when working together, and the H3 receptors are sensitive to even lower doses of synthetic histamine. Within a few minutes, the injected histamine starts breaking down and leaves behind only its stimulatory effect. Like a pendulum that swings for some time after it is released, the weak receptors temporarily continue their natural function of turning off histamine leakage. The length and degree of their activation 29 Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 30 30 THE PLOT AGAINST ALLERGY PATIENTS ontinuous and excessive histamine spillage from the cells that have inefficient H2/3 receptors (“off C switches”) produces mostly unopposed H1 effect, and this maintains histamine leakage and the disease state. Synthetic histamine, with its short half-life, much lower concentrations and independence of the pro-disease chemistry, produces only a mild signal, which leaves H1 receptors cannot be determined by any test; they become clearly evident through observation of the patient during the course of treatment. The judgment is clinical, which means it is based on observed and reported improvement. Through careful observation, a doctor quickly gains experience on how to gauge the dose that would provide further stimuli to keep the H2/3 receptors active. Since histamine injections involve all the H2/3receptor-bearing cells, the tissues containing these cells improve their functioning. The change of the symptoms after each injection is the indicator what organs are involved in the disease. Similar to an exercise program, repeated histamine injections strengthen the receptors and enable them to oppose the negative H1receptor effect. THE BIAS AGAINST HISTAMINE RECEPTORS IN ALLERGY MEDICINE unresponsive, but stimuBias in the description of the H1 and H2/3 receptors in lates the weak receptors allergy and related diseases is obvious: while H1 receptor is described in detail, the role of H2 and H3 which are sensitive to receptors in allergy is virtually absent from medical H2 and H3 receptors. Activation of H2/3 recepsources of the ’90s. Most of the commercially available tors counterbalances or allergy medications are designed to block the activity of reduces the diseasethe H1 receptors. All antihistamines are such medicapromoting H1-receptor tions. Description of the H2 receptors is also drugeffect. Repeated stimuoriented and limited to their role in blocking excessive lation strengthens H2/3 gastric secretions, which promote the use of the H2receptors and enables receptor blockers. Yet, the knowledge exists that H2them to balance the receptor activation may enable the immune system to cellular production. control allergy without medications. Similarly, the selfinhibiting features of histamine could also help in certain gastrointestinal disorders, and this will be discussed later in the book. But making this scientific data widely known would go against the interests of the drug industry. It is no secret that the medical elite is closely connected with drug developers and depends on them for most of their research funding.10 This explains why the curative H2-receptor effect in allergy is not common Plot/Allergies•i-xii•1-317 11/21/03 12:39 PM Page 31 Immune Mechanisms knowledge. The H3-receptor effect is also kept in the theoretical domain even though both animal testing and trials on humans are very promising. HISTAMINE: THEORY AND PRACTICE Histamine was first synthesized by two German chemists, A. Windhause and W. Vogt in 1907, and its physiological activity was discovered by Sir Henry Dale and P. Laidlaw in 1910. Shortly afterhe histaminewards it was empirically used as a drug for asthma inhibiting ability of and allergies. Over all these years, histamine has fascinated physicians as a naturally occurring chem- the H2/3 receptors is ical and as a medication. During Sir Henry Dale’s obscured in the allergy time, a Histamine Club was formed to unite those literature and virtually scientists and doctors who studied and/or used never applied in prachistamine. In the ’60s, with the establishment of tice, primarily because allergy as a medical branch, interest was channeled in of the financial interests involved in the widethree directions: spread sales of numerous a) allergists were busy with presenting histamine in its medications designed negative light only, developing antihistamines to only to block histamine suppress it and advertising their drugs; activity. b) researchers, using animal and