Asthma Immunology Quiz

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Questions and Answers

What is the primary function of alveolar macrophages?

To enhance airway inflammation

To produce antibodies

To release hypochlorous acid

To recognize and remove damaged cells (correct)

Which of the following mediators is associated with immunosuppression in asthmatic macrophages?

IL-10 (correct)

IL-12

IL-17

TNFα

What effect do reactive oxygen intermediates have in asthma?

They cause suppression of inflammatory responses

They are responsible for airway remodeling

They promote apoptosis of macrophages

They aid in antimicrobial defense and can lead to lung injury (correct)

Which cytokine is primarily pro-inflammatory and amplified by IFNγ?

TNFα Signup and view all the answers

Hypochlorous acid can cause damage to which type of tissue if released inappropriately?

Lung tissue Signup and view all the answers

What is primarily produced by activated B cells?

Antibodies Signup and view all the answers

What type of response does IL-17 primarily influence in asthmatic conditions?

Airway inflammation Signup and view all the answers

Which of the following effects is associated with nitric oxide in asthmatic macrophages?

Suppresses Th2 response Signup and view all the answers

What is the primary function of effector B cells (plasma cells)?

To secrete antibodies specific to an antigen Signup and view all the answers

Which cytokines are particularly influential in promoting isotype switching to IgE in B cells?

IL-4 and IL-13 Signup and view all the answers

What distinguishes eosinophilic asthma from neutrophilic asthma?

Type of infiltrating immune cells Signup and view all the answers

What role does isotype switching play in antibody production?

Modifies the constant region while maintaining antigen specificity Signup and view all the answers

How do corticosteroids affect asthma treatment?

They primarily serve as anti-inflammatory therapy for asthma Signup and view all the answers

What is the relationship between IgE levels and asthma prevalence in asthmatics?

Asthmatics can have significantly higher IgE levels than non-asthmatics Signup and view all the answers

What does the order of exons in isotype switching indicate?

The arrangement of heavy chain genes involved in antibody classes Signup and view all the answers

What is a characteristic feature of severe asthmatics who do not respond to corticosteroids?

Neutrophil infiltration in airways Signup and view all the answers

What causes bronchoconstriction in the context of mast cell degranulation?

Histamine Signup and view all the answers

Which receptors are associated with histamine and their respective G-proteins?

H1 - Gqα, H2 - Gsα, H3 - Giα, H4 - Giα Signup and view all the answers

Which type of leukotrienes are produced from arachidonic acid by 5-lipoxygenase?

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) Signup and view all the answers

What is the role of CysLT1 receptors in the respiratory system?

They mediate the effects of cysteinyl leukotrienes. Signup and view all the answers

Which of the following components is NOT released from mast cells during degranulation?

Eicosanoids Signup and view all the answers

What happens to the precursor form LTA4 during mast cell activation?

It is formed into LTB4 or cysteinyl leukotrienes. Signup and view all the answers

Which cytokines are commonly produced by mast cells that are involved in inflammation?

IL-4, IL-5, IL-13 Signup and view all the answers

What is the function of FLAP in relation to leukotriene synthesis?

It helps in the conversion of arachidonic acid into LTA4. Signup and view all the answers

Which pro-inflammatory cytokines are associated with causing steroid insensitivity?

IL-1β and TNFα Signup and view all the answers

What role does oxidative stress play in steroid insensitivity?

It contributes to the development of steroid insensitivity. Signup and view all the answers

Which of the following describes a mechanism contributing to corticosteroid insensitivity?

Up-regulation of Glucocorticoid Receptor β Signup and view all the answers

How do smoking and infection influence steroid insensitivity?

They are important factors in the disease state producing insensitivity. Signup and view all the answers

What effect does the combination of a glucocorticoid with a long-acting β2-adrenoceptor agonist (LABA) have according to the research?

It provides superior asthma control compared to glucocorticoid monotherapy. Signup and view all the answers

Which statement about the impact of multidrug resistance efflux pumps is correct?

They are involved in defective glucocorticoid receptor binding. Signup and view all the answers

What is the reported impact of using Symbicort and Advair in asthma and COPD treatment?

They improve symptom control and reduce exacerbation rates. Signup and view all the answers

What is a potential consequence of defective glucocorticoid receptor binding?

Reduced effectiveness of corticosteroid therapy. Signup and view all the answers

What enzyme does the eosinophil produce that converts 5-HETE into leukotriene A4?

5-LO Signup and view all the answers

Which type of T-lymphocyte is primarily responsible for coordinating immune responses?

Helper T-cells Signup and view all the answers

Which cytokines are primarily associated with a high Th2 response in allergic asthma?

Interleukin-4 and Interleukin-5 Signup and view all the answers

What is the primary role of eosinophils in the immune response?

Destruction of parasites Signup and view all the answers

What does the Th2 imbalance in asthma contribute to?

Allergic responses and asthma severity Signup and view all the answers

Which compound is known for its strong helminthotoxin effect in eosinophils?

Major basic protein (MBP) Signup and view all the answers

What receptor do leukotriene receptor antagonists primarily block?

CysLTR1 Signup and view all the answers

What is the correlation between the number of eosinophils and the severity of asthma?

Higher eosinophil counts correlate with increased severity Signup and view all the answers

Which of the following is NOT a function of eosinophil degranulation products?

Improve phagocytosis of bacteria Signup and view all the answers

Which mechanism is involved in bronchoconstriction due to eosinophil signaling?

Increased intracellular calcium levels Signup and view all the answers

What role does HDAC2 play in the effects of corticosteroids?

It is recruited to promoters of inflammatory genes. Signup and view all the answers

Why can't nGREs fully explain the anti-inflammatory effects of corticosteroids?

Only a few genes possess nGREs and are not pro-inflammatory. Signup and view all the answers

What effect does acetylation of histone tails have on gene transcription?

It increases gene transcription. Signup and view all the answers

What is the implication of genomic analysis regarding the presence of nGREs?

Only a small number of genes have nGREs. Signup and view all the answers

What is suggested by microarray profiling regarding corticosteroids?

Corticosteroids can induce hundreds of genes with anti-inflammatory potential. Signup and view all the answers

Which statement about negative glucocorticoid response elements (nGREs) is accurate?

They can overlap binding sites of essential transcription machinery. Signup and view all the answers

What is the primary function of corticosteroids as indicated in the content?

Recruiting transcription factors to downregulate inflammatory genes. Signup and view all the answers

Which of the following cytokines is NOT mentioned in the context presented?

IL-10 Signup and view all the answers

Study Notes

Asthma

Asthma is a chronic inflammatory condition of the airways.
The cause of asthma is not completely understood.
Inflammation causes airways to be hyper-responsive and narrow easily.
Symptoms include coughing, wheezing, chest tightness, and shortness of breath.
Nighttime symptoms are often worse.
Airway narrowing is usually reversible but can be irreversible in some.
Pathological features include inflammatory cells, plasma exudation, edema, smooth muscle hypertrophy, mucus plugging, and epithelial shedding.
These changes can be present even with few symptoms.

Asthma Definition(s)

British Thoracic Society (1993): A common, chronic inflammatory condition of the airways, hyper-responsive to stimuli, potentially resulting in coughing, wheezing, chest tightness, and shortness of breath, frequently worse at night. Inflammation can cause irreversible airflow obstruction in some.
Global Initiative for Asthma (GINA) (2006): A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, associated with airway hyperresponsiveness leading to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable airflow obstruction within the lung.
Global Initiative for Asthma (GINA) (2015): A heterogeneous disease, usually characterized by chronic airway inflammation. Defined by respiratory symptoms like wheezing, shortness of breath, chest tightness and cough varying in intensity and time alongside variable expiratory airflow limitation.

Asthma Timeline

460-370 BC: Hippocrates of Kos described breathlessness and many lung diseases.
1698 AD: Sir John Foyer described "asthma", classifying it as "periodic" and "continued."
1892 AD: Sir William Osler noted bronchial asthma as a specific form of inflammation in the small bronchioles.
1960 AD: Dunnill et al fully described airway inflammation in patients who died from acute asthma. Post-1960 definitions increasingly emphasized inflammation even in asymptomatic states.

Asthma Stratification

Asthma is a heterogeneous disease with diverse forms (phenotypes).
Severity stratification is one approach. Key characteristics are:
- Intermittent: Symptoms <2 days/week, nocturnal awakenings <2 times/month.
- Mild Persistent: Symptoms >2 days/week but not daily, nocturnal awakenings 3-4 times/month, not more than 1 time/day.
- Moderate Persistent: Symptoms daily, nocturnal awakenings >1 time/week.
- Severe Persistent: Symptoms throughout the day, exacerbations frequent leading to severe limitation of activity.

Asthma Phenotypes

Allergic Asthma: Typically begins in childhood, often linked to allergic diseases like eczema, allergic rhinitis, and food/drug allergies. Eosinophilic airway inflammation is often seen in induced sputum. Generally responds to inhaled corticosteroids.
Non-allergic Asthma: Asthma not associated with allergy. Cellular profiles of sputum can be neutrophilic, eosinophilic, or paucigranulocytic. Patients may respond less well to inhaled corticosteroids.
Late-onset Asthma: Asthma developing first in adulthood. Typically non-allergic and may require higher doses of ICS. Or may be relatively refractory to corticosteroid treatment.
Asthma with fixed airflow limitation: Long-standing severe asthma, with fixed airflow limitation attributed to airway wall remodeling.
Asthma with obesity: Asthma with prominent respiratory symptoms, but minimal eosinophilic airway inflammation.

Asthma Prevalence

Asthma prevalence is likely underestimated due to lack of clear definition and underreporting of milder forms.
Globally, asthma affects millions of people, and is increasing.
Rates increase as communities adopt western lifestyles and become urbanized.

Asthma Burden

Asthma is one of the most common chronic diseases worldwide, with an estimated 300 million affected.
Increasingly prevalent amongst both children and adults globally.
Western lifestyles, urbanization, estimated increase in urban population projection likely to significantly increase asthma burden in the future (100 million additional cases by 2025).
Asthma accounts for approximately 1 in 250 deaths worldwide. Preventable deaths due to suboptimal long-term care and delayed help-seeking.

Normal Lung Physiology

Lung structure with details about conducting and respiratory zones, as well as alveolar structures.
Diagram demonstrating the respiratory zone and important anatomical elements such as the trachea, bronchi, bronchioles, and terminal respiratory bronchioles.

Asthmatic Lung Physiology

Normal versus asthmatic airway anatomy and function and how that may change during an asthma attack, with high magnification to note altered lung tissue.

Immunology - Lines of Defence

First line of defense: Physical (e.g., skin, mucous membranes) and chemical barriers.
Second line of defense: Innate immune system (e.g., phagocytes, complement system).
Third line of defense: Adaptive immune system (e.g., lymphocytes, antibodies).

Innate Immune System

Cells such as: Macrophages, Dendritic cells, Mast cells, Natural killer cells, complement protein, Basophils, Eosinophils, and Granulocytes.

Adaptive Immune System

Cells such as: B cells, T cells, and antigen presenting cells.

Inflammation

Calor (heat), Rubor (redness), Tumor (swelling), Dolor (pain)- symptoms of inflammation.
Inflammation is a critical process response to damage or pathogen.

Inflammation in Asthma

Different forms of asthma include mild/moderate Asthma and Severe/Refractory Asthma.
Distinct immune cells & key mediators (eosinophils, neutrophils, macrophages, CD4+ T cells. IL-4, IL-5, IL-13, IL-8, Nitric Oxide).
Different location of inflammation in the airways, including proximal and peripheral airways and the possible impact on the epithelium.
Response to therapy differs for both forms, including response to inhaled corticosteroids.

Cascades in Allergic/Atopic Asthma

Inflammatory cascade triggered by allergens/irritants, leading to mast cell activation and the release of mediators, including eosinophils, T lymphocytes and CD4+ TH2 cells.
This cascade results in bronchoconstriction and airway hyper-responsiveness. Inflammation leads to reversible airflow limitation.
Graph demonstrating increased manifestations over time following allergen exposure.

Activators of Asthma Exacerbations

A variety of factors triggers exacerbations, including, but not limited to: viruses, bacteria, fungi, pollen, dust mites, Cockroach, indoor allergens, irritants, occupational chemical exposures, air pollution, and cigarette smoke.

Immunopathology

The study of the interplay of the immune system in pathology/disease.

Epithelial Cell

The epithelium is the first line of contact for inhaled pathogens and irritants.
It plays a crucial role in asthma pathogenesis, and directly impacts how patients respond to inhaled therapies.
The beating of cilia and the presence of mucus-producing goblet cells, function to clear inhaled particles from the airway. Epithelial injury, loss of cilia, and mucus hypersecretion are all associated with asthma.

Airway Smooth Muscle

Smooth muscle plays a role in regulating airway diameter via muscle contraction and relaxation.
Receptors, including GPCRs, regulate this process.

Bronchoconstriction

Airway constriction is a prominent feature of asthma. It is triggered by a number of factors. Activation of smooth muscle is initiated by a variety of mechanisms with significant implications for airway function.

The Asthmatic Airway Smooth Muscle

The asthmatic airway smooth muscle shows enhanced contraction, and impaired relaxation functions.
Increased airway smooth muscle mass and wall thickening characterize this form of the disease.
Exposure to inflammatory mediators leads to further downstream implications for tissue inflammation.

The Mast/Basophil Cell

Mast/basophil cells, embedded within the smooth muscle layers of the airway wall release a variety of products and are tightly connected to asthma.
During degranulation they release mediators like histamine, leukotrienes, prostaglandins, and cytokines.

The Mast/Basophil Cell (input/output)

The input to mast cells includes multiple factors relevant to asthma immunopathology, including adaptive responses to antigen, and antigen-independent components.
The output products of mast cell activation are key mediators of asthma inflammatory responses as outlined in previous sections.

Histamine

Histamine, a cell-derived mediator, acts on various receptors. H1, H2, H3, and H4 receptors are linked to different Gprotein subunits to affect various functions.

Leukotrienes

Leukotrienes are derived from arachidonic acid precursor, functioning as inflammatory mediators.
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are important mediators in asthma.

Signaling via Gq

The signaling pathway illustrates how ligands like histamine or leukotrienes activate secondary signaling events leading to bronchoconstriction.

The T-lymphocyte

T cells are part of the adaptive immune response which vary in function and are important in asthma.
There are different subtypes of T lymphocytes that coordinate different functions and are important aspects of asthma. Including helper T cells, Cytotoxic, and Regulatory T cells.

The T helper lymphocyte

Different types of T cells, in particular, TH1, TH2 and TH17 cells are implicated in asthma.
Each TH cell subtype produces numerous cytokines that coordinate various inflammatory or immune responses.

The Th2 imbalance in asthma

An imbalance towards TH2 cells is believed to drive asthma. Possible environmental factors contributing to this imbalance are reviewed and discussed.
A range of factors impact the development and expression of this imbalance, including exposure to a range of pathogens and allergens.
Possible reasons for the tendency toward a TH2 imbalance have led to the "hygiene hypothesis".

Th2 cytokines

Key Th2 cytokines (IL-4, IL-5, IL-9, IL-13) initiate and propagate the Th2 response.
These cytokines influence and play key roles in the pathology/biology of asthma, directly impact the airway's structure and function.

Eosinophils

Eosinophils are a type of immune cell relevant in asthma which were originally understood to primarily defend against parasitic infection. These cells now contribute toward the inflammatory processes observed in asthma.
They are associated with, and key components of, the inflammatory cascade that perpetuates asthma.

Eosinophil degranulation products

Eosinophil degranulation releases various proteins. Eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) have roles in inflammation and tissue damage.

The Alveolar Macrophage

Alveolar macrophages are professional phagocytes in the lungs.
Maintaining lung health by removing pathogens and cellular debris in the lung tissues. They are critically important in asthma, and their functional activity influenced by inflammation or immune response.

The Asthmatic Macrophage - a double edged sword

Alveolar macrophages can be both pro-inflammatory and anti-inflammatory in asthma. Both positive and negative impacts of macrophages exist in the disease progression.

Activated B cells

Activated B cells, differentiation to antibody-secreting effector cells, produce antibodies (especially IgE) that target allergens in asthma.
An antibody response is elicited upon exposure to an allergen.

Antibodies

Antibodies are proteins produced by B cells, including immunoglobulins.
Different types of immunoglobulins with varying functions in immune responses. Including but not limited to IgE, IgG, IgM, IgA, and IgD.

The B-Lymphocyte in Asthma

B cells, in particular, IgE production, is closely associated with asthma and allergic diseases.
The production and function of antibodies is a critical aspect in asthma.

Severe Neutrophilic Asthma

Features of severe neutrophilic asthma contrasted with mild and moderate forms of asthma.

Overview - Immunopathology

An overall summary emphasizing the different cell types and their contributions to asthma, and the impact on the airways, mucus production, and inflammation. An overview emphasizing the importance of immunopathology in the pathogenesis of asthma.

Treating Inflammation - Corticosteroids

Corticosteroids are a cornerstone therapy for asthma treatment.
Reducing chronic inflammation is an important aspect of treating asthma, and corticosteroids are important in controlling many of the symptoms and mediators.

Corticosteroids/glucocorticoids

A class of drugs that exert a critical anti-inflammatory response.
Various formulations can be used in the treatment of asthma, and have roles in treating other inflammatory diseases. Such as the treatment of allergic rhinitis.

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is a critical pathway in the endocrine system. Key hormones relevant to stress response, inflammation, and immune response and directly impacted by corticosteroids.

A Brief History of Corticosteroids

A brief overview of the time course of understanding and developing/deploying inhaled corticosteroids in asthma treatment.

Common Side Effects of Corticosteroids

Potential adverse/negative effects associated with broad anti-inflammatory therapy, including but not limited to: adrenal suppression, growth suppression, dysphonia, bruising, oro-pharyngeal candidiasis, osteoporosis, cataracts, glaucoma, and psychiatric disturbances.

Nuclear Hormone Receptors

Nuclear hormone receptors that directly regulate gene expression. A discussion of various receptors and important signaling cascades..
. A comparison and contrast of relevant structures and functions.

The Glucocorticoid Receptor Signalling Pathway

A description of the signaling pathways related to corticosteroids as outlined in various parts of the text.

Transactivation Vs Transrepression

Mechanisms of glucocorticoid action in transactivation versus transrepression. Different pathways and resultant cellular effects of corticosteroids are highlighted.

Negative Glucocorticoid Response Elements

Negative glucocorticoid response elements (nGREs) and their role in potentially influencing the effects of negative corticosteroid responses, even if these effects are complex and not always clearly defined.

The HDAC Hypothesis

Outline the roles of acetylation and deacetylation of histones in regulating gene transcription, and how corticosteroids may affect this to impact immune function.

HDAC2 and the Transrepression Effects of Corticosteroids

A description of the mechanisms by which HDAC2, a critical enzyme for deacetylation, function in suppressing inflammation, and specifically in the pathways of corticosteroid mechanisms.

Evidence for Corticosteroid Inducibile Genes as Anti-inflammatory Mediators

Data highlighting the relationship between corticosteroids, gene expression and anti-inflammatory effects within the lung. Methods and evidence are outlined to support this data with emphasis on the impact of corticosteroids to elicit an anti-inflammatory response.

Corticosteroids and Redundancy

The complexities of corticosteroid effects, noting redundancy in downstream systems that may not be directly impacted by corticosteroids is described. Additional information may be presented as to how these systems might function in a manner that is not completely understood, but can potentially impact treatment response.

Do anti-inflammatory genes require 'classical' transactivation?

Different possibilities as to the types of transactivation mechanisms used in differing cell types and the potential implications for treatment.

Corticosteroid Insensitivity vs Resistance

A delineation of the potential ways in which corticosteroids may or may not be effective. Factors influencing corticosteroid efficacy are discussed.

What Causes Steroid Insensitivity?

Multiple factors influencing steroid insensitivity are analyzed. This includes cytokines, oxidative stress, viral infections, and factors that help balance immune function in the lungs.

What are the molecular mechanisms?

Important mechanisms for steroid insensitivity include, but are not limited to: upregulation of the dominant-negative GRβ, inhibition of HDAC2, downregulation of glucocorticoid-dependent transcription, defective glucocorticoid receptor binding, changes in the balance of lymphocytes, and multidrug resistance efflux. These can act independently or in combination.

Enhancing Corticosteroid Potency and Efficacy – LABAS and PDE Inhibitors.

A description of how combining LABAs and PDE inhibitors can further enhance corticosteroid efficacy and may potentially lower the required dose needed to obtain a beneficial therapeutic effect.
Methods and data are reviewed to evaluate whether adding additional treatment strategies may impact the efficacy of corticosteroids.

Take Home Message

A concise, overarching recap summarizing the complexity of steroid activity, especially as it relates to diverse pathways in the regulation of immunity within the lung.

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Description

Test your knowledge on the immunological aspects of asthma, including the roles of various cells, cytokines, and mediators involved in this condition. This quiz covers topics such as alveolar macrophages, B cells, and cytokine responses. Challenge yourself and deepen your understanding of asthma's complex immune responses.