This has reduced the global differences in prevalence; however, the global burden of asthma and allergies continues to rise, and new therapies are warranted [ 3 , 4 ]. Interestingly, negative associations are found between the prevalence of allergic asthma and growing up on traditional European farms or rural tropical areas, usually exposed to higher ambient concentrations of microbial pollutants or higher rates of parasitic infections [ 5 , 6 ].
Currently used medication against asthma is aimed at symptom relieve and does not restore this immune disbalance. As a consequence, treatment is chronic and sometimes resulting in severe side effects. New therapies should focus on reducing inflammatory responses against allergens at an early age preventing the onset of structural damage and changes to the lungs, by targeting natural tolerizing mechanisms as found in healthy individuals.
In this review, we will focus on one of these mechanisms and describe the potential of inducing IgA responses by modulation of dendritic cell function and controlling unwanted allergic responses. Allergic asthma is a chronic inflammation of the airways controlled by effector Th2 cells and characterized by eosinophilic airway inflammation and high levels of allergen-specific IgE antibodies, hallmarks of a persistent Th2 response [ 2 ] Figure 3 a. Upon encounter with the allergen, effector responses can be divided into immediate and late phase reactions.
The immediate allergic inflammatory reaction is initiated by crosslinking of IgE molecules which are bound to IgE receptors on basophils and mast cells. This immediate reaction may be followed by the late phase response, initiated by inflammatory cytokines and type 2 cytokines, such as IL-4, IL-5, Il-9, and IL, which recruit and activate eosinophils and basophils and induce gobleT-Cell metaplasia and overproduction of mucus [ 11 , 12 ].
In severe forms of asthma, also Th17 cells are found, which enhance the effects of the Th2 cytokines and recruit neutrophils and other inflammatory leukocytes [ 13 — 15 ]. In addition to distortion of immunological pathways during allergen sensitization and challenge, also aberrant structural airway remodeling is involved in the development of asthma. Some groups have even suggested that the airway structural changes occur before the deranged immune response is present.
Indeed, basement membrane thickening is detectable in children younger than three years old with persistent wheezing before the diagnosis of asthma [ 16 , 17 ]. Airway remodeling includes marked changes in the airway wall, like epithelial injury, extracellular matrix deposition under the epithelial basal membrane, gobleT-Cell hyperplasia, and increased smooth muscle mass. These changes lead to a defective physical and functional barrier of the airway epithelium in severe asthma.
Dendritic cells DCs play a crucial role in the described processes leading to asthma pathogenesis Figure 3 a. Immature DCs reside in peripheral and mucosal tissues, such as the lungs, where they continuously sample the environment for foreign soluble antigens and small particles, including inhaled allergens [ 20 , 21 ]. DCs express different types of pattern recognition receptors PRRs , such as toll-like receptors TLRs , NOD-like receptors, and C-type lectin receptors, that allow the recognition of different classes of molecules broadly shared by pathogens pathogen-associated molecular patterns PAMPs [ 22 , 23 ].
Various studies have demonstrated that DCs are necessary for inducing allergic sensitization [ 27 ], for driving the development of Th2 immunity and eosinophilia [ 28 — 30 ], and are crucial for maintaining the inflammatory processes in the airways as well as bronchial hyperreactivity and chronic airway remodeling [ 31 , 32 ]. After allergen uptake, the function of DCs is strongly influenced by signals encountered during their stay in the peripheral tissues, which can include microbial signals induced by the ligation of pattern recognition receptors PRRs on the DCs or alarming signals from structural cells like local epithelial cells of the airways [ 33 — 35 ].
Crosstalk between airway epithelial cells and DCs may form a critical link for the induction and continuation of allergic inflammation in the lungs as several EC-derived molecules can influence DC migration, differentiation, and function [ 20 , 33 , 36 ].
In healthy individuals, T-cell responses to allergens are commonly observed, yet are usually dominated by anergy or by regulatory T Treg cells that can suppress various effector Th cell subsets [ 37 , 38 ]. In almost all patients with asthma, one can find the counterregulatory Treg cells, but these fail to or insufficiently suppress allergic inflammation [ 39 ].
It has therefore been suggested that asthma may result from aberrant of defective Treg mechanisms. Humoral responses of healthy individuals consist of mainly low IgG1, IgG4, and secretory IgA sIgA antibodies to allergens in the presence or absence of low amounts of IgE [ 37 , 40 , 41 ].
Although the presence of allergen-specific IgA has drawn relatively little attention so far, it is still unclear what its relative role is in the protection or exacerbation of allergic disease [ 42 ]. Although most individuals with immunoglobulin A IgA deficiency are asymptomatic, allergic disorders appear to be more common among patients with IgA deficiency [ 43 ].
Indeed, Balzar et al. In contrast, high salivary secretory IgA levels were associated with less development of allergic symptoms in sensitized Swedish children [ 45 ]. Furthermore, high levels of specific IgA antibodies in salivary of sensitized infants were associated with significantly less late-onset wheezing [ 46 ].
Moreover, in an experimental setting, Schwarze was able to protect mice against the development of eosinophilic airway inflammation and hyperresponsiveness by treating with antigen-specific IgA during challenge [ 48 ]. Taken together, these data show an inverse relationship between IgA and allergy development, suggesting a protective role for IgA in allergic diseases such as asthma. The antibody IgA can occur as a monomer Figures 1 a and 1 b , but also in dimeric or even polymeric forms through interactions with the joining chain J-chain Figure 1 c.
All these different forms are mainly found in the circulation, while secretory IgA sIgA is only found at mucosal surfaces and is generated by the binding of dimeric IgA via the J-chain to the polymeric immunoglobulin receptor pIgR at the basolateral side of the epithelium which is subsequently transported to the luminal side Figures 1 d and 1 e. Here, IgA is released at the mucosal surface lumen by cleavage from the pIgR.
Mouse and human IgA biology differ in several aspects. In human serum, IgA occurs mainly in a monomeric form, while in mice polymeric IgA is the main isotype in serum. Furthermore, human IgA, but not mouse IgA, is divided into closely related subclasses, IgA1 and IgA2, of which the later one is less susceptible for proteolytic degradation Figures 1 a and 1 b. The consequences after ligation are not very clear for most of these receptors. Intriguingly, this receptor has not been identified in mice.
Although this receptor is associated with an immunoreceptor tyrosine-based activation motifs ITAM , its signaling can be activating as well as inhibitory. In contrast, IgA complexes show a stronger binding and subsequent activating signal, resulting in cell activation [ 52 , 53 ].
IgA is classically known for neutralizing toxins and bacteria viruses at mucosal surfaces [ 54 , 55 ], by interfering with their motility, by competing for epithelial adhesion sites, and by improving the viscoelastic properties of the airway secretions [ 56 ].
Interestingly, it has been suggested that IgA can also directly reduce inflammatory responses by inhibiting effector functions of inflammatory cells. Triggering ITAMi signaling also prevented marked inflammation and leukocyte infiltration in kidney inflammation models such as glomerulonephritis [ 59 ].
Furthermore, it can competitively block the IgG-mediated activation of complement [ 8 , 65 ]. Of note, a few specific diseases are associated with an increase in serum IgA levels, often paralleled by IgA tissue deposition [ 66 ]. In IgA nephropathy, the formation of aggregated IgA immune complexes in the kidney causes severe inflammatory responses [ 67 , 68 ].
However, there are indications that in these patients, glycosylation e. Collectively, these data suggest that under homeostatic conditions, secretory IgA contributes to the maintenance of mucosal tolerance by dampening immune responses.
Therefore, IgA can have a role in preventing the development of hyperinflammatory responses towards environmental allergens that otherwise could cause allergic inflammation as observed in allergic rhinitis or asthma.
Humoral responses in the mouse are mediated by at least three different subpopulations of mature B cells. These B cells can acquire the expression of various antibody isotypes, including IgA, by undergoing class switch recombination CSR.
Nonfollicular B cells, such as the splenic marginal zone B cells and the B-1 cells, which are mostly enriched in the peritoneal and pleural cavity and the lamina propria of the small and large intestines, primarily respond to T-cell-independent antigens and secrete natural or polyspecific antibodies [ 73 ].
The alternative TI pathway occurs locally at effector sites and is a much faster mechanism to generate IgA. These IgA costimulatory factors can be produced by both resident epithelial cells of mucosal organs and by local DCs. It is increasingly clear that gut IgA-producing B cells can be both generated from follicular B cells or the B-1 cells by complementary pathways, requiring different signals to undergo IgA switching which links back to their capacity to respond to TD or TI antigens.
Interestingly, B-1 cells can switch to all immunoglobulins in vitro , while in vivo studies with SCID mice or irradiated mice reconstituted with bone marrow or peritoneal cavity cells have suggested that B-1 cells preferentially switch to IgA [ 77 , 78 ], where they accounted for most of the gut IgA plasma cells.
However, studies in gnotobiotic allotype Ig chimeric mice allowing the distinction between Abs derived from B1 and B2 cells based on different allotypes suggested that in normal immunocompetent mice intestinal B-2 cells contributed for most of the IgA found in the gut in response to gut bacteria [ 79 ].
Importantly, also in the respiratory tract and their draining lymph nodes local B-1 cells have been demonstrated [ 80 ]; however, the respective role of B-1 or follicular B cells in the production of IgA has not been studied yet.
The relative role of B-1 versus B-2 cells in IgA-mediated immunity is reviewed elsewhere [ 72 ]. Shifting the allergen-specific antibody response from IgE to IgA2 would result in neutralization of allergen in the mucosal lumen, before it could interact with IgE, and could therefore constitute a therapeutic target. As the main RA producing subset, they are also responsible for imprinting gut-homing molecules on B cells and support IgA synthesis [ 74 ]. How these DCs acquire their tolerogenic properties is not yet fully understood, but a role for microbial activation was suggested [ 88 , 89 ].
The use of CD11b as a marker for lung DCs is however confusing, as CD11b is not only found on a subset of conventional c DCs, but also on the population of monocyte-derived DCs moDCs that are recruited to the lungs at times of inflammation [ 91 ]. In addition to the conventional mouse DC subsets which drive IgA synthesis and are portrayed in the previous paragraph, also a plasmacytoid p DC subset has been described [ 92 ].
Altogether DCs form a crucial cell type in the differentiation of IgA responses. Although by different mechanisms, both cDCs and pDCs can promote Ig responses, and their IgA inducing capacity can be enhanced by local factors produced by mucosal tissues as well as by local microbial products such as TLR ligands. The establishment of commensal flora in the intestine, and most likely also the respiratory tract [ 96 ], starts at birth and is considered to be crucial for stimulating and directing the development of the host immune system.
Animals raised under germ-free conditions have an undeveloped immune system with fewer germinal centers and decreased number of IgA-producing plasma cells [ 97 ]. Interestingly, gut microbiota is necessary for a protective immune system, including mucosal IgA responses, in the airways. In response to OVA, germ-free GF mice developed more severe features of airway inflammation compared to control specific pathogen free SPF mice, which could be reversed by recolonization of GF mice with complex commensal flora.
Furthermore, the absence of commensal bacteria was associated with less pDCs and attenuated production of IgA in the airways [ 98 ]. Human studies have also suggested the link between commensals and allergy. Indeed, children who developed allergy had significantly less diverse gut microbiota and lower levels of salivary SIgA [ 99 ], while, intestinal colonization by Staphylococcus aureus was associated with high circulating IgA levels and with a lower frequency of eczema [ ].
Several mouse and human studies have shown that early life prenatal, preconception exposure to environments characterized by a diverse and concentrated microbial milieu such as traditional farming sites may protect against the development of allergic diseases [ — ]. A rich microbial environment contributes to mucosal tolerance and protective IgA responses, which are associated with protection against allergic asthma.
The ideal candidate for an adjuvant stimulating protective IgA responses and thereby preventing development of allergic asthma could therefore be a microbial-derived molecule. Cholera toxin is the most widely experimentally used mucosal adjuvant, potentiating serum and local immune responses to coadministered antigens [ ].
The enterotoxin Cholera Toxin is produced by the bacterium Vibrio cholerae and consists of an A and B subunit, each with distinct effects on cells of the immune system. The A subunit is known for its toxic side effects: after entering the cell cytosol, the A subunit triggers electrolyte efflux via activation of adenylate cyclase and increased cyclic AMP cAMP production, resulting in severe watery diarrhea.
The B subunit of CT CTB is more considered as a nontoxic subunit, as it is not linked to the activation of cAMP and its adjuvant activity seems to be mainly associated with immunoregulatory events [ , ].
For example, feeding of CTB conjugated to myelin basic protein before or after disease induction protected rats from experimental autoimmune encephalomyelitis [ ], and nasal administration of CTB insulin significantly delayed incidence of spontaneous diabetes in NOD mice [ ].
The tolerizing effect of CTB has also been shown to extend to other immune- mediated diseases. In a delayed type hypersensitivity model, prolonged oral treatment with low doses of OVA conjugated to CTB prevented sensitization and suppressed IgE antibody responses in sensitized mice [ ]. Furthermore, intranasal pretreatment of CTB linked to the BetV1, a major allergen of birch pollen, prevented sensitization to the antigen by shifting the Th2 response towards Th1 and the induction of allergen-specific IgA responses [ ].
Likewise, we found that CTB administration in the lungs stimulates local secretory IgA responses which protected against the development of allergic airway inflammation AAI , while mice deficient for polymeric Ig receptor pIgR and lacking SIgA were not [ ]. LPS is a known trigger of moDC recruitment [ ]. Until we have more specific depleting antibodies or transgenic mouse strains to selectively deplete moDCs, we can however only speculate at this stage whether this is true.
If we are to exploit the full potential of IgA as an immunomodulatory immunoglobulin in allergic asthma and other immune mediated diseases, the role of different DC subsets in the regulation of humoral IgA responses and modulation by adjuvants should be studied in more detail. Allergen-specific immunotherapy SIT represents the only curative treatment of allergic diseases currently available and involves the incremental delivery of the allergen to which the individual is sensitive [ ].
Successful IT components of the regulatory network such as Treg cells and the cytokine IL are elevated, while allergen-specific IgE levels are reduced. It is hypothesized that the enhanced immunoregulatory network is instrumental in suppressing allergen-specific effector T cells which are responsible for many of the characteristics of allergic diseases. IL does not only contribute to T-Cell tolerance but also potently suppresses total and allergen-specific IgE, and it simultaneously increases IgG4 and IgA production in cultures [ , ].
Interestingly, successful immunotherapy is also associated with increases in IgA responses in vivo. In its current form, SIT has major drawbacks and cannot compete with treatment on the basis of symptom relief antihistamines and corticosteroids for many asthma patients. This introduces a risk of potentially life-threatening allergic reactions [ ].
For example, when the allergen is coupled to the adjuvant CTB, it will be efficiently targeted to the DC [ ], allowing the use of lower allergen doses and decreasing the risk of anaphylactic shocks.
The establishment of commensal flora in the intestine and respiratory tract starts at birth and is considered to be crucial for stimulating and directing the development of the host immune system, including the mucosal IgA response [ 97 , , ]. In our in vitro coculture system, we confirmed the role for microbial-derived TLR ligands in the conditioning of DCs for stimulating IgA responses.
This is interesting considering the hypothesis that decreased or altered microbial exposure associated with an affluent life style is contributing to the increase in asthma prevalence during the last decades.
Only recently we have started to appreciate the importance of the microbiota on human health, and restoring or manipulating disrupted host-microbiota relationship has become a potent strategy for treating inflammatory diseases, including asthma [ ]. CTB could contribute to broad antibody repertoire and sufficient mucosal IgA levels in people with impaired or delayed IgA synthesis, by reducing the threshold for microbial signals or providing the necessary cosignals, to maintain mucosal immunity and local homeostasis Figure 3.
It was shown that children who developed allergy had less diverse gut and airway microbiota [ 99 ] and decreased serum or mucosal IgA responses [ 45 , 46 , ] compared to healthy controls.
Studies that measured IgA levels at different time points showed an increase over time which may be due to microbial exposure and microbiota development [ 45 , ]. Indeed, in a cohort of adult allergic asthmatic patients, we did not find reduced secretory IgA levels in nasal washes compared to nonallergic controls Gloudemans et al. Alternatively, in a fraction of the allergic infants with a slowly developing mucosal IgA repertoire, allergy symptoms may relieve together with the establishment of a fully developed IgA response.
Thus, one should keep in mind that the association between IgA and asthma may be misinterpreted using an adult cohort. The effector function of IgA is very much depending on local inflammatory factors present and needs to be carefully examined before applying IgA enhancing therapy.
For example, IgA immune complexes bind with stronger affinity, subsequently resulting in cell activation and elimination of the pathogen [ 52 , 53 ]. In certain cases, IgA complexes can even cause severe inflammation and pathology, like in immune complex glomerulonephritis [ 68 , ]. Therefore, also in severe asthma, where in addition to eosinophils also neutrophils are important mediators, IgA may aggravate the inflammation instead of promoting tolerance. In addition to the isoform of IgA and local tissue factors, reactivity or specificity of the antibody will determine the receptor binding affinity and thus the immunological effect of Ig-receptor ligation.
Primitive or polyreactive natural IgA antibodies are sufficient to protect the host from excess mucosal immune stimulation by harmless commensal bacteria and may protect against some noninvasive parasites [ , ]. However, affinity maturation of IgA is necessary to provide protection from more invasive commensal bacteria and from true pathogens. However, it still remains unclear how this applies for environmental particles in the lung, such as inhaled allergens.
Therefore, to evaluate the efficacy of IgA-based treatment against allergic diseases, not only the level of mucosal IgA responses need to be carefully studied in health and disease, but also aspects such as the affinity and reactivity of the antibodies should be taken into account.
Although local IgA induction during specific immunotherapy may have potential to improve the treatment of allergic airway inflammation, based on the dynamics of the development of IgA responses in life and the functional duality of the IgA-receptor interaction, it seems essential to stimulate IgA responses under noninflammatory conditions.
Gloudemans et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Gloudemans, 1,2 Bart N. Lambrecht, 1,3 and Hermelijn H. Academic Editor: Mohamad Mohty. Received 31 Jan Revised 15 Mar Accepted 16 Mar Published 11 Apr Abstract Allergic asthma is characterized by bronchial hyperresponsiveness, a defective barrier function, and eosinophilic lower airway inflammation in response to allergens.
Introduction Allergic asthma is a major health problem worldwide, causing episodes of wheezing, coughing, and breathlessness in susceptible individuals after repeated inhalation of harmless environmental allergens, such as house-dust mites HDMs , molds, plant pollen, and animal dander [ 1 , 2 ].
Immune Responses against Allergens 2. Inflammatory Reactions against Inhaled Allergens in Allergic Asthma: Th2 Cells and IgE Allergic asthma is a chronic inflammation of the airways controlled by effector Th2 cells and characterized by eosinophilic airway inflammation and high levels of allergen-specific IgE antibodies, hallmarks of a persistent Th2 response [ 2 ] Figure 3 a. Immunoglobulin A Antibodies and Its Functions 3. Isoforms and Receptors The antibody IgA can occur as a monomer Figures 1 a and 1 b , but also in dimeric or even polymeric forms through interactions with the joining chain J-chain Figure 1 c.
Figure 1. Human IgA structure. Figure 2. Figure 3. Crosstalk between epithelial cells and dendritic cells DCs in the lungs determines the balance between immunity and tolerance. References P. Pearce, N. Beasley et al. Smits, B. Everts, F. Hartgers, and M. Schaub, R. Lauener, and E. Woof and M. Dullaers, B. De, F. Ramadani, H.
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Stress the importance of smoking cessation. Urge patients to receive annual vaccinations, as asthma increases the risk of complications from respiratory diseases, such as pneumonia and influenza. Selected references Asthma overview. American Academy of Allergy Asthma and Immunology. Corbridge S, Corbridge TC. Asthma in adolescents and adults.
Am J Nurs. Fanta CH. Treatment of acute exacerbation of asthma in adults. Last updated February 5, Global Initiative for Asthma. Updated Kaufman G. Asthma: pathophysiology, diagnosis and management. Nurs Stand. National Asthma Education and Prevention Program. Section 2: Definition, pathophysiology and pathogenesis of asthma and natural history of asthma.
Pruitt B, Lawson R. Assessing and managing asthma: a Global Initiative for Asthma update. Shari J. Four years ago I experienced a severe breathing problems. I came across Herbal HealthPoint ww w. I immediately started on the COPD treatment; i began to notice a reduction in symptoms till it all vanished. I feel better and breath better.
I Just wanted to share for people suffering from this horrible lungs disease. My son has asthma because he has been complaining of chest tightness whenever our cat is around. Save my name, email, and website in this browser for the next time I comment. Powered by www. No part of this website or publication may be reproduced, stored, or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the copyright holder.
American Nurse American Nurse. Sign in. Forgot your password? Get help. Create an account. Password recovery. Home Clinical Topics Asthma Understanding asthma pathophysiology, diagnosis, and management. Clinical Topics Asthma Features. Understanding asthma pathophysiology, diagnosis, and management. July 7, Pathophysiology Understanding asthma pathophysiology helps you understand how the condition is diagnosed and treated.
Classifying asthma Asthma may be atopic, nonatopic, or a combination. Atopic asthma begins in childhood and is linked to triggers that initiate wheezing. It may arise after exposure and response to a specific allergen, such as dust mites, grass or tree pollen, pet dander, smoke, or certain drugs or foods.
On exposure to a trigger, excessive release of IgE occurs, which initiates B-lymphocyte activation. IgE binds to cells related to inflammation. Women who smoke during pregnancy may predispose their unborn children to higher IgE levels, causing hyperresponsiveness and asthma development.
Exposure to pollution may have the same effect. It may have fewer obvious triggers and usually occurs in adults, possibly secondary to a viral infection. Diagnosis Asthma diagnosis goes beyond symptoms, such as coughing, chest tightness, wheezing, and dyspnea—and even beyond signs and symptoms that worsen at night and improve after treatment. Management Asthma management involves both acute and long-term treatment. Rescue quick-relief drugs Meant for short-term symptom relief, rescue drugs cause bronchodilation and are used mainly to prevent or treat an asthma attack.
Ipratropium bromide, an anticholinergic, may be given in combination with short-acting beta2-agonists in some cases.
Beta2-agonists used for quick relief include albuterol, levalbuterol, metaproterenol, and terbutaline. Long-term use can lead to high blood pressure, muscle weakness, cataracts, osteoporosis, decreased ability to resist infection, and reduced growth in children.
Long-term control agents Used to prevent asthma attacks and control chronic symptoms, these agents include inhaled corticosteroids, leukotriene modifiers, long-acting beta-agonists LABAs , theophylline, and combination inhalers that contain both a corticosteroid and an LABA. Patient education Patient education is crucial in asthma management. Asthma assessment tips.
J Nurse Pract.
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