The role of shock organs in influencing the clinical expression of allergy
Authors: S. Bonini, J.A. Denburg
Journal: Allergy (1999)

The original description by Coombs & Cell of a specific immune (IgE) mechanism underlying symptoms induced by allergens in different target organs has long guided our understanding of the pathophysiology of allergic diseases such as asthma, rhinitis, conjunctivitis, urticariaangioedema, and atopic eczema (1). More recently, studies of allergen challenge to the lung, nose, eye, and skin have shown that the typical immediate reaction (early phase) is usually followed by a late inflammatory reaction phase causing ongoing symptoms. This has led to the current view of a complex inflammatory network common to various allergic diseases (2), the final clinical picture depending on the site where allergens interact with immune cells. However, data from one organ are often extrapolated to all organs, and thus potential differences among organs in influencing the clinical expression of allergy are neglected. It is not easy to obtain an overview of similarities and Differences in the hypersensitivity mechanisms underlying the various types of allergic diseases because most studies initiated by organ - oriented specialists (respirologists, otorhinolaryngologists, ophthalmologists, and dermatologists) are focused on one organ, often not providing information on what happens in other tissues. However, allergists should see this as a major issue, and they should cultivate a more unified approach to the allergic patient. Since the disease in a given subject is not necessarily the sum of his/her various organs, patient - oriented medical advice is preferable to a jumble of specialists' reports. Accordingly, both experimental and clinical studies of allergy should devote more attention to the allergic patient than to allergic “disease”. Epidemiologic data (3) demonstrate that some allergic patients are affected by either asthma, rhinitis, conjunctivitis, or skin allergy, whereas others experience various combinations of these allergic manifestations. Clinical observations have shown that some patients progress from one allergic disease to another (4). However, this progression cannot be explained solely by a preferential age of prevalence for a given disease or the increasing severity of the allergic process. In fact, the order of appearance of allergic diseases is not constant in different subjects: sometimes two or more manifestations occur together. It has long been known that “atopy” is based on genetic predisposition: susceptibility genes of allergy have been identified and can be considered risk factors for different phenotypes of clinical allergy involving various organs (5). However, several allergic diseases, such as asthma, show a familial aggregation which is independent of or additional to familial aggregation of atopy. Consequently, .separate genes controlling the susceptibility of various tissue sites of clinical allergy have been suggested, although they have been less studied than allergy genes. Environmental factors can also influence the clinical expression of allergy in a given organ, but not in others. For instance, while the role of pollutants in inducing clinical asthma has been recognized (6), their influence on hypersensitivity phenomena is still controversial. Moreover, respiratory viral infections can induce exacerbations (7) and possibly the de novo appearance of asthma; in childhood, early systemic viral and bacterial infections have been thought to protect from allergy by influencing the Th1/Th2 balance (6, 9). Undoubtedly, the bronchi, the nose, and the eye have specific anatomic and functional features that may account for a given allergic response or for preferential pathophysiologic inflammatory pathways. It is also evident that the type of allergen responsible for sensitization, as well as the route of exposure, can influence the localization of allergic reactions. In fact, sensitization to seasonal airborne allergens — such as grass and tree allergens — is more frequently associated with rhinitis, while sensitization to perennial allergens — such as Parietaria or mite allergens — is more frequently associated with asthma. Ingested allergens are more frequently associated with skin allergy. Whether or not and to what extent specific sensitization of other target tissues has occurred in subjects with a single clinical allergic disease has not yet been extensively studied. For example, some studies have shown that the conjunctiva is far less sensitive than the skin. It can also be assumed that the nasal mucosa is more exposed and sensitive to airborne allergens than the bronchial mucosa, thus explaining the higher prevalence of allergic rhinitis than allergic asthma. However, some patients have only asthma or conjunctivitis, and the progression of allergic diseases cannot be explained solely on the basis of a different degree of specific sensitivity of target organs. Certainly, subjects with a single allergic manifestation can react when challenged in “noninvolved” organs, provided that adequate doses of allergen are used, as shown by the diagnostic value of skin tests or of conjunctival provocation in respiratory allergy, or by a positive bronchial response to allergen challenge in subjects with allergic rhinitis, or by the increase in bronchial responsiveness after nasal allergen challenge (10). Also unknown is whether or not there is a nonspecific hyperactivity of a given tissue; this may represent the cofactor required to trigger, in a specific site, the clinical expression of allergy. To put it another way, it is not clear whether allergic disease is a local or a systemic disease, regardless of the prevailing clinical expression. Studies of in vivo models of allergic rhinitis and asthma representing human allergic airways diseases have shown that inflammatory cell progenitors are increased in the blood during natural allergen exposure (11, 12) or after allergen provocation (10, 14). This can be reversed by topical steroids administered via the airways (14). The effect of steroids may not be as potent in patients with allergic rhinitis given inhaled (to the lung) steroids (13). These observations support the hypothesis that bone - marrow progenitors respond to tissue - specific inflammatory changes, including cytokine production (15, 16). In the dog, serum hemopoietic activity is released, probably from the lung, only in animals that develop airway hyperactivity after allergen challenge, but not in nonresponder animals (17). In this and recent studies on human bone - marrow responses following allergen challenge, the concept that local allergen provocation can set in motion systemic events, including changes in cytokine responsiveness, has been put forward. An interesting model for studying the relationships between local and systemic aspects of allergy is represented by transplantation of bone marrow or organ transplantation. In 9/12 nona topic patients receiving bone marrow from atopic donors, there was a change in skin test responses to standard allergens and/or airway hyperresponsiveness (18). Further studies are needed to determine whether the bone marrow and the lung are both necessary and sufficient for the development of atopic asthma. An additional issue regarding the relationships between local and systemic aspects of allergy is represented by the selective homing of effector cells to target tissues. For lymphocytes, it has been recently suggested that sitedirected migration is determined by the functional phenotype, independently of the site of induction (19). A preferential expression of adhesion molecules and of receptors for chemoattractants — such as chemokines — in some tissues, but not in others, as well as the presence of "protective factors" for some tissues, leads to a hypothesis that can now be testedi such studies could begin to explain whether and how eosinophils and basophils produced by the bone marrow after natural or allergen - challenge exposure of an organ, and activated by locally released cytokines, migrate from the blood to that organ, and not to other tissues. Apart from the above pathophysiologic speculations, the role of target organs in influencing the clinical expression of allergy also has some interesting practical implications. For instance, at the diagnostic level, allergy tests — such as lgE or eosinophil cationic protein measurement — can provide information on the type and degree of sensitization and of the severity of eosinophilic activation, but do not give information on the clinical picture at the target organ level. Specific and nonspecific provocation tests should therefore be accompanied by a wide range of laboratory tests investigating the susceptibility of individual organs to manifest clinical allergy. With reference to treatment, the demonstration of a preferential pathophysiologic allergic pathway in different organs might suggest more selective therapeutic approaches depending on the target organ involved. Are antihistamines effective on skin, nose, and eye manifestations but less so on the bronchial, even in seasonal episodic juvenile asthma? Are antileukotrienes indicated only in asthma? Do topical steroids — which are indicated in asthma and rhinitis, but which may have severe side - effects in conjunctivitis — have an effect only on the site of administration, or do they have additional indirect effects? This series of reviews does not aim to describe the features of allergic asthma, allergic rhinitis, allergic conjunctivitis, and allergic skin diseases, but rather to address some of the complex issues mentioned above. Indeed, an understanding of these controversial aspects may lead to a more specific diagnostic and therapeutic approach to the single allergic disease, as well as to a better understanding and management of the heterogeneity of allergy in individual allergic patients.