Chemical immunology and allergy最新文献

There were remarkable achievements in the 19th century in our understanding of the cells of the allergic response, the clear descriptions of hay fever and asthma, as well as the role of pollen in seasonal rhinitis. Although allergy as a concept was not developed until well into the 20th century, the foundations of our present understanding of these diseases were laid in the 1800s. The outstanding physicians and scientists of this time included Paul Ehrlich (who described mast cells, eosinophils and basophils), John Bostock (who provided the first detailed account of hay fever), Charles Blackley (who showed that pollen was the cause of hay fever), Morrill Wyman (who demonstrated that autumnal catarrh was due to ragweed pollen), Henry Hide Salter (who made the first classic description of asthma) and Henri Laënnec (the inventor of the stethoscope).

From its very beginning, the 20th century represented the period of the main breakthrough for allergology as a clinical and scientific entity. The first years of this period were extraordinarily exciting because of the discovery of the anaphylactic reaction in 1902 and its clinical diagnosis as 'local anaphylaxis', 'serum sickness' (1903) or even as 'anaphylactic shock' (1907). The term 'allergy' was coined in 1906 and led to the recognition of allergic diseases as a pathogenetic entity. The first patient organization of hay fever sufferers was founded in Germany in 1900, the same year in which the very first report on immunotherapy was published in New York. In 1911 the era of actual immunotherapy started in London, becoming scientific with the first double-blind study in 1956, and still today being regarded as the backbone of allergology. In 1919 it was shown that allergy could be transferred by blood, in 1921 by serum (Prausnitz-Küstner test) and in 1966 the mystic 'reagins' were recognized as immunoglobulin (Ig) E. The development of the radioallergosorbent test for quantifying specific IgE antibody was a diagnostic landmark for allergists all over the world. The history of allergy diagnosis started with the introduction of a 'functional skin test', named the patch test in 1894. The scratch test was described in 1912 and the patch test in 1931. From 1908 the skin was tested by intracutaneous injections, and from 1930 by a 'puncture test' (a precursor of the prick test) which has been in worldwide use in modified variations since 1959. The rub test ('friction test') was added in 1961. Systematically applied provocation tests started with conjunctival provocation (1907), followed by nasal and bronchial provocation with allergens (1914 and 1925).

Allergic rhinitis is a very frequent disease with a prevalence of 15-20%. Symptoms are most pronounced in young people while, for some unknown reason, the elderly become clinically hyposensitized. Pollen is the cause of seasonal allergic rhinitis, and house dust mite and animals are the main causes of perennial allergic rhinitis. Histamine is the main cause of sneezing and hypersecretion, while other mediators probably also play a role in nasal blockage. In polyposis, a local denervation is an important cause of vascular leakage, edema and polyp formation. Antihistamines have a positive effect on sneezing and hypersecretion, but not on blockage. As they have a quick onset of action they are useful in patients with mild and occasional symptoms. A nasal steroid is preferable in patients with persistent symptoms, since it is more effective on all nasal symptoms. Short-term use of a systemic steroid can be a valuable adjunct to topical treatment, especially in nasal polyposis, when there is a temporary failure of topical treatment in a blocked nose. A nasal vasoconstrictor can be added for short-term treatment, and an ipratropium spray can be beneficial in perennial non-allergic rhinitis, when watery secretion is the dominant symptom. Immunotherapy can be added in allergic rhinitis, when pharmacotherapy is insufficient. This chapter is based on the author's personal experience with allergic rhinitis, as a patient, a doctor and a researcher. Therefore, it is not a balanced review and the references will be highly selected as they largely consist of the author's own publications. As the text is mainly based on personal research, steroids are described in detail, while, with regard to immunotherapy, the reader is referred to another chapter. In addition to allergic rhinitis, nasal polyposis will be described. It was formerly believed to be an allergic disease, but we now know that it is not. However, with regard to histopathology and drug responsiveness this disease is very similar to allergic rhinitis.

Historically, horse dandruff was a favorite allergen source material. Today, however, allergic symptoms due to airborne mammalian allergens are mostly a result of indoor exposure, be it at home, at work or even at school. The relevance of mammalian allergens in relation to the allergenic activity of house dust extract is briefly discussed in the historical context of two other proposed sources of house dust allergenic activity: mites and Maillard-type lysine-sugar conjugates. Mammalian proteins involved in allergic reactions to airborne dust are largely found in only 2 protein families: lipocalins and secretoglobins (Fel d 1-like proteins), with a relatively minor contribution of serum albumins, cystatins and latherins. Both the lipocalin and the secretoglobin family are very complex. In some instances this results in a blurred separation between important and less important allergenic family members. The past 50 years have provided us with much detailed information on the genomic organization and protein structure of many of these allergens. However, the complex family relations, combined with the wide range of post-translational enzymatic and non-enzymatic modifications, make a proper qualitative and quantitative description of the important mammalian indoor airborne allergens still a significant proteomic challenge.

In chronic inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), changes in bronchial microvasculature are present and contribute to airway wall remodeling. Angiogenesis and vascular leak seem to be prevalent in asthma, while vasodilatation and vascular leak seem to be prevalent in COPD. The functional meaning of bronchial vascular remodeling is not completely known. The increase in vessel number and size as well as the vascular leakage may concur to the thickening of the airway wall and to the narrowing of the bronchial lumen. Accordingly, pharmacological control of bronchial vascular remodeling may be crucial for symptom control in asthma and COPD. In asthmatic airways, steroids can downregulate vascular remodeling by acting on proangiogenic factors, whereas long-acting β2-agonists seem to be mostly effective in decreasing vascular permeability. In COPD, there is less available experimental evidence on the effect of the currently used drugs on airway microvascularity changes. Importantly, vascular endothelial growth factor, the most specific grow factor for vascular endothelium, is crucially involved in the pathophysiology of the airway vascular remodeling, both in asthma and COPD. The inhibition of vascular endothelial growth factor and its receptors has the potential for the treatment of the vascular changes in the airway wall.

Urticaria and angioedema are ancient diseases. Many different names have been used to describe them, and many different theories have been postulated to explain their origin and pathogenesis. The current classification and nomenclature of urticaria and angioedema have evolved over several millennia, with many detours and problems, some of which still remain to be solved. This chapter describes the history of urticaria and angioedema. The evolution of selected aspects of today's understanding of both conditions is also traced, based on the review of original sources and previously published research on this topic.

Hypersensitivity reactions to acetylsalicylic acid and non-steroidal anti-inflammatory drugs constitute a major medical concern worldwide. This article presents an overview of the observations that led to the discovery of cyclooxygenase inhibitors, as a prerequisite to better understand the basic concepts supporting seminal investigations carried out in order to elucidate the clinical features, pathogenic mechanisms, diagnosis and modern management of these common conditions. There are some unmet needs in this clinical area which will have to be solved in the future, especially concerning the pathogenesis of these reactions and the availability of novel in vitro diagnostic methods sparing both patient and physician of the risks inherent to in vivo provocation tests.

Diseases which have been demonstrated to be caused by increased plasma levels of bradykinin all have angioedema as the common major clinical manifestation. Angioedema due to therapy with angiotensin-converting enzyme (ACE) inhibitors is caused by suppressed bradykinin degradation so that it accumulates. This occurs because ACE metabolizes bradykinin by removal of Phe-Arg from the C-terminus, which inactivates it. By contrast, angioedema due to C1 inhibitor deficiency (either hereditary types I and II, or acquired) is caused by bradykinin overproduction. C1 inhibitor inhibits factor XIIa, kallikrein and activity associated with the prekallikrein-HK (high-molecular-weight kininogen) complex. In its absence, uncontrolled activation of the plasma bradykinin cascade is seen once there has been an initiating stimulus. C4 levels are low in all types of C1 inhibitor deficiency due to the instability of C1 (C1r, in particular) such that some activated C1 always circulates and depletes C4. In the hereditary disorder, formation of factor XIIf (factor XII fragment) during attacks of swelling causes C4 levels to drop toward zero, and C2 levels decline. A kinin-like molecule, once thought to be a cleavage product derived from C2 that contributes to the increased vascular permeability seen in hereditary angioedema (HAE), is now thought to be an artifact, i.e. no such molecule is demonstrable. The acquired C1 inhibitor deficiency is associated with clonal disorders of B cell hyperreactivity, including lymphoma and monoclonal gammopathy. Most cases have an IgG autoantibody to C1 inhibitor which inactivates it so that the presentation is strikingly similar to type I HAE. New therapies for types I and II HAE include C1 inhibitor replacement therapy, ecallantide, a kallikrein antagonist, and icatibant, a B2 receptor antagonist. A newly described type III HAE has normal C1 inhibitor, although it is thought to be mediated by bradykinin, as is an antihistamine-resistant subpopulation of patients with 'idiopathic' angioedema. The mechanism(s) for the formation of bradykinin in these disorders is unknown.

Immunoglobulin E (IgE) was discovered in 1967. Today, more than 40 years after the discovery, the normal beneficial function in the body of this enigmatic immunoglobulin still remains unclear. However, ever since the discovery new knowledge about allergic diseases and allergens, new treatments and new diagnostic tools have continued to emerge as a direct result of our ability to identify and measure IgE and IgE antibodies.