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Questions and Answers
What role do dendritic cells play in the allergic activation pathway?
Which cytokines are primarily stimulated by T cells during the allergic activation pathway?
What is the result of the interaction between B cells and mast cells in an allergic response?
What is the main function of mast cells in the allergic response?
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What triggers the non-allergic activation pathway?
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What is the primary characteristic of asthma as a disease?
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What does FEV1 measure in asthma physiology?
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What happens to FEV1 in individuals with eosinophilic asthma?
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Which type of inflammation is primarily mediated by eosinophils in asthma?
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What is measured through spirometry in regard to asthma?
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Which of the following statements about basement membrane thickening in asthma is correct?
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Eosinophils in asthma can be activated through which pathways?
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In healthy lungs, what percentage of FVC is typically covered by FEV1?
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What happens when the integrity of the epithelium is compromised?
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Which of the following best describes an agonist?
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What is a key characteristic of medications considered to be effective?
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How do drugs typically exert their therapeutic effects in the body?
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What is the function of antagonists in pharmacology?
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Why is atropine considered effective as a therapeutic agent?
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What defines a medication as convenient?
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What is a primary benefit of low-risk medications?
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What is the primary role of monoclonal antibodies in treating allergic conditions?
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Which of the following symptoms is characteristic of gastroenteritis?
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Which phase of allergic rhinitis occurs approximately 4-8 hours after allergen exposure?
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How does climate change primarily affect asthma triggers?
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Which immune response is characterized as broad and rapid but short-lived?
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What is the primary mechanism by which Salmonella enterica causes disease?
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Which component is essential for the diagnosis of asthma?
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What distinguishes pathogenic microbes from beneficial ones in the gut?
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Which treatment is commonly utilized for gastroenteritis?
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In what way can the immune system cause damage during gastroenteritis?
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What is a common trait of non-typhoidal Salmonella serovars?
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What signifies the adaptive immune response's potential?
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Which symptom is NOT commonly associated with an allergic response?
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What benefit does the microbiota provide in the immune response within the gut?
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What is primarily affected by mitochondrial diseases?
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Which of the following is NOT a clinical presentation of mitochondrial disease?
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What are mitochondrial diseases often caused by?
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Which type of mutation is often linked to childhood-onset mitochondrial diseases?
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What is characteristic of Primary Mitochondrial Disease (PMD)?
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Which of these methods is currently considered the gold standard for mitochondrial disease diagnosis?
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What is a possible outcome of an impaired electron transport chain?
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Which of the following is true regarding mitochondrial disease classification?
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What kind of conditions may a patient with mitochondrial disease experience?
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What is an example of a symptom associated with myopathy?
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Which biochemical test is commonly used to hint at mitochondrial dysfunction?
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What is a common feature of mitochondrial diseases regarding their inheritance?
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What type of muscle condition can result from mitochondrial dysfunction?
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Study Notes
Asthma Physiology
- Asthma is a disease of the conducting airways of the lung that causes variable airflow obstruction
- Asthma involves inflammation and wall remodeling, including thickening of the basement membrane
- Airflow obstruction in asthma can be measured by spirometry, which measures the lung's performance during breathing
- Spirometric measurements include Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 second (FEV1)
- People with healthy lungs have an FEV1 of around 70-80% or more of the FVC
- People with asthma have a reduced airflow on expiration (breathing out)
- FEV1 reduced to ~250 is often associated with eosinophilic asthma
Allergic and Non-Allergic Activation Pathways
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Allergic Activation Pathway:
- Allergens are inhaled and land on the respiratory epithelium
- Dendritic cells pick up the allergens and present them to naive T cells in the airway submucosa
- This stimulation leads to the release of cytokines IL4 and IL13, which induce B cells to produce IGE
- The B cells bind to mast cells, which become allergen receptors
- Mast cells contain histamine and other mediators that constrict airway smooth muscle and increase mucus secretion
- Mast cells and T-cells also release IL5, which recruits eosinophils to the airway
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Non-Allergic Activation Pathway:
- Fungi or other pollutants (cigarette smoke) can activate the non-specific/innate immune system
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Epithelial Barrier Hypothesis:
- Damage to the epithelium allows greater entry of microorganisms and triggers inflammatory responses that contribute to asthma symptoms
Pharmacology and Treatment of Asthma
- Effective drugs have a therapeutic action for the specific condition they are indicated for.
- Convenient drugs are easy to use, like a once-a-day tablet.
- Well-tolerated drugs have manageable side effects.
- Safe drugs have a low risk of toxicity or drug allergy.
- Drugs are not too expensive.
- Medicines bind to proteins called receptors.
- Agonists stimulate receptor protein function.
- Antagonists bind to the receptor protein but do not stimulate function, effectively preventing action.
Drugs as Medicines
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Examples of plant-derived medicines (drugs) include atropine, which is an antagonist of muscarinic receptors.
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Atropine prevents the action of acetylcholine, a naturally occurring agonist of muscarinic receptors.
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Acetylcholine can cause muscle spasms, so atropine is useful as a therapy for muscle spasms.### Allergic Rhinitis and Asthma
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Allergic rhinitis is an inflammation of the nose caused by allergen inhalation.
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Allergic rhinitis has an early and late-phase response, the initial allergic response is caused by IgE crosslinking and degranulation leading to oedema.
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Allergic rhinitis late-phase response occurs 4-8 hours after exposure and causes nasal congestion.
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Repeated exposure to allergens leads to a priming effect, increasing the severity of the response.
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Diagnosis of allergic rhinitis can be achieved through clinical history, aeroallergen skin prick testing, and specific IgE testing.
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Allergic rhinitis treatment includes allergen avoidance, intranasal corticosteroids, and patient education on thunderstorm asthma, especially for people sensitive to rye grass pollen.
Asthma
- Asthma is caused by triggers such as infections, allergens, and irritants.
- Asthma symptoms include recurrent wheeze and breathlessness that respond to beta agonist (salbutamol).
- Asthma diagnosis uses clinical history and lung function testing to confirm the diagnosis.
- Asthma is managed using preventers, such as inhaled corticosteroids to suppress airway inflammation.
- Asthma relievers are used as needed to relax airway smooth muscle.
- Advanced asthma treatments target IgE and eosinophilic inflammation with monoclonal antibodies.
- Effective asthma care includes medication adherence and avoidance of known triggers.
Climate Change and Asthma
- Climate change impacts aeroallergen concentration by increasing air temperatures and CO2 concentrations, leading to increased pollen production and longer pollen seasons.
- Climate change increases the frequency of extreme weather events, including flooding and tropical cyclones, which can cause mold growth in homes.
- Climate change increases thunderstorm frequency.
- Climate change leads to greater exposure to aeroallergens, increasing sensitization rates and the frequency of epidemic events.
- Climate change impact is predicted to lead to similar environmental conditions in major cities.
The Gastrointestinal Tract and Microbes
- The gastrointestinal (GI) tract is part of the digestive system, extending from the mouth to the large intestines and bowels.
- The GI tract is an open tube that is exposed to the external environment, making it susceptible to microbial entry.
- The GI tract plays a crucial role in absorbing nutrients and fluids.
- Different sections of the GI tract are specialized for the uptake of specific components:
- Esophagus
- Small intestine: absorbing mainly nutrients
- Large intestine: absorbing fluids
- The GI tract is lined with mucosal tissue that helps to select and regulate the entry and uptake of external components.
- The immune system plays a role in the GI tract by recognizing and responding to potential threats.
- The two arms of the immune system:
- Innate immunity: broad, short-lived, but rapid response.
- Adaptive immunity: specific, with memory, but takes time to respond.
- Maintaining a balance in immune responses is crucial for the gut's health, involving the microbiome and trained immunity.
Good and Bad Microbes in the Gut
- The gut microbiome is composed of a diverse population of microbes with varying impacts on the host.
- Some microbes reside in the gut and help with digestion.
- Other microbes can cause damage to the host.
- Harmful microbes need to find a favorable niche to thrive without being eliminated by host defenses.
Pathogenic Traits of Microbes
- Pathogenic microbes possess traits that allow them to colonize new areas, antagonize host defenses, and facilitate the spread of other microbes.
- These pathogenic traits include:
- Promoting colonization in sterile locations like urine or blood.
- Antagonizing host defenses, preventing them from functioning correctly.
- Facilitating the spread of other microbes.
- Most pathogenic microbes require a range of virulence factors:
- Needles to inject genetic material or proteins into host cells, taking control of cellular machinery.
- Production of different proteins that inhibit the function of immune cells.
Gastroenteritis
- Gastroenteritis is an inflammation of the gastrointestinal tract, characterized by symptoms such as diarrhea, vomiting, abdominal cramping, and fever in cases of infection.
- Gastroenteritis causes fluid loss, and treatment mainly involves rehydration therapy.
- Most cases of gastroenteritis are self-limiting, but access to resources for rehydration therapy can be crucial, especially in disadvantaged countries.
- Gastroenteritis can be categorized as infectious or non-infectious:
- Infectious gastroenteritis is caused by microorganisms that damage the host or produce toxins that disrupt cellular mechanisms.
- Non-infectious gastroenteritis is caused by an overreaction of the host's immune system, leading to damage.
Inflammation and the Gut
- Inflammation is a natural response to injury or infection, characterized by the five cardinal signs: heat, redness, swelling, pain, and loss of function.
- While inflammation helps with immune responses, excessive inflammation can cause damage to the gut lining.
- Excessive inflammation leads to the release of inflammatory molecules that cause blood vessel dilation, disrupt tight junctions between cells, and promote fluid leakage from blood into interstitial spaces, resulting in swelling.
- Chronic inflammation can lead to the formation of a "leaky gut", making it easier for substances to enter and exit the gut.
Salmonella Enterica: Disease and Host Immunity
- Salmonella enterica is a faecal-orally transmitted bacterial pathogen, considered a major food safety risk, particularly from undercooked poultry.
- Salmonella enterica comprises over 2500 subgroups known as serovars, causing infections in both humans and animals.
- Salmonella enterica serovars associated with human infections can be grouped into two categories:
- Human-restricted serovars (Typhi, ParatyphiA):
- Have no Animal Hosts
- Cause enteric fever (typhoid and paratyphoid fever, respectively).
- Non-typhoidal Salmonella (NTS) serovars (Typhimurium, Enteritidis):
- Have a broad host range, including meat-producing animals, and can be transmitted between humans and animals.
- Cause gastroenteritis and Invasive NTS (iNTS).
- Human-restricted serovars (Typhi, ParatyphiA):
Salmonella Infection Progression
- Salmonella infection begins with ingestion through contaminated food or water, entering the small intestine.
- Salmonella initially resides in the gut lumen:
- Competes for space and resources with the normal gut flora.
- Depletes oxygen in the anaerobic environment.
- Utilizes the lumen as an extracellular niche for growth.
- Interactions with other gut flora can influence disease pathology.
- Some Salmonella are excreted in feces, potentially contaminating food and water and infecting others.
- Some Salmonella remain in the gut and proliferate, eventually breaching the epithelial lining:
- They may actively infect M cells and gain access to the internal face of gut epithelial cells.
- They may express specific virulence factors to infect epithelial cells.
- They may be passively captured by macrophages or dendritic cells.
- Crossing the gut barrier is a crucial step in the infection process.
- Once Salmonella crosses the barrier, it travels to local draining lymph nodes and enters the bloodstream, causing sepsis and disseminating to other tissues (spleen, liver, bone marrow, gallbladder).
- Salmonella invasion of these normally sterile sites is essential for systemic dissemination.
- Salmonella predominantly grows in an intracellular niche (Salmonella-containing vacuole - SCV) of infected cells, providing a physical barrier against host immune detection.
- Salmonella infection is controlled by various host immune cells.
Immune Response to Salmonella
- The specific recognition mechanisms of Salmonella by the immune system highlight the distinct roles of innate and adaptive immunity.
Mitochondrial Disease (Mito)
- Long-term, genetic, often inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly
- Disease of energy production: Problems from ETC or other components
- Genetically and clinically heterogeneous: two mutations in the same gene can present with different clinical presentations → Poses a clinical challenge
- Any or all tissues can be affected.
- Mutations in > 280 nuclear genes (or even mitochondrial mutations) linked to mitochondrial disease
- Affects 1 in 5,000 live births
- Severe condition in children (often fatal)
- Currently, there is a lack of effective treatments or therapies
- Mutations leading to Mito:
- Inherited from parents
- Happen for the first time in a child (de novo mutations): during embryogenesis
Clinical Features of Mito
- Affect tissues that are heavily reliant on oxidative metabolism, including:
- The central nervous system
- Peripheral nerves, eye
- Skeletal and cardiac muscle
- Endocrine organs
- Many individuals with Mito have a multi-system disorder that often involves skeletal muscle and the central nervous system, but some individuals have a disorder that only affects one organ system
Clinical Presentations of Mito
- Encephalopathy: disorder or disease of the brain
- Neuropathies: nerve damage/dysfunction
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‘Stroke-like’ episodes: ischemia (loss of blood flow)
- convulsions, visual abnormalities, numbness, hemiplegia (weakness on one side of body), and aphasia (language impairment)
- Myoclonic epilepsy: seizures, involving uncontrolled muscle contractions or twitching
- Ataxia: loss of muscle coordination (neurological)
- Dystonia: sustained muscle contractions (twisting, spasms etc, neurological)
- Myopathy: disease of the muscle, resulting in weakness
- Deafness and Blindness
- Lactic acidosis: anaerobic glucose metabolism → increase in blood lactate and decrease in pH
- Cardiomyopathy: disease of the heart muscle that makes it harder for your heart to pump blood to the rest of your body
Mito Onset
- Childhood-onset mitochondrial diseases can be linked to both mitochondrial and nuclear mutations
- Adult-onset mutations are often linked to mitochondrial mutations
Classification of Mito
- Many other genes/processes (transcription, translation) / proteins (import) if mutations / not working properly are linked to mitochondrial diseases
- Primary mitochondrial disease (PMD): genes with a primary link to the function of the electron transport chain (including mtDNA mutations)
- Secondary mitochondrial disease (SMD): genes with an indirect function on the electron transport chain, or linked to another mitochondrial function
Mitochondrial Disease Diagnosis
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Biochemical tests*
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Blood and urine samples as a first step: measurements of lactate and pyruvate in plasma, cerebrospinal fluid (CSF) and urine, measuring specific amino and organic acids → Hint perturbations / disturbances in metabolism → Can be a reflection of dysfunctional mitochondria and mito
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Additional tests may be included: neuroimaging, electromyography (EMG) to measure muscle activity, and nerve conduction studies (NCS)
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Genetic studies of mitochondrial and nuclear DNA*
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Replace muscle biopsies as the gold standard for diagnosis
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Very specific: identify mutations in a particular gene
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Expensive → requires a good deal of evidence that the cause of symptoms is mitochondrial
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Things to consider:*
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Clinicians are using muscle and tissue biopsies less frequently for mitochondrial diagnosis because these tests may not be as comprehensive as genetic testing and may not be well tolerated by mitochondrial disease patients
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PMD and SMD cannot be differentiated with laboratory tissue testing alone
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Functional tests (evaluations of how mitochondria are functioning in cells) remain important measures of mitochondrial function.
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