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I think have a functional understanding of how an allergic reaction (Type I Hyper Sensitivity) occurs: basically the allergen causes production of antibodies that attach to mast cells and basophils. Later, if the same allergen binds to those antibodies, the cells release histamine and other unpleasant chemicals.
However, it's clear that the degree of allergic reaction varies a lot from person to person. For example, if my wife goes outside all day during peek grass pollen season, she'll end up with a sinus reaction, and not much else. If I go outside for a few minutes, I'll develop that, and if I stay longer, I'll get hives, weepy eyes, and so on.
Clearly I'm more sensitive to grass than my wife, but what exactly causes this? I can imagine a lot of possible factors!
- Maybe I have many more antibodies (but why?)
- Maybe I absorb more of the allergen per unit time (but why?)
- Maybe my mast cells require less allergen to react (but why?)
- Maybe my mast cells contain more histamine per cell (but why?)
So I guess my question is: What drives the variation in allergic hyper sensitivity responses?
Network of possible factors that contribute to the variability of the immune reaction between individuals is still not well investigated.
Type I hypersensitivity is mediated by IgE antibodies, which means that lymphocytes B after initial contact with antigen undergo oligoclonal selection. Only these with the highest affinity towards the antigen will survive. During this process (see: germinal centre reaction) genomic regions responsible for antigen binding change their sequence in non-deterministic manner. So, each individual has slightly different set of antibodies targeting the same antigen.
Moreover, within the same antigen (allergen), different regions (epitopes) can trigger the immune reaction in different individuals.
Other, more general factors also contribute to the symptoms associated with hypersensitivity reaction. For example: hormones, infections, medications, microflora condition, genetics (eg. major histocompatibility complex) or even psychological status.
Also see: Article 1 Article 2 Article 3
Pathophysiology of Allergic and Nonallergic Rhinitis
Allergic and nonallergic rhinitis affect approximately 30% of the U.S. population. Although allergic rhinitis has a clear definition and its pathophysiology has been thoroughly investigated, nonallergic rhinitis remains poorly defined and understood. There is consensus, however, that nonallergic rhinitis consists of a variety of heterogeneous conditions. In allergic rhinitis, the process of allergen sensitization involves the participation of antigen-presenting cells, T lymphocytes, and B lymphocytes and depends on environmental allergen exposure. Sensitization results in the generation of allergen-specific IgE that circulates in the peripheral blood and attaches itself on the surface of all mast cells and basophils including those that home to the nasal mucosa. Subsequent nasal exposure to allergen activates these cells and, through the release of the classic mediators of the allergic reaction, produces acute nasal symptoms. Over a short period of time, these symptoms become indolent, whereas inflammatory and immune cell infiltrate, including eosinophils, basophils, neutrophils, T lymphocytes, and monocytes, characterizes the late stages of the allergic response. In parallel, and probably as a result of the development of mucosal inflammation, the nose becomes primed to allergen and reacts more vigorously to subsequent allergen exposure but also becomes hyperresponsive to irritants and to changes in atmospheric conditions. In nonallergic rhinitis, several conditions may have been identified that are of interest for further research and phenotyping. These include a group of patients with apparent hyperresponsiveness of the C-fiber sensory nerves with no inflammatory changes in the nasal mucosa and a group with mucosal eosinophilia who may have allergic sensitization to common aeroallergens that is, however, manifested only in the nasal mucosa.
Rhinitis is a term that describes the acute or chronic intermittent or persistent presence of one or more nasal symptoms including runny nose (nasal discharge), itching, sneezing, and stuffy nose due to nasal congestion. These symptoms can also reflect the nose's natural responses to daily exogenous or endogenous stimuli and may occasionally be experienced by everybody. In the clinical setting, the presence of rhinitis becomes evident by the fact that individuals having bothersome symptoms seek medical attention. In epidemiological research, however, there is some difficulty distinguishing people with rhinitis from normal individuals, and one recognizes that the boundaries between health and disease are blurred.
Although the term “rhinitis” implies inflammation of the nasal mucous membranes, some rhinitis disorders are not associated with inflammation. These include some forms of nonallergic, irritant-induced rhinitis as well as some forms of rhinitis of unknown etiology. For these conditions, the term “rhinopathy” may be more appropriate.
The classification of rhinitis can be based on etiology and/or the temporal pattern of symptoms. Unfortunately, there is no widely accepted, scientifically valid classification of rhinitis, mostly because of poor phenotyping of those forms that do not fall under the allergic and the infectious categories. A common classification is shown in Table 1.
TABLE 1. CLASSIFICATION OF RHINITIS
Chronic rhinosinusitis with or without polyps, two possibly distinct conditions that have not been included in this classification are hypertrophic inflammatory states affecting the paranasal sinuses and the nasal mucosa that can affect allergic or nonallergic individuals (1).
Traditionally, allergic rhinitis has been classified as seasonal or perennial based on temporal patterns of symptoms. The guidelines produced by the international working group ARIA (Allergic Rhinitis and its Impact on Asthma) have reclassified allergic rhinitis on the basis of the severity and duration of symptoms this helps in the classification of rhinitis when the temporal patterns are not clear or are not globally applicable, and allows harmonization with the classification of asthma. On the basis of ARIA, patients with rhinitis are placed into one of four categories: (1) mild intermittent, (2) mild persistent, (3) moderate/severe intermittent, and (4) moderate/severe persistent (2).
Nasal symptoms represent exaggerated defensive and homeostatic functions of the nasal mucosa. The nasal mucosa is lined by pseudostratified squamous ciliated epithelium interspersed with goblet cells and serous, mucous, and seromucous glands capable of producing large amounts of mucus that traps large particles in inhaled air (including infectious agents) and contributes to inhaled air humidification (3, 4). Excessive production of mucus generates rhinorrhea (runny nose) or, if drainage occurs toward the nasopharynx, postnasal drip. A prominent system of subepithelial capillary beds, capacitance vessels (venous sinusoids), and arteriovenous anastomoses allows for large amounts of blood to pool in the nasal submucosa and rapidly engorge it (5, 6). This provides a wide surface for heat and water exchange and supports the homeostatic functions of the nose (air conditioning of inhaled air) (7). However, excessive blood pooling causes a significant increase in nasal airway resistance and is perceived as nasal “congestion,” “blockage,” or a “stuffy nose.”
Nasal seromucous glands and blood vessels are highly regulated by parasympathetic and adrenergic innervation deriving from the vidian (branch of the facial nerve) and other nerves (8). Parasympathetic stimulation through acetylcholine and possibly through vasoactive intestinal peptide results in mucus production. Adrenergic nerve stimulation through noradrenaline and possibly through neuropeptide Y has a primarily nasal decongestant effect by constricting blood vessels, reducing blood flow, and emptying the venous sinusoids (9, 10). Thus, vascular engorgement is largely the result of reduced sympathetic tone. The parasympathetic and sympathetic control of the nasal glandular apparatus and vasculature is influenced by extrinsic and possibly intrinsic stimuli that result in activation of sensory nerves and the generation of central neural reflexes. Nasal sensory nerve fibers are predominantly supplied by the olfactory and trigeminal nerves. These fibers are mostly nonmyelinated C-fibers and myelinated Aδ-fibers and can sense noxious chemical and physical stimuli (11). In addition to the generation of autonomic central reflexes, nasal sensory nerves are the site of initiation of the sensation of nasal pruritus and of sneezing, typical allergic rhinitis symptoms. Activation of C-fibers is also believed to induce axon reflexes (antidromic activation of collateral fibers), which result in the release of a plethora of sensory neuropeptides in the nasal mucosa (e.g., the tachykinins substance P and neurokinin) with contribution to tissue responses, including plasma leakage (12).
Nasal responsiveness refers to the normal functional (not immunologic) responses of the nasal mucosa to endogenous or exogenous physical or chemical stimuli. An example of nasal responsiveness is how the nose handles cold air. Cold air induces significant water loss, especially under conditions of hyperventilation. To preserve homeostasis and to avoid mucosal dryness and damage, water is being constantly replenished by passive transfer through the paracellular spaces of the nasal airway epithelium. This process is not perceived as abnormal as minimal rhinorrhea is produced (13).
The term nasal hyperresponsiveness describes the state of exaggerated response to one or more endogenous or exogenous stimuli. This may arise because of alterations in normal responsiveness as a result of pathological, or perhaps, genetic factors affecting one or more structural or functional elements of the nasal mucosa. Nasal mucosal inflammation represents such a pathological factor. The example of the nasal response to cold air can be used again to juxtapose normal responsiveness and hyperresponsiveness: some individuals complain of excessive symptoms when they are exposed to cold and windy weather conditions these can be either individuals with perennial allergic rhinitis in whom allergic inflammation has up-regulated the sensorineural apparatus (14) or people with some defect that impairs homeostatic mechanisms for mucosal water loss (15). In the first case, water loss from cold air breathing, even if it results in only slight mucosal dryness, leads to activation of sensory nerves and the induction of glandular secretions and rhinorrhea through a reflex mechanism. In the latter case, mucosal hypertonicity rapidly develops, leading to sensorineural activation and, possibly, mast cell activation with mediator release. In the first case, the stimulus is not excessive, but the end-organ perceives it as such in the latter case, the stimulus becomes excessive because of inadequate homeostasis. In both cases, exaggerated responses associated with nasal symptoms are generated ( Figure 1 ).
Figure 1. Schematic diagram of hyperresponsiveness in comparison with normal nasal responsiveness. Normal responsiveness (left) consists of defensive or homeostatic responses to a stimulus or normal intensity and may or may not produce mild nasal symptoms. Hyperresponsiveness either manifests as an excessive response to a stimulus of normal intensity, which is secondary to alterations in the function of nasal end-organs, or as a response to a stimulus of normal intensity that, because of defective homeostatic function, develops into an excessive stimulus (e.g., cold air causing hypertonicity see text for details).
Figure 2. The biology of allergic sensitization and of the allergic reaction in the nasal mucosa leading to the generation of symptoms and to functional alterations such as nasal hyperresponsiveness. See text for details. Ach/VIP = acetylcholine/vasoactive intestinal peptide CGRP = calcitonin gene-related peptide ECP = eosinophil cationic protein EPO = eosinophil peroxidase FcεR1 = high-affinity Fc receptor for IgE GM-CSF = granulocyte-macrophage colony-stimulating factor ICAM-1 = intercellular adhesion molecule-1 LFA-1 = lymphocyte function–associated antigen-1 MBP = major basic protein MCP-1, -3, -4 = monocyte chemotactic protein-1, -3, -4, respectively MHC = major histocompatibility complex MIP-1α = macrophage inflammatory protein-1α NKA = neurokinin A PAF = platelet-activating factor RANTES = regulated on activation, normal T-cell expressed and secreted sLT = sulfidoleukotriene TARC = thymus and activation-regulated chemokine TGF-β = transforming growth factor-β Th1, Th2 = helper T type 1 and type 2 cells, respectively TNF-α = tumor necrosis factor-α Treg = regulatory T cell TxA2 = thromboxane A2 VCAM-1 = vascular cell adhesion molecule-1 VLA-4 = very late antigen-4.
Hyperresponsiveness is not a single pathophysiological entity. Theoretically, every functional element of the nasal mucosa that is related to the generation of one or more symptoms may become hyperresponsive. Therefore, to test for hyperresponsiveness with the use of a provocative stimulus, one should be aware of the characteristics of this stimulus. For example, methacholine can only generate nasal secretions in the nose and, therefore, exaggerated secretory response to methacholine reflects glandular hyperresponsiveness. On the other hand, histamine has multiple actions including stimulation of nasal sensory nerves leading to sneezing, itching, and reflex glandular activation, as well as direct effects on the vasculature leading to increased nasal resistance (16).
Allergic rhinitis is the most common form and a prototype of IgE-mediated disease. The hallmark of allergic rhinitis is an IgE-mediated, type 1 hypersensitivity reaction to an inciting inhaled allergen. The result of this reaction is a cascade of immunological and biochemical events leading to clinical expression of the disease ( Figure 2 ). Genetic predisposition and environmental factors including allergen exposure and, perhaps, exposure to environmental adjuvants or immune response suppressors probably exert important influences on the development of allergic rhinitis.
Allergens implicated in allergic rhinitis are in their vast majority proteins that derive from airborne particles including pollens, dust mite fecal particles, cockroach residue, and animal dander. After inhalation of allergenic particles, allergens are eluted in nasal mucus and subsequently diffuse into nasal tissues.
The sensitization process is initiated in nasal tissues when antigen-presenting cells (APCs), which are primarily dendritic cells, engulf allergens, break them into allergenic (antigenic) peptides, and migrate to lymph nodes, where they present these peptides to naive (never exposed to antigen) yet epitope-specific CD4 + T lymphocytes (T cells) (17, 18). CD4 + lymphocyte activation requires the interaction of specific T-cell receptors on the surface of T cells with allergen peptide–MHC class II complexes on the APCs and the ligation of costimulatory receptors of the CD28 family on T cells by B7 family members of costimulatory molecules (CD80 and CD86) on APCs (19). Naive helper T cells are known as Th0 cells, because they produce a pattern of cytokines that spans both the Th1 and Th2 phenotypes. If given the proper stimulus, naive helper T cells can differentiate into the biased Th1 or Th2 subset. In the case of allergy, the Th2 subset plays a central role (20). In the development of Th2 cells, IL-4 is a required stimulus.
Dendritic cells (DCs) form a network that is localized within the epithelium and submucosa of the entire respiratory mucosa, including the nasal mucosa (21). The number of both DCs and T cells at the surface of the nasal epithelium is increased in rhinitis. For example, increased numbers of CD1a + and CD11c + DCs in the epithelium and lamina propria of the nasal mucosa clustered with CD4 + T lymphocytes and eosinophils have been found in this disease (18). In addition to presenting antigen, DCs can polarize naive T cells into either Th1 or Th2 cells according to their own phenotype and with signals received from processed antigens and from the tissue microenvironment during antigen presentation. For example, plasmacytoid DCs matured by IL-3 and CD40 ligand engagement promote T cells toward a Th2 phenotype, whereas cells that mature through contact with a virus promote a Th1 phenotype (22). Other signals affecting DCs and their influence on Th2 polarization of T cells include prostaglandin E2 and thymic stromal lymphopoietin released from epithelial cells, which switch the maturation of myeloid DCs into Th2-promoting DCs, and lead to the expression of OX40 ligand and inducible costimulatory ligand on DCs (23).
A distinct subtype of T cells, the so-called regulatory T cells (Tregs), suppress immune responses (both Th2 and Th1) through the secretion of inhibitory cytokines and cell surface molecules including IL-10 and transforming growth factor-β, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1). Tregs can also inhibit effector T cells via a direct cell–cell contact mechanism to induce apoptosis. In addition, Tregs crosstalk with APCs to suppress T-cell activation. Tregs are categorized as natural or adaptive (inducible, Tr1). The former are characterized by the expression of high levels of CD25 on their surface and by the transcription factor forkhead box P3 (FoxP3) (24).
Both nonallergic and allergic individuals retain allergen-specific IL-4–producing effector T cells, IL-10–producing Tr1 cells, and CD25 + Tregs, but in different proportions. Thus, the balance between Th2 and certain Treg populations may decide whether clinical allergy will develop (25, 26). There is evidence that CD25 + regulatory T cells are defective in patients with allergic rhinitis. For example, peripheral blood CD4 + CD25 + cells have reduced ability to suppress T-cell proliferation during the pollen season in patients with birch-induced allergic rhinitis (27), and FoxP3 gene expression is reduced in nasal secretions from patients with allergic rhinitis (28).
IgE, like all immunoglobulins, is synthesized by B lymphocytes (B cells) under the regulation of cytokines derived from Th2 lymphocytes. Two signals are required. IL-4 or IL-13 provides the first essential signal that drives B cells to IgE production by inducing ε-germline gene transcription. In the case of IgE-expressing memory B cells, these cytokines induce clonal expansion. The second signal is a costimulatory interaction between CD40 ligand on the T-cell surface and CD40 on the B-cell surface. This signal promotes B-cell activation and switch recombination for the production of IgE (29).
Once produced by B cells, IgE antibodies attach on tetrameric (αβγ2) high-affinity receptors (FcεRI) on the surface of mast cells and basophils, rendering them “sensitized” (30). IgE can also bind to trimeric (αγ2) FcεRI on the surface of various cells including dendritic cells (31), as well as on low-affinity IgE receptors (CD23, FcεRII) that are present on monocyte-macrophages and on B lymphocytes (32, 33). However, it is the IgE–FcεRI interaction on mast cells and basophils that induces the classic allergic reaction at the cellular level. The functions of the trimeric FcεRI and of FcεRII are not fully elucidated. On the surface of DCs, FcεRI binds to IgE and this seems to facilitate allergen uptake by the DCs for processing and presentation (31).
In presenting and discussing the inflammatory consequences of allergic reactions in the nose and the role of the many biological products, many assumptions are made. Information is obtained from snapshot imaging of the nasal mucosa, from animal models, and from basic knowledge about the in vitro activity of various mediators, chemokines, cytokines, and so on. Yet, little confirmatory information is available on the precise role of these biological products in the in vivo setting, in allergic rhinitis, as pharmacological or other inhibitory/blocking approaches do not exist or have failed to produce significant clinical results.
The allergic reaction in the nose has early and late components (early and late phases), both of which contribute to the clinical presentation of allergic rhinitis. The early phase involves the acute activation of allergy effector cells through IgE–allergen interaction and produces the entire spectrum of allergic rhinitis symptoms. The late phase is characterized by the recruitment and activation of inflammatory cells and the development of nasal hyperresponsiveness with more indolent symptoms.
Within minutes of contact of sensitized individuals with allergens, the IgE–allergen interaction takes place, leading to mast cell and basophil degranulation and the release of preformed mediators such as histamine and tryptase, and the de novo generation of other mediators, including cysteinyl leukotrienes (LTC4, LTD4, LTE4) and prostaglandins (primarily PGD2) (34, 35). Mast cells and basophils do not produce exactly the same array of mediators for example, PGD2 is almost exclusively a mast cell product. The targets of these mediators vary for example, histamine activates H1 receptors on sensory nerve endings and causes sneezing, pruritus, and reflex secretory responses, but it also interacts with H1 and H2 receptors on mucosal blood vessels, leading to vascular engorgement (nasal congestion) and plasma leakage (36). Sulfidopeptide leukotrienes, on the other hand, act directly on CysLT1 and CysLT2 receptors on blood vessels and glands, and can induce nasal congestion and, to a lesser extent, mucus secretion (37). Additional substances such as proteases (tryptase) and cytokines (tumor necrosis factor-α) are released at this early stage of the allergic reaction, but their role in the generation of acute symptoms is unclear. Other mediators are produced through indirect pathways for example, bradykinin is generated when kininogen leaks into the tissue from the peripheral circulation and is cleaved by tissue kallikrein that is produced by serous glands (38, 39).
The symptoms produced immediately after exposure to allergen reach their peak within a few minutes and tend to dissipate within 1 hour. Some individuals continue experiencing symptoms for several hours others enter a quiescent phase and their symptoms recrudesce after several hours (40). The nature of the late symptoms is somewhat different than that of the acute symptoms in that sneezing and pruritus are not prominent, whereas nasal congestion is. Overall, these late symptoms occur in approximately 50% of people and, because their relative indolence resembles the clinical presentation of chronic rhinitis, the late phase is of particular scientific interest as a model of chronic allergic disease.
Allergen exposure also results in nasal mucosal inflammation characterized by the influx and activation of a variety of inflammatory cells and by alterations in nasal physiology, namely priming and hyperresponsiveness. Cells that migrate into the nasal mucosa include T cells, eosinophils, basophils, neutrophils, and monocytes (41–43). Also, mast cells are increased in number in the submucosa and infiltrate the epithelium after allergen exposure or during pollen season (44, 45). In biopsies obtained hours after nasal allergen provocation on individuals with allergic rhinitis, T cells predominate in the tissue infiltrate. In nasal secretions, the total number of leukocytes increases by many fold over several hours and the majority of leukocytes are neutrophils and eosinophils (42, 46). It is likely that cell migration is due to the chemokines and cytokines released by the primary effector cells, mast cells, and basophils, acutely and over several hours after allergen exposure. Interestingly, some of the acutely released mediators may have cytokine-like effects. For example, histamine regulates dendritic cells and T cells via its four distinct histamine receptors, H1–H4 (47), and the sulfidopeptide leukotrienes can attract and activate eosinophils. A reduction in eosinophil accumulation in nasal tissues is observed with CysLT1 receptor antagonists (48). Some of the products of the acute allergic reaction affect the vascular endothelium and up-regulate adhesion molecules, some of which have relative cellular specificity (e.g., vascular cell adhesion molecule-1 expression is important in the recruitment of eosinophils as it interacts with very late antigen-4 on the eosinophil surface ). Other effector cell products can activate structural cells in the nasal mucosa, such as epithelial cells and fibroblasts, to release additional chemokines (e.g., eotaxin, RANTES [regulated on activation normal T cell expressed and secreted], and thymus and activation regulated chemokine [TARC]) that facilitate cell influx from the peripheral blood (50). Furthermore, the cells that arrive at the site of allergic inflammation become activated in situ and release additional cytokines and chemokines, resulting in the perpetuation of inflammation.
Th2 cytokines probably play a central role in the development of mucosal inflammation after allergen exposure. For example, IL-5 is central in the recruitment of eosinophils (51) and IL-4 is important in the recruitment of both eosinophils and basophils (52). IL-13, which derives from basophils, mast cells, and Th2 cells, induces the expression of several chemokines that are thought to selectively recruit Th2 cells, namely TARC and monocyte-derived chemokine (53). IL-13 can also recruit dendritic cells to the site of allergen exposure via the induction of matrix metalloproteinase-9 and TARC. Most importantly, as discussed earlier, Th2 cytokines deriving from T cells and other cells perpetuate allergy by promoting continuous IgE production by B cells.
The role of the eosinophil needs to be emphasized. These cells arrive rapidly in the nasal mucosa after allergen exposure. Eosinophils produce several important cytokines such as IL-5, which has strong chemoattractant properties and acts in an autocrine fashion to promote eosinophil survival and activation (54, 55). Most importantly, eosinophils serve as a major source of lipid mediators such as LTC4, thromboxane A2, and platelet-activating factor (56). The influx of activated eosinophils results in the release of toxic granule products, particularly major basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO), which can damage nasal epithelial cells (57). Even at low concentrations, MBP can reduce ciliary beat frequency in vitro. MBP has also been shown in animals to alter neuronal function by interfering with muscarinic (M2) receptors, allowing increased release of acetylcholine at neuronal junctions or endplates (58). These effects may contribute to the inflammatory features of the late-phase response and to nasal hyperresponsiveness.
In asthma, it is believed that chronic inflammation leads to airway remodeling, but the concept of remodeling in allergic rhinitis is controversial as studies have reported conflicting findings on epithelial damage or thickening of the reticular basement membrane (59). Growth factors that have been implicated in lower airways remodeling have also been detected in the nasal mucosa of individuals with allergic rhinitis. It appears that alterations of mucosal structural elements are far less extensive in the nasal mucosa compared with the lower airways, even though the nasal mucosa is more exposed to allergens and environmental toxins. One could speculate that the nasal mucosa may have a much higher capacity for epithelial regeneration and repair, perhaps because of its different embryological origin (60).
Priming to allergen refers to the phenomenon of increased nasal responsiveness to allergen with repeated allergen exposure. One can argue that priming is a form of nasal hyperresponsiveness specific to the allergic reaction. Priming can be documented on natural allergen exposure. Connell was the first to describe the “priming effect” in the nose after allowing his study volunteers to spend time outdoors on consecutive days in the middle of the pollen season (61). Also, Norman demonstrated that nasal symptoms are higher at the end of the pollen season, compared with the beginning, despite equal levels of ragweed pollen in the air (62). In the clinical research setting, where a high dose of allergen is administered as a challenge over a short period of time, priming can be demonstrated within a few hours (63, 64).
The mechanism of priming is believed to involve several factors. First, increased numbers of mast cells in the epithelium and the influx of basophils provide many more targets for IgE–allergen interaction and mediator release. There is more evidence supporting the role of basophils in this mechanism because increased levels of histamine, but not PGD2, a mast cell marker, are found in nasal fluids after an allergen challenge that shows the priming effect (64). Second, the inflammation that develops after allergen exposure can result in increased permeability of the epithelium and easier allergen penetration to IgE-bearing cells. Third, again because of inflammation, the responses of the nasal end-organs may become exaggerated this mechanism would be the same as that of nonspecific nasal hyperresponsiveness (see below). Nasal allergen priming is ablated by oral or topical glucocorticosteroid treatment, providing evidence for the role of inflammation in this phenomenon (64, 65).
Patients with allergic rhinitis, particularly those with perennial disease, experience symptoms on exposure to several nonallergic stimuli such as smoke, strong odors, and other irritants. Because these clinical sensitivities are similar to those reported by patients with nonallergic rhinitis, some clinicians consider this a distinct clinical phenotype, “mixed rhinitis” (allergic and nonallergic) (66). However, the prevalence of these clinical sensitivities in individuals with perennial allergic rhinitis is so high that it is cogent to consider the nonallergic symptom triggers a phenotypic component of allergic disease. Furthermore, there is enough experimental evidence in allergic rhinitis for increased responsiveness of the nasal mucosa to a variety of stimuli that are not allergens and, even more importantly, this increased responsiveness can be induced by allergen challenge (67).
As discussed earlier, different stimuli act on different end-organs (glands, blood vessels, nerves) and some stimuli act on multiple end-organs simultaneously. Hyperresponsiveness may exist in one end-organ but not another. For example, hyperosmolar saline induces a secretory response, which is believed to be secondary to C-fiber activation. In perennial allergic rhinitis, the nasal secretory response to hyperosmolar saline was found to be augmented compared with healthy control subjects, but a question was raised concerning whether this represents hyperresponsiveness of C-fibers or of the glandular apparatus (68). However, in the same study it was shown that the secretory response to methacholine, which stimulates only the glands, was not different in the subjects with perennial allergic rhinitis compared with the control subjects this was a convincing demonstration that the sensorineural apparatus is in a hyperresponsive state in allergic rhinitis. Other stimuli demonstrating hyperresponsiveness in perennial or seasonal allergic rhinitis include histamine, bradykinin, capsaicin, and cold air. Allergen challenge has been shown to induce hyperresponsiveness to histamine and this phenomenon can be blocked by topical steroid pretreatment (67).
The pathways leading to end-organ hyperresponsiveness in allergic rhinitis are not understood. Because of the inhibitory effect of glucocorticosteroids, it is believed that allergic inflammation is the culprit the question remains, however, as to which element(s) of inflammation result(s) in end-organ hyperresponsiveness. In the case of sensorineural hyperresponsiveness, which is the only well-documented form, it has been postulated that nerve growth factor (NGF) or other neurotrophins may play a role. NGF is abundant inside nasal glandular epithelial cells and in the majority of eosinophils (69). Interestingly, NGF is released in nasal secretions on experimental allergen challenge, but not on challenge with histamine, suggesting a specific release pathway (70). The biological effects of NGF include changes in ongoing neuroterminal function, as well as C-fiber sprouting. These effects could render nociceptor nerves more responsive due to either lower firing thresholds or to increased numbers of C-fibers.
As discussed earlier, nonallergic rhinitis is a broad term encompassing a number of nasal conditions, the only common denominator of which is the lack of systemic allergic sensitization (negative skin testing and/or lack of serum-specific IgE) to the aeroallergens implicated in allergic rhinitis (Table 1). Because of such definition, these conditions are heterogeneous and of widely diverse pathophysiology. Moreover, the lack of agreement on clinical phenotypes and the lack of strict diagnostic criteria have made most of these conditions difficult to study.
The most common form of nonallergic rhinitis is the idiopathic condition also known as vasomotor rhinitis. Individuals categorized as such are those who not only lack conventional evidence of allergic disease, but are also devoid of any evidence of sinusitis/nasal polyposis, anatomic abnormalities, or a known infection. In addition, pharmacological (iatrogenic) or endocrine causes need to be ruled out. Their nasal symptoms are chronic, without a seasonal pattern (although cases of seasonal symptomatology have been described), and are more likely to include nasal congestion and clear rhinorrhea and less likely sneezing and pruritus. Patients with idiopathic/vasomotor rhinitis report a family history of rhinitis less frequently than patients with allergic disease. Clinical sensitivity to irritants and to changes in atmospheric conditions is common, but it is not known whether it is more common than in patients with perennial allergic rhinitis. These patients are characterized by relatively modest responses to nasal corticosteroids (71). Surprisingly, the topical antihistamine azelastine has also shown moderate effectiveness (72), raising some interesting hypotheses as to the pathophysiology of this condition. Another important observation is that up to one-quarter of these patients, if reevaluated at a later stage, may show evidence of allergic sensitization and may be reclassified into the allergic rhinitis category (73). Although adequate research in the pathophysiology of idiopathic rhinitis is lacking, some observations raise the possibility that this condition may indeed encompass a number of distinct entities. In the following sections, we present information about three conditions with potentially distinct pathophysiology that require further exploration for nosological confirmation and more in-depth research to determine mechanisms and optimal treatment.
A series of studies conducted primarily in the Netherlands led to the hypothesis that, in a subgroup of patients with nonallergic rhinitis, neural function abnormalities may be responsible for their symptoms. The Dutch investigators have made the following observations: (1) the nasal mucosa of such patients is indistinguishable from that of healthy control subjects lacking any evidence of inflammation or of a particular cell infiltrate (74) (2) nasal responsiveness to histamine, which is highly up-regulated in perennial allergic rhinitis, is normal in this group of patients with nonallergic disease (75) (3) in contrast to histamine, these patients appear to be hyperresponsive to cold air provocation in the nose (75) (4) repetitive nasal application of capsaicin, which is meant to defunctionalize nasal nociceptor C-fibers, leads to prolonged (up to 6 mo) improvement in symptomatology, an observation that has been confirmed by several other European research teams (76–78) and (5) improvement of this condition by capsaicin is accompanied by reduction in nasal responsiveness to cold air (76). Taken together, these observations suggest a sensorineural dysregulation in which capsaicin-sensitive nerve fibers play a central role. The sensitivity to cold air can be explained by the fact that the primary stimulus in a cold air challenge may be hyperosmolarity and that the capsaicin receptor TRPV1 on nerve fibers is also sensitive to hypertonicity. Stimulation of nasal secretory responses by hypertonic saline can be reduced by capsaicin pretreatment (68). The lack of mucosal inflammation justifies the term “rhinopathy” as opposed to “rhinitis.”
British researchers and, more recently, researchers from Spain have published a series of interesting observations raising the hypothesis that another subgroup of patients with idiopathic rhinitis suffers from a form of localized allergic disease. In contrast to the neurogenic rhinopathy group, these patients show evidence of inflammation in their nasal mucosa, primarily eosinophilia and, perhaps, increased mast cell numbers (79). In fact, it may not be surprising if these are the same patients as those that have been classified for 3 decades as having NARES (nonallergic rhinitis with eosinophilia syndrome) (80) (Table 1).
Despite having negative skin tests and no detectable serum-specific IgE antibodies, these individuals develop nasal symptoms on nasal provocation with various allergens (including house dust mite, grass, and olive pollen) (81, 82). In addition to the symptoms, inflammatory mediators indicative of mast cell activation (tryptase) and eosinophil activation (ECP) are released in nasal secretions at early and late phases after allergen challenge, respectively (82, 83). In the absence of experimental allergen exposure, nasal secretions of some of these patients contain specific IgE antibodies against the allergens to which they react locally. What has not been demonstrated yet is the presence of IgE-producing B cells in the nasal mucosa of these individuals and the ability of nasal mucosal explants to produce IgE ex vivo, on allergen exposure, as has been demonstrated in patients with allergic rhinitis (84).
Even less characterized, compared with the groups described previously, are patients with nonallergic rhinitis who present evidence of systemic autonomic dysfunction. Theoretically, excessive parasympathetic tone will produce rhinorrhea, whereas suppressed sympathetic activity can result in nasal congestion. A few studies have provided data indicating abnormal responses to autonomic tests in patients with nonallergic rhinitis. For example, heart rate variability according to various standard parameters was found to be higher in patients with idiopathic (vasomotor) rhinitis, without nasal eosinophilia, compared with nonrhinitic control subjects, indicative of increased parasympathetic activity (85). More generalized dysautonomia including both the parasympathetic and sympathetic nervous systems has been suggested by other studies (86–88). It remains to be seen whether dysautonomia characterizes a specific group of patients with idiopathic, nonallergic rhinitis and, if so, what the clinical attributes of these patients are. Furthermore, it remains to be seen whether dysautonomia can be a predictor of a therapeutic response to particular forms of treatment such as nasal ipratropium, which is indicated for patients with difficult-to-control rhinorrhea as their primary complaint.
Multiple Sclerosis: Current Status and Strategies for the Future.
Multiple sclerosis (MS) literally means “many scars,” which refers to the lesions that accumulate in the brain and spinal cord throughout the course of the disease. These scars, or lesions, consist mostly of dead nerve cells, whose axons have been denuded of the myelin sheaths that normally protect them and permit the conduction of nerve impulses. MS is a chronic, degenerative disease that usually begins in young adulthood and most visibly destroys muscular control, although many other brain functions are affected. Most people will live with MS for decades after their diagnosis. MS reduces life expectancy after onset (as measured by current diagnostic criteria) by only about 10-15 years, and about half of the patients survive 30 years or more from onset. 110
Las alergias son reacciones de hipersensibilidad que ocurren mediante mecanismos inmunológicos específicos de tipo Th2. Se caracterizan por distintos mediadores solubles, así como células específicas del sistema inmune. En las últimas décadas ha surgido evidencia que asocia esta enfermedad con el desarrollo de cáncer. Sin embargo, los resultados obtenidos, en su mayoría de estudios epidemiológicos, han sido controversiales y contradictorios. Lo anterior se debe a que existen dos principales tendencias. Mientras algunos estudios han demostrado que las alergias pueden reducir el riesgo de cáncer, otros estudios muestran que puede aumentarlo. Lo primero puede explicarse por la hipótesis de inmunovigilancia, que establece que el aumento de la vigilancia después de la hiperreactividad inmune puede inhibir o ejercer un efecto protector contra el desarrollo de cáncer. Del mismo modo, la hipótesis de la profilaxis sugiere que los efectos físicos de síntomas de las alergias pueden prevenir el cáncer mediante la eliminación de los carcinógenos potenciales. Las hipótesis opuestas proponen que existe un desvío de la respuesta inmune hacia Th2 lo cual favorece el desarrollo del cáncer, o que el proceso de inflamación crónica favorece la generación de mutaciones, y por tanto el desarrollo del cáncer. Con el propósito de entender más acerca de estas dos hipótesis, en esta revisión se consideraron los principales factores solubles y celulares de las enfermedades alérgicas que pudieran estar desempeñando un papel clave en el desarrollo o inhibición del cáncer.
Asthma is often linked to other medical conditions, such as:
- Allergies. Asthma is usually a type of allergic reaction. People who have asthma often have other types of allergies. They may have food allergies or get a runny or stuffy nose from pollen. You may be at higher risk for developing asthma if you had allergic reactions in early childhood to substances in the air, such as pollen, dander, mold, or dust. The more things you are allergic to, the higher your risk of asthma.
- Obesity can increase the chances of developing asthma or worsening asthma symptoms. This may be because people who have obesity can have inflammation or changes in the immune system.
- Respiratory infections and wheezing. Young children who often have respiratory infections caused by viruses are at highest risk of developing asthma symptoms early in life.
A Radical Path
Miller did not start her career thinking about low-dose poisons. She was a newly minted industrial hygienist with long, blond hair and wide-set blue eyes when, in 1979, she was hired for the United Steelworkers union in Pittsburgh. The union had 1.2 million mostly male members. “I loved visiting steel mills, smelters and mines,” she recalls. “I found it fascinating to go to coke ovens and see steel being made in the blast furnace and watch parts made by pouring molten metal into molds in foundries.”
Miller sometimes got headaches after a few hours in the same environments the workers had worked in for decades, but she didn’t think much about those headaches at the time. She was just trying to make sure the companies complied with standards set by the Occupational Safety and Health Association (OSHA).
But then the National Institute for Occupational Safety and Health (NIOSH) asked her to examine some female steelworkers diagnosed with psychological and management problems. The women soldered piecework for electronics in two different plants. They worked in rooms without fume vents, and they complained of headaches, fatigue and difficulty concentrating.
In a paper she presented that year at a NIOSH symposium, Miller proposed that toxicants in fumes from the soldering might be responsible for their complaints. “I was the only non-psychiatrist at the meeting,” she recalls, “and by the time I finished my talk, the experts were lined up at the microphone to attack my ideas.”
It was another heretic, controversial Chicago allergist Theron Randolph, who first lent support. Randolph broke with his profession around 1950 and had begun to test and treat individuals for a wide range of sensitivities vastly different from typical allergies, which could be diagnosed through the appearance of elevated immune cells, called immunoglobulins, in the blood. Randolph was convinced that his patients suffered from food and chemical sensitivities that couldn’t be measured in traditional ways. He invited Miller to attend his weekly staff meetings, where cases were discussed.
When Randolph took a patient history, Miller recalls, it lasted hours. He would begin an appointment by saying, “Tell me the last time you felt truly well, and go from there.” He would type out the history directly as the patient talked. Miller remembers details like, “She felt ill in the train station in Chicago. … She felt nauseous on the foam rubber mattress.”
Randolph would “hospitalize” patients for a few weeks in specially constructed units near his Chicago offices. During their confinement, they breathed filtered air, slept on untreated cotton bedding, drank purified water and fasted for days. Their symptoms, from arthritis to headaches to fatigue, would often melt away.
Then he would do blinded challenges on patients — feed a patient an organic apple and a sprayed apple, or expose them to a whiff of copy paper in a glass jar. Symptoms such as migraines or joint pain would recur in response to whatever substances the individual patient was sensitive to. Avoiding those triggers was the inevitable prescription when they left the clinic.
“Many patients were able to get off their medications and get well. These people were reacting to tiny doses of substances, doses that simply should not be causing symptoms. It broke every paradigm of medicine I knew,” explains Miller. “I decided to go to medical school, and then to work as a researcher within a university setting, to establish scientific credibility for this amazing work, which at the time, virtually nobody in academic medicine or science believed.”
All authors participated in the design, interpretation of the studies and analysis of the data, and review of the manuscript. Yeon-Yong KIM, In-Gyu JE, Min Jong KIM, and Byeong-Cheol KANG performed the major experiments and wrote the manuscript Young-Ae CHOI, Moon-Chang BAEK, Byung-Heon LEE, and Jin Kyeong CHOI made substantial contributions to the conception and design of the study Soyoung LEE, Seung-Bin YOON, and Sang-Rae LEE analyzed the data and Tae-Yong SHIN, Dongwoo KHANG, and Sang-Hyun KIM supervised the research and co-wrote the manuscript.
Jutel M, Akdis CA . Immunological mechanisms of allergen-specific immunotherapy. Allergy 2011 66: 725–32.
Kalesnikoff J, Galli SJ . New developments in mast cell biology. Nat Immunol 2008 9: 1215–23.
Na H, Cho M, Chung Y . Regulation of Th2 cell immunity by dendritic cells. Immune Netw 2016 16: 1–12.
Galli SJ, Tsai M . Ige and mast cells in allergic disease. Nat Med 2012 18: 693–704.
Je IG, Choi HG, Kim HH, Lee S, Choi JK, Kim SW, et al. Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of ikappab kinase complex. Toxicol Appl Pharmacol 2015 287: 119–27.
Galli SJ, Tsai M, Piliponsky AM . The development of allergic inflammation. Nature 2008 454: 445–54.
Amin K . The role of mast cells in allergic inflammation. Respir Med 2012 106: 9–14.
Kim SH, Jun CD, Suk K, Choi BJ, Lim H, Park S, et al. Gallic acid inhibits histamine release and pro-inflammatory cytokine production in mast cells. Toxicol Sci 2006 91: 123–31.
Choi JK, Oh HM, Lee S, Kwon TK, Shin TY, Rho MC, et al. Salvia plebeia suppresses atopic dermatitis-like skin lesions. Am J Chin Med 2014 42: 967–85.
Longui CA . Glucocorticoid therapy: Minimizing side effects. J Pediatr 2007 83: S163–77.
Bellik Y, Hammoudi SM, Abdellah F, Iguer-Ouada M, Boukraa L . Phytochemicals to prevent inflammation and allergy. Recent Pat Inflamm Allergy Drug Discov 2012 6: 147–58.
Newman DJ, Cragg GM . Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016 79: 629–61.
Kim SH, Lee S, Kim IK, Kwon TK, Moon JY, Park WH, et al. Suppression of mast cell-mediated allergic reaction by amomum xanthiodes. Food Chem Toxicol 2007 45: 2138–44.
Itoh A, Isoda K, Kondoh M, Kawase M, Kobayashi M, Tamesada M, et al. Hepatoprotective effect of syringic acid and vanillic acid on concanavalin a-induced liver injury. Biol Pharm Bull 2009 32: 1215–9.
Kumar S, Prahalathan P, Raja B . Antihypertensive and antioxidant potential of vanillic acid, a phenolic compound in L-NAME-induced hypertensive rats: A dose-dependence study. Redox Rep 2011 16: 208–15.
Bae Y, Lee S, Kim SH . Chrysin suppresses mast cell-mediated allergic inflammation: Involvement of calcium, caspase-1 and nuclear factor-kappab. Toxicol Appl Pharmacol 2011 254: 56–64.
Kim HH, Park SB, Lee S, Kwon TK, Shin TY, Park PH, et al. Inhibitory effect of putranjivain a on allergic inflammation through suppression of mast cell activation. Toxicol Appl Pharmacol 2014 274: 455–61.
Singh TS, Lee S, Kim HH, Choi JK, Kim SH . Perfluorooctanoic acid induces mast cell-mediated allergic inflammation by the release of histamine and inflammatory mediators. Toxicol Lett 2012 210: 64–70.
Choi JK, Oh HM, Lee S, Park JW, Khang D, Lee SW, et al. Oleanolic acid acetate inhibits atopic dermatitis and allergic contact dermatitis in a murine model. Toxicol Appl Pharmacol 2013 269: 72–80.
Finkelman FD, Rothenberg ME, Brandt EB, Morris SC, Strait RT . Molecular mechanisms of anaphylaxis: Lessons from studies with murine models. J Allergy Clin Immunol 2005 115: 449–57.
Kawakami T, Kashiwakura J, Kawakami Y . Histamine-releasing factor and immunoglobulins in asthma and allergy. Allergy Asthma Immunol Res 2014 6: 6–12.
Lin KC, Huang DY, Huang DW, Tzeng SJ, Lin WW . Inhibition of AMPK through lyn-syk-akt enhances fcepsilonri signal pathways for allergic response. J Mol Med 2016 94: 183–94.
Caamano J, Hunter CA . Nf-kappab family of transcription factors: Central regulators of innate and adaptive immune functions. Clin Microbiol Rev 2002 15: 414–29.
Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M . Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005 23: 749–86.
Galli SJ . Mast cells and basophils. Curr Opin Hematol 2000 7: 32–9.
Pablos-Tanarro A, Lopez-Exposito I, Lozano-Ojalvo D, Lopez-Fandino R, Molina E . Antibody production, anaphylactic signs, and T-cell responses induced by oral sensitization with ovalbumin in BALB/c and C3H/HeOuJ mice. Allergy Asthma Immunol Res 2016 8: 239–45.
Chen J, Zhang J, Zhao R, Jin J, Yu Y, Li W, et al. Topical application of IL-28a attenuates allergic conjunctivitis in an ovalbumin-induced mouse model. Invest Ophthalmol Vis Sci 2016 57: 604–10.
Lim HB, Kim SH . Inhallation of e-cigarette cartridge solution aggravates allergen-induced airway inflammation and hyper-responsiveness in mice. Toxicol Res 2014 30: 13–8.
Je IG, Kim DS, Kim SW, Lee S, Lee HS, Park EK, et al. Tyrosol suppresses allergic inflammation by inhibiting the activation of phosphoinositide 3-kinase in mast cells. PLoS One 2015 10: e0129829.
Cheng C, Ng DS, Chan TK, Guan SP, Ho WE, Koh AH, et al. Anti-allergic action of anti-malarial drug artesunate in experimental mast cell-mediated anaphylactic models. Allergy 2013 68: 195–203.
Guo Z, Turner C, Castle D . Relocation of the t-snare snap-23 from lamellipodia-like cell surface projections regulates compound exocytosis in mast cells. Cell 1998 94: 537–48.
Eisenhut M, Wallace H . Ion channels in inflammation. Pflugers Arch 2011 461: 401–21.
Hart PH . Regulation of the inflammatory response in asthma by mast cell products. Immunol Cell Biol 2001 79: 149–53.
Walczak H . TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev 2011 244: 9–28.
Chen L, Grabowski KA, Xin JP, Coleman J, Huang Z, Espiritu B, et al. IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils. J Immunol 2004 172: 2059–66.
Pasparakis M . Role of NF-kappaB in epithelial biology. Immunol Rev 2012 246: 346–58.
Lee SH, Shin HJ, Kim DY, Shim DW, Kim TJ, Ye SK, et al. Streptochlorin suppresses allergic dermatitis and mast cell activation via regulation of Lyn/Fyn and Syk signaling pathways in cellular and mouse models. PLoS One 2013 8: e74194.
Ishimata N, Ito H, Tai A . Structure–activity relationships of vanillic acid ester analogs in inhibitory effect of antigen-mediated degranulation in rat basophilic leukemia RBL-2H3 cells. Bioorg Med Chem Lett 2016 26: 3533–6.
Savjani KT, Gajjar AK, Savjani JK . Drug solubility: Importance and enhancement techniques. ISRN Pharm 2012 2012: 195727.
de Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA, Cassidy A, et al. The pharmacokinetics of anthocyanins and their metabolites in humans. Br J Pharmacol 2014 171: 3268–82.
'Stretching rack' for cells
The behavior of cells is controlled by their environment. Besides biological factors or chemical substances, physical forces such as pressure or tension are also involved. Researchers from Karlsruhe Institute of Technology (KIT) and Heidelberg University developed a method that enables them to analyze the influence of external forces on individual cells. Using a 3D printing process, they produced micro-scaffolds, each of which has four pillars on which a cell is located. Triggered by an external signal, a hydrogel inside the scaffold swells and pushes the pillars apart, so that the cell must "stretch."
The work is part of the "3D Matter Made to Order" (3DMM2O) Cluster of Excellence. The researchers report on their results in Science Advances.
Many cellular biological processes, such as wound healing or the development of tissue, are strongly influenced by the properties of their environment. Cells react, for example, to biological factors or chemical substances. However, research is increasingly focusing on physical forces acting on the cells: How exactly do the cells adapt to these forces?
Within the framework of the German-Japanese University Consortium HeKKSaGOn and in cooperation with Australian scientists, the 3DMM2O team has taken a particularly ingenious approach to this question. For the production of their cell "stretching racks" they used "direct laser writing", a special 3D printing process in which a computer-controlled laser beam is focused into a special printer ink liquid. Its molecules react only at the exposed areas and form a solid material there. All other areas remain liquid and can be washed away. "This is an established method in our Cluster of Excellence for building three-dimensional structures - on the micrometer scale and below," explains Marc Hippler from the KIT Institute of Applied Physics, lead author of the publication.
In the current case, the researchers used three different printer inks: The first ink, made of protein-repellent material, was used to form the actual micro-scaffold. Using a second ink of protein-attracting material, they then produced four horizontal bars that are connected to one of the scaffold pillars each. The cell is anchored to these four bars. The real showstopper, however, is the third ink: The scientists used it to "print" a mass inside the scaffold. If they then add a special liquid, the hydrogel swells. It thus develops a force sufficient to move the pillars - and the bars with them. This, in turn, has the effect of stretching the cell that is fixed to the bars.
Cells counteract deformation
The scientists of the Cluster of Excellence placed two completely different cell types on their micro stretching rack: human bone tu-mor cells and embryonic mouse cells. They found that the cells counteract the external forces with motor proteins and thus greatly increase their tensile forces. When the external stretching force is removed, the cells relax and return to their original state. "This be-havior is an impressive demonstration of the ability to adapt to a dynamic environment. If the cells were unable to recover, they would no longer fulfill their original function - for example wound closure," says Professor Martin Bastmeyer from the Zoological Institute of KIT.
As the team further discovered, a protein called NM2A (non-muscle myosin 2A) plays a decisive role in the cells' response to mechani-cal stimulation: Genetically modified bone tumor cells that cannot produce NM2A were barely able to counteract the external defor-mation.
Work in the cluster of excellence was carried out by Heidelberg scientists from the field of biophysical chemistry as well as physics and cell- and neurobiology from KIT. Members of the German-Japanese University Consortium HeKKSaGOn include, among oth-ers, Heidelberg University, Karlsruhe Institute of Technology and Osaka University.
Cluster of Excellence 3D Matter Made to Order
In the 3D Matter Made to Order (3DMM2O) Cluster of Excellence, scientists of Karlsruhe Institute of Technology and Heidelberg Uni-versity conduct interdisciplinary research into innovative technolo-gies and materials for digital scalable additive manufacture to en-hance the precision, speed, and performance of 3D printing. Work is aimed at completely digitizing 3D manufacture and materials pro-cessing from the molecule to the microstructure. In addition to fund-ing as a cluster of excellence under the Excellence Strategy compe-tition launched by the federation and the federal states, 3DMM3O is financed by Carl Zeiss Foundation.
FDA EUA Fact Sheet for Pfizer/BioNTech COVID-19 Vaccine Does Not List History of Severe Allergic Reactions to Drugs, Foods or Other Vaccines as Contraindication
According to a Dec. 9 USA Today article, Moncef Slaoui, MD, co-head of Operation Warp Speed (OWS) said that he assumed that the U.S. Food and Drug Administration (FDA) would advise those with severe allergies that they, “should not take the vaccine until we know exactly what happened.” 12
However, on Dec. 11 when the FDA issued its EUA giving Pfizer the go-ahead to distribute its COVID-19 vaccine in the U.S. for persons aged 16 and older, the FDA Fact Sheet for Vaccine Recipients and Caregivers included only one contraindication (reason to not get the vaccine) that was confined to an allergic reaction to a previous dose of Pfizer’s COVID-19 vaccine or an ingredient in the vaccine: “You should not get the Pfizer/BioNTech COVID-19 vaccine if you had a severe allergic reaction after a previous dose of this vaccine [or] had a severe allergic reaction to any ingredients of this vaccine.” 13
The only other mention in the FDA Fact Sheet about allergic reactions was a recommendation to “tell the vaccination provider about all your medical conditions, including if you have any allergies” and this warning: 14
There is a remote chance that the Pfizer/BioNTech COVID-19 Vaccine could cause a severe allergic reaction. A severe allergic reaction would usually occur within a few minutes to one hour after getting a dose of the Pfizer/BioNTech COVID-19 Vaccine. Signs of a severe allergic reaction can include: • Difficulty breathing • Swelling of your face and throat • A fast heartbeat • A bad rash all over your body • Dizziness and weakness. These may not be all the possible side effects of the Pfizer/BioNTech COVID-19 Vaccine. Serious and unexpected side effects may occur. Pfizer/BioNTech COVID-19 Vaccine is still being studied in clinical trials.
The Hazards of Inequality and Racism
Beyond the inner layers, a wide range of external stressors also shape vulnerability to a virus such as SARS-CoV-2. As the pandemic has torn through the population of the U.S., it has taken an uneven toll. The CDC&rsquos mid-June analysis looked at 599,636 U.S. cases where race and ethnicity were reported. It found that 33 percent occurred in people of Latinx origin and 22 percent in Black people, even though these groups form, respectively, just 18 percent and 13 percent of the U.S. population. Some Native American groups, such as the Navajo, are also being hit tremendously hard. Mortality is disproportionate as well: Overall, Black Americans are dying at more than twice the rate of white people. In some states, their deaths occur at four or five times that rate.
Many factors contribute to this excessive toll, but they stem from the biased attitudes and actions of American society, not from Black American biology, says epidemiologist and family physician Camara Phyllis Jones of the Morehouse School of Medicine. &ldquoRace doesn&rsquot put you at higher risk. Racism puts you at higher risk,&rdquo says Jones, who is a past president of the American Public Health Association. &ldquoRacism puts you at higher risk through the two mechanisms of being more infected because we are more exposed and less protected, and then, once infected, we are more likely to have a very severe course and die.&rdquo
The higher risk of catching the virus comes both on the job and at home. An analysis conducted for Bloomberg found, for example, that only 19.7 percent of Black workers were in a position to work remotely during lockdowns, as opposed to 29.9 percent of white workers. A larger proportion of the jobs held by people of color are essential but low-paid ones. These are positions such as home health aide, grocery store worker, meatpacker, delivery worker and hospital orderly&mdashroles that require constant contact with the public or crowded conditions with co-workers, both of which lead to high exposure to the coronavirus. The jobs do not come with the protections, such as telecommuting, afforded to those in higher-paid positions. For such workers, Jones says, &ldquothe personal protective equipment has been very slow in coming.&rdquo
On top of that, she says, many people of color live in high-density, lower-income neighborhoods. &ldquoYou&rsquore in a one-bedroom apartment with five people living there, and one is your grandmother,&rdquo Jones relates. &ldquoYou can&rsquot safely isolate, so people are more exposed by family members who are frontline workers that have gone out and then bring the infection home.&rdquo In addition, compared with white Americans, a higher proportion of minority group members are held in prisons and sleep in homeless shelters, where infections spread quickly.
When people of color get the coronavirus, they are more at risk of becoming severely ill because they shoulder a greater burden of the chronic illnesses that can make COVID-19 more deadly. Black Americans, for example, suffer a 40 percent higher rate of hypertension and a 60 percent higher rate of diabetes than white Americans. Native Americans, meanwhile, are twice as likely to have diabetes as white Americans. Structural inequities&mdashsuch as neighborhoods that lack high-quality food options, the absence of safe places and leisure time to exercise, and poor air quality&mdashcontribute to these elevated levels of illness, noted Sherita Hill Golden, an endocrinologist at Johns Hopkins Medicine, at a May seminar on racial disparities and COVID-19.
Poorer access to medical care and discrimination within the health care system add to these burdens. As the pandemic got worse in early spring, many people of color had a hard time getting tested for COVID-19. &ldquoTesting sites were often located in more affluent neighborhoods,&rdquo Jones says. &ldquoOr there was drive-through testing. And what if you don&rsquot have a car?&rdquo
Golden points out that fear of immigration authorities and concerns about the Trump administration&rsquos new public charge rule&mdashwhich makes it difficult for people who use Medicaid to gain legal immigration status&mdashmight be leading undocumented individuals to &ldquoavoid using [health] services they might otherwise have used.&rdquo
Epidemiologists who study health inequities have found that lifelong stressors related to racial and ethnic discrimination take a direct toll on health. Ongoing elevated levels of stress hormones, such as cortisol and catecholamines, are thought to mediate this wear and tear and aggravate tissue damage. As a result, Black Americans tend to develop hypertension, glaucoma and some other aging-associated disorders earlier than white people do. The phenomenon has been termed &ldquoweathering&rdquo by Arline Geronimus, a professor of public health at the University of Michigan. Her research indicates that this premature aging cannot be explained by poverty and posits that it is the direct result of race-based injustice and bias.
As these and other COVID-19 risk factors become clearer, physicians and scientists say, health authorities need to shift resources and intensify protections for communities, groups and individuals who are most vulnerable. That effort has begun to happen in nursing homes, for example&mdash though only after tremendous losses of life. Diagnostic testing for the virus is one such resource. &ldquoWe know that there are communities at higher risk, and we need to be doing more testing there,&rdquo Jones says. And that means examining people without symptoms who are able to spread the virus without knowing they are infected. &ldquoIf we restrict ourselves to only testing people who are symptomatic,&rdquo she warns, &ldquowe will just be documenting the course of the pandemic, but we will lose the opportunity to change the course of the pandemic.&rdquo
On an individual level, people need to take stock of every layer of their own vulnerability, from the biological to the societal, and do what they can to mitigate hazards through pandemic-specific practices such as social distancing, mask wearing and avoiding crowds. (It is also important to try to maintain healthy habits, such as a good diet and regular exercise, although current circumstance can make doing so difficult.) At the same time, it is wise to remember that risk-group analyses reflect averages. An individual might have no obvious risk factors and still wind up desperately sick or dead. &ldquoThe only job of this virus is to replicate itself,&rdquo Jones points out. &ldquoIt will make its way through all the susceptibles that it can find.&rdquo
Read more about the coronavirus outbreak from Scientific American here. And read coverage from our international network of magazines here.