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Allergy - Mechanisms Section A Allergy - MECHANISMS * What is allergy * B cells * The discovery of IgE * Immunoglobulin E and other antibodies in allergy * Allergens: structure and function; mechanisms of * Role of superantigens in allergic diseases allergenicity; allergens and cross-reactivity; house dust * Cytokines in allergy mite allergens; pet allergens; tree pollen allergens; grass * Cell migration and chemokines pollen allergens; weed pollen allergens; food allergens; * Complement-mediated regulation of the allergic response venom allergens; emerging allergens; pollen allergens and * Lipid mediators of hypersensitivity and inflammation geographical factors * Lipid mediators in resolution of allergic inflammation * The underlying mechanisms in allergy * Allergy and the epithelial barriers * Innate immune response in allergy * Epithelial proteases and allergic diseases * Dendritic cells * Mechanisms of immune regulation in allergy * Natural killer cells and natural killer-T cells * Neuro-immune regulation of allergic inflammation * Innate lymphoid cells * United airways and immune regulation * Mast cells * Genetics of allergy * Basophils * Epigenetics of allergy * Eosinophils * Endotypes of allergic diseases * T cells * Animal models of allergic disease GLOBAL ATLAS OF ALLERGY 1 WHAT IS ALLERGY Johannes Ring Technische Universität München München, Germany The term “Allergy” was born on July 24, 1906 in the Münchener KEY MESSAGES Medizinische Wochenschrift as “specifically altered reactivity of • The term “Allergy” was first coined on July 24, 1906 as the organism”. Today, we define al- “specifically altered reactivity of the organism lergy as immunological hypersen- • Today, we define allergy as an immunologically-mediated and sitivity that can lead to a variety allergen-specific hypersensitivity of different diseases via different • Allergies can be seen in almost every organ, most commonly in pathomechanisms and thus differ- the skin and the mucous membranes ent approaches in diagnosis, ther- • Allergology is the science regarding allergic diseases and their apy and prevention can be taken. differential diagnoses and mechanisms (Table 1). Several misconceptions can be delineated (Table 2). Allergology is the science regard- - Allergy from genetics to mechanisms ing allergic diseases and their A differential diagnoses and mech- anisms. It requires clinical experi- ence in allergic diseases, basic un- ECTION S derstanding of the immune system in physiology and pathology and finally extensive knowledge of en- vironmental factors in eliciting or modulating allergic reactions. Allergy is not a disease itself, but a mechanism leading to disease. In clinical practice, allergy mani- fests in form of various different conditions such as anaphylaxis, urticaria, angioedema, allergic rhi- noconjunctivitis, allergic asthma, serum sickness, allergic vasculitis, Figure 1 The word “allergy” first appeared on July 24, 1906 in the Münchener Medizinische Wochenschrift in an essay written by Clemens von Pirquet, a hypersensitivity pneumonitis, at- pediatrician from Vienna. (Reproduced with permission from Ring J: Allergy in opic dermatitis (eczema), contact Practice. Springer Berlin, Heidelberg, New York, 2005.) dermatitis and granulomatous 2 What is allergy GLOBAL ATLAS OF ALLERGY TABLE 1 Definitions of terms frequently used in allergy TABLE 2 Sensitivity Normal response to a stimulus The most common misconceptions of allergy Hypersensitivity Abnormally strong response to a stimulus Sensitation Development of increased sensitivity after repeated • natural reaction contact • a symptom or sign (e.g. rhinitis) Allergy Immunologically mediated hypersensitivity leading to • incompatibility of toxic/irritant disease substances (e.g. tobacco smoke) Anaphylaxis severe, life-threatening, generalized or systemic • psychological aversion hypersensitivity reaction • incurable Enviroment-induced disease Toxicity Hypersensitivity S ECTION of a substance of the individuum A - Allergy from genetics to mechanisms non- immune immune mediated Irritation, Psycho- Intoxication, Idio- Intolerance neurogenic Allergy chronic syncrasy reaction damage Figure 2 Classification of environmentally related health these disorders. Reproduced( with permission from Ring J: Allergy in Practice. Springer Berlin, Heidelberg, New York, 2005.) reactions, as well as the colorful patients may out grow their al- allergy for global use: Report of the spectrum of food- or drug – in- lergic disease spontaneously. We nomenclature committee of the duced hypersensitivity reactions. should study these patients in- World Allergy Organization. J Al- 2004; 113: 832- Allergies can be seen in almost tensively, who spontaneously lose lergy Clin Immunol 836. every organ. Most commonly, their allergy. Many allergic diseas- 3. Ring J. Allergy in Practice. Berlin: however, it is the skin and the mu- es have a chronic course, but there Springer, 2005. cous membranes that are involved are ways to cure. Allergic diseases 4. Adkinson NF, Bochner BS, Burks can be influenced by psychological since they represent the frontier AW, Busse WW, Holgate ST, Le- between the individual organism processes in a positive or in a neg- manske LF, O’Hehir RE. Middleton’s and its environment. ative way. Allergy Principles and Practice. 8th edition. Philadelphia: Elsevier Allergy often starts in the first KEY REFERENCES 2014. three months of life but very 1. Bergmann KC, Ring J. History of Al- 5. Ring J, Akdis C, Behrendt H, Lauen- rarely at birth, although there is a lergy. Basel:Karger, 2014 – in press. er RP, Schäppi G, Akdis M et al. strong genetic background. Aller- 2. Johansson SGO, Bieber C, Dahl R, Davos declaration: allergy as a glob- gy in some cases does not persist Friedmann PS, Lanier BQ, Lockey al problem. Allergy 2012;67:141- over life-time; it starts and some RF et al. Revised nomenclature for 143. What is allergy 3 GLOBAL ATLAS OF ALLERGY 2 THE discovery OF IgE S.G.O. Johansson Karolinska Institute Stockholm, Sweden Allergic asthma and rhinitis were already recognized in the 19th KEY MESSAGES century, but the mechanisms be- hind the diseases were not under- • In 1921, Prausnitz and Küstner demonstrated passive stood. In 1919 Ramirez noticed sensitization of the skin, since then referred to as the PK-test that blood transfusion could trans- • In the 1960’s K. and T. Ishizaka published several articles fer allergic asthma and passively describing an antiserum that could block the PK-test indicating sensitize the recipient. In 1921, that it reacted with regain Prausnitz and Küstner demon- • In 1965 S.G.O. Johansson in Uppsala detected in the serum of a strated passive sensitization of myeloma patient an M-component that could not be identified as the skin, since then referred to as any of the 4 known immunoglobulin classes the PK-test. • The discovery of IgE and the understanding of the IgE-mediated inflammation, allergic asthma and rhino-conjunctivitis, food The search for reagin, the factor allergy and eczema has had a significant impact on diagnosis and in plasma causing the positive PK- treatment of allergy test, was unsuccessful for about - Allergy from genetics to mechanisms A 45 years and some rather confus- ing proposals were published, e.g. identifying reagin as IgA. In the ECTION 1960’s K. and T. Ishizaka published S several articles describing an an- tiserum that could block the PK- test indicating that it reacted with reagin. They referred to this anti- serum as anti-γE. Not surprisingly considering the very low serum concentration of IgE, they did not succeed in isolating their γE. In 1965 S.G.O. Johansson in Uppsala detected in the serum of a myeloma patient an M-component that could not be identified as any of the 4 known immunoglobulin classes. Working with H. Bennich, the unique immunological and physicochemical characteristics 4 The discovery of IgE GLOBAL ATLAS OF ALLERGY S ECTION A - Allergy from genetics to mechanisms Figure 1 From left L. Wide, H. Bennich and S.G.O. Johansson presenting RAST in 1974. of the new immunoglobulin, pro- port on the fifth immunoglobulin KEY REFERENCES visionally labelled IgND after the class, IgE. 1. Ramirez MA. Horse asthma fol- initials of the patient, were docu- lowing blood transfusion. JAMA The discovery of IgE has had a mented and published. Very small 1919;73:984. significant impact on the diagno- amounts of IgND did, in dose-re- 2. Prausnitz C, Küstner H. “Studien sis and management of allergic sponse, block the PK-test and the über die Ueberempfindlichkeit”, disease, enabling clinicians to dif- active structure was located in the Zentralbl Bakteriol 1921;86:160– ferentiate between IgE-mediated 169. Fc-fragment. A sensitive radio-im- allergic diseases and other hyper- muno assay was developed for 3. Ishizaka K, Ishizaka T. Identifica- sensitivity reactions, and to man- IgND. Extremely low serum con- tion of γE-antibodies as a carri- age allergic diseases according er of reaginic activity. J Immunol centrations, in the order of a few to their underlying mechanisms. 1967;99:1187. nanograms per ml, were found in Tests became available that al- 4. Johansson SGO, Bennich H. Im- healthy individuals but, interest- lowed a more simple and reliable munological studies of an atypical ingly, 10-100 fold higher levels diagnosis covering a very broad (myeloma) immunoglobulin. Immu- were found in allergic individuals. spectrum of allergens. The char- nology 1967;13:381-394. Purified IgND was sent to the acterization and standardization 5. Stanworth DR, Humphrey JH, Ben- Ishizakas
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