Type I Hypersensitivity & Asthma

• The following are study notes, based on the information provided

Type I Hypersensitivity Response & Asthma

• Atopic individuals' immune systems react abnormally to harmless airborne allergens
• Allergens include pollen, dust mites, and animal dander
• Antigen-presenting cells (APCs) capture allergens in the respiratory mucosa

Sensitization Phase (Initial Exposure)

• APCs present allergen to naïve CD4+ T cells, which become T-helper 2 (Th2) cells
• Th2 cells secrete cytokines, IL-4 & IL-13 promotes IgE production in B cells for specific allergens
• IL-5 recruits and activates eosinophils
• IgE antibodies bind to FcεRI receptors on mast cells, sensitizing them for future allergen exposure

Early Phase Reaction (Subsequent Exposures)

• Re-exposure causes inhaled allergens to cross-link IgE on mast cells, triggering degranulation
• Mast cells release histamine, prostaglandins, leukotrienes, and cytokines
• Release leads to bronchoconstriction via smooth muscle contraction
• Increased vascular permeability causes airway edema
• Increased mucus secretion contributes to airway obstruction

Late Phase Reaction (Sustained Inflammation)

• Eosinophils and other immune cells (neutrophils, basophils) are recruited to airways via Th2 cytokines (IL-5)
• Eosinophils degranulate, releasing toxic proteins like major basic protein and eosinophilic cationic protein
• Release causes epithelial cell damage and increased airway hyperresponsiveness
• Chronic inflammation and remodeling of the airway can result in smooth muscle hypertrophy and fibrosis

Clinical Manifestations of Asthma

• Recurrent episodes of wheezing, dyspnea, chest tightness, and coughing occur, especially at night or after allergen exposure
• Airway hyperresponsiveness makes the bronchi sensitive to triggers
• Reversible airway obstruction can be relieved with bronchodilators like β2-agonists
• Untreated chronic inflammation can lead to irreversible airway remodeling and persistent asthma

Factors Causing Airway Obstruction During Asthma

• Bronchoconstriction is triggered by mast cell degranulation (histamine, leukotrienes, prostaglandins)
• Airway edema arises from increased vascular permeability, leading to swelling of the airway lining
• Excess mucus production occurs as goblet cells secrete thick mucus that obstructs airways
• Airway hyperresponsiveness means smooth muscle contraction narrows the bronchi

Late Phase Response of Asthma Exacerbation

• The response occurs 4-12 hours after the initial response
• Involves persistent inflammation due to recruitment of eosinophils, T cells, and basophils
• Cytokines (IL-5, IL-4, IL-13) sustain airway hyperresponsiveness and epithelial damage
• Increased mucus secretion further obstructs airflow
• Bronchial remodeling begins with fibrosis and smooth muscle hypertrophy

Chronic Changes in Asthma

• Airway remodeling involves thickening of the airway walls
• Goblet cell hyperplasia leads to excessive mucus secretion
• Smooth muscle hypertrophy and hyperplasia contribute to chronic bronchoconstriction
• Fibrosis and collagen deposition stiffens the airways, reducing their ability to dilate
• Persistent eosinophilic inflammation occurs, even in symptom-free periods

Alpha-1 Antitrypsin Deficiency & Emphysema

• Alpha-1 antitrypsin (AAT) normally inhibits neutrophil elastase, which breaks down elastin in lung tissue
• A deficiency leads to uncontrolled elastase activity, degrading alveolar walls
• Results in loss of alveolar elasticity, leading to permanent air trapping and hyperinflation

Causes of Hypoxemia in Emphysema

• Destruction of alveolar walls reduces surface area for gas exchange
• Loss of capillary networks decreases oxygen diffusion
• Ventilation-perfusion mismatch (V/Q mismatch) occurs if poorly ventilated alveoli lead to low oxygen and CO2 retention
• Air trapping and hyperinflation reduce alveolar ventilation, leading to CO2 buildup

Increased Chest Diameter in Emphysema

• Air trapping and hyperinflation cause lung overdistension
• Flattening of the diaphragm forces reliance on accessory muscles
• Prolonged lung expansion leads to a barrel chest appearance

Impact of Smoking on COPD

• Smoking damages cilia, leading to chronic inflammation and mucus hypersecretion (chronic bronchitis)
• Smoke exposure increases neutrophil elastase activity, leading to alveolar destruction (emphysema)

Differentiation of Chronic Bronchitis and Emphysema

• Chronic bronchitis presents with chronic productive cough, cyanosis (blue bloater), and recurrent infections
• Emphysema presents with dyspnea, barrel chest (pink puffer), and weight loss

Increased Risk of Respiratory Infections

• Individuals with chronic bronchitis are prone to developing respiratory infections
• Mucus hypersecretion traps bacteria and viruses
• Ciliary dysfunction impairs mucus clearance
• Airway inflammation provides an ideal environment for bacterial growth

COPD & Right Ventricular Failure

• Chronic hypoxemia leads to pulmonary vasoconstriction (hypoxic pulmonary hypertension)
• Increased afterload on the right ventricle causes hypertrophy and failure
• Results in cor pulmonale (right heart failure due to lung disease)

Underlying Cause of Cystic Fibrosis

• Cystic Fibrosis (CF) arises from a mutation in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator)
• Defective chloride ion transport leads to thick, sticky mucus in airways and other organs
• Impaired mucociliary clearance causes chronic infections and lung damage

Genetics of Cystic Fibrosis

• CF is autosomal recessive, meaning both parents must be carriers (heterozygous)
• There is a 25% probability of an affected child if both parents are carriers

Respiratory Issues in Cystic Fibrosis

• Severe airway obstruction due to mucus plugging
• Respiratory infections (Pseudomonas, Staphylococcus aureus, Burkholderia cepacia)
• Acute respiratory failure, bronchiectasis, and hemoptysis can occur

Malnutrition & Weight Loss in Cystic Fibrosis

• Pancreatic enzyme deficiency leads to malabsorption of fats and proteins
• Thick mucus blocks pancreatic ducts, preventing digestive enzyme secretion
• Increased metabolic demand due to chronic lung infections

Diabetes in Cystic Fibrosis

• Cystic Fibrosis-related diabetes (CFRD) occurs due to pancreatic damage
• Fibrosis of the pancreas destroys insulin-producing β-cells

Sterility in Males with CF

• Congenital bilateral absence of the vas deferens (CBAVD)
• The vas deferens fails to develop due to mucus obstruction in fetal development
• Sperm production is normal, but sperm transport is blocked

Genetic Clotting Disorders

• Summarized patient information regarding a 26-year-old male
• He developed blood clots in superficial and deep veins of the lower leg after a non-traumatic fall

Factor V Leiden Mutation

• Cause: F5 gene mutation causes resistance to degradation by activated Protein C
• The mutation leads to prolonged clot formation
• Inheritance: Autosomal dominant
• Risk of Clots: Heterozygous carriers (5-10x increased risk of VTE), homozygous individuals (50-80x increased risk)
• Common complications: Deep vein thrombosis (DVT), pulmonary embolism (PE), increased risk during pregnancy and surgery

Protein C Deficiency

• Cause: Mutation causes resistance to degradation by activated Protein C
• The mutation leads to prolonged clot formation
• Inheritance: Autosomal dominant
• Risk of Clots: Heterozygous carriers (5-10x increased risk of VTE), homozygous individuals (50-80x increased risk)
• Common complications: Deep vein thrombosis (DVT), pulmonary embolism (PE), increased risk during pregnancy and surgery

Additional Clotting Disorders

• Cerebral venous thrombosis (CVT) involves clot formation in brain veins
• May lead to stroke-like symptoms
• Arterial thrombosis can cause myocardial infarctions or ischemic strokes
• Superficial thrombophlebitis involves clots in superficial veins and is often painful
• Recurrent pregnancy loss can be due to clotting in placental vessels

Pregnancy Risks of Factor V Leiden

• Increased risk of miscarriage due to placental thrombosis
• Preeclampsia and intrauterine growth restriction is due to reduced placental blood flow
• Higher risk of deep vein thrombosis (DVT) occurs during pregnancy and postpartum
• Management involves low-molecular-weight heparin (LMWH) as recommended

Assessing VTE Risk on a Post-operative Unit

• Immobility slows venous return, increasing clot risk
• Surgical trauma activates clotting factors
• Inflammation from the post-op inflammatory response can promote clot formation
• Dehydration increases blood viscosity
• Use of central lines or catheters can trigger clotting

Venous Thromboembolism

• Genetic mutations (Factor V Leiden, Protein C/S deficiency)
• Immobility (bed rest, long flights, paralysis)
• Obesity (increased venous stasis)
• Pregnancy and postpartum period (hormonal changes)
• Smoking (endothelial damage)
• Oral contraceptives/Hormone therapy (increased coagulation factors)
• Cancer (tumor cells can activate clotting pathways)

Pathophysiology of Pulmonary Embolism Consequences

• Hypoxemia and respiratory acidosis
• Increased risk of miscarriage due to placental thrombosis
• Preeclampsia and intrauterine growth restriction from reduced placental blood flow
• A higher risk of deep vein thrombosis (DVT) during pregnancy and postpartum. Management involves low-molecular-weight heparin (LMWH)
• PE releases inflammatory mediators (thromboxane A2, serotonin) that constrict bronchi, worsening hypoxemia
• Increased capillary permeability due to endothelial injury leads to fluid leakage into alveoli, resulting in pulmonary edema

Hemodynamic Consequences of Massive PE

• Pulmonary hypertension occurs due to increased resistance in pulmonary arteries
• Right ventricular strain/failure leads to acute cor pulmonale
• Decreased cardiac output occurs due to reduced left ventricular filling
• Shock and sudden death can occur if the clot is large

Respiratory Defense Mechanisms

• Mucociliary clearance traps and removes pathogens
• Alveolar macrophages engulf bacteria
• The cough reflex expels irritants
• Secretory IgA and defensins prevent microbial adhesion

Populations at Risk for Pneumonia

• Elderly individuals and those who are immunocompromised
• Chronic lung disease increases risks, along with post-surgical and hospitalized patients
• Alcoholics and smokers whose cilia are weakened

Factors Increasing Pneumonia Risk

• Decreased immune function and a weak cough reflex increases risk in the elderly
• Pre-existing lung disease makes individuals more prone
• Malnutrition and delayed diagnosis due to atypical symptoms can raise risks

Bacterial Pneumonia causing Hypoxemia

• Alveolar filling with exudate impairs gas exchange
• Shunting occurs if blood bypasses ventilated alveoli
• V/Q mismatch occurs in some alveoli receiving no ventilation

Factors Leading to Lung Consolidation on Chest X-Ray

• Inflammatory exudate fills alveoli
• Accumulation of bacteria and debris cause radiographic opacities
• Neutrophil infiltration thickens lung tissue and fibrin deposits solidify lung segments

Differences Between Pneumonias

• Bacterial pneumonia affects alveoli, causing exudative consolidation, neutrophil-dominant inflammation, and a higher likelihood of pleural effusion
• Viral pneumonia affects interstitial spaces, causes a lymphocyte-dominant response, and has more diffuse bilateral infiltrates

Joint Function

• Articular cartilage is made of hyaline cartilage and its major function is to reduce friction between articulating bones
• The meniscus in the knee is made of fibrocartilage and helps to cushion the join and stabilize the knee
• The function of the synovial fluid is to lubricate the joint, reduce friction, and provide nutrients to the cartilage.
• The synovial membrane secretes the synovial fluid
• The subchondral bone lies beneath the joint cartilage
• The main cells in cartilage are called chondrocytes
• The cartilaginous matrix is composed of collagen fibers and proteoglycans

Osteoarthritis Risks

• Repetitive joint stress and microtrauma accelerate cartilage wear
• High-impact movements cause increased joint loading, leading to cartilage breakdown
• Joint instability from previous injuries contributes to early-onset OA

Enzymatic Degradation of Cartilage in Osteoarthritis

• Chondrocytes release pro-inflammatory cytokines (IL-1, TNF-α) when stressed
• Cytokines stimulate matrix metalloproteinases (MMPs), which degrade collagen, and proteoglycans
• Loss of proteoglycans reduces cartilage resilience, leading to softening and fissures
• Chondrocyte apoptosis diminishes cartilage repair ability

Pathological Features of Osteoarthritis

• Fibrillations: Early cartilage degradation leads to superficial cracks and fraying
• Osteophytes: Bone responds to cartilage loss by forming bone spurs, which limit movement and cause pain
• Osteoarthritic cysts: Synovial fluid penetrates subchondral bone, forming fluid-filled cavities
• Synovitis: Inflammation of the synovial membrane occurs to release cartilage debris and cytokines

Lumbar Vertebral Osteophytes

• Nerve impingement leads to radiculopathy (sciatica) or numbness/weakness
• Limited spinal flexibility occurs, along with chronic lower back pain

Osteoarthritis Joint Pain

• Subchondral bone exposure causes pain due to bone-on-bone contact
• Inflammatory mediators irritate nerve endings
• Joint effusion (swelling) increases pressure within the joint capsule
• Muscle weakness and joint instability increase mechanical stress

Rheumatoid Arthritis

• Anti-cyclic citrullinated peptides (anti-CCPs) are autoantibodies that attack citrullinated proteins
• Rheumatoid factors (RFs) are IgM antibodies that bind to self-IgG, triggering synovial inflammation
• RANKL is overexpressed in RA and activates osteoclasts, leading to bone resorption

Pannus

• Pannus is an abnormal fibrovascular tissue over cartilage
• Includes macrophages, fibroblasts, and inflammatory cells and releases MMPs and cytokines
• Leads to cartilage destruction and bone erosion

Rheumatoid Arthritis Features

• Symmetric polyarthritis is an autoimmune attack occurring on bilateral joints
• A positive rheumatoid factor (RF) indicates immune complexes in the blood
• Anti-CCP is a specific marker, along with morning stiffness due to inflammatory joint swelling
• Joint deformities such as swan neck deformity, boutonniere deformity, and ulnar deviation

Causes of Gout

• Overproduction of uric acid is due to genetic mutations and excessive dietary intake of purine-rich foods
• Decreased excretion of uric acid results from kidney dysfunction and chronic dehydration

Tissue Injury Seen in Gout

• Urate crystals deposit in joints, triggering an inflammatory response
• Neutrophils ingest urate crystals, releasing inflammatory mediators, leading to joint inflammation (pain, swelling, redness, and warmth)

Gout Lead to Renal Failure

• Crystal deposition in renal tubules damages kidney function
• Recurrent inflammation leads to fibrosis and scarring
• Nephropathy progresses to chronic renal failure

Biological Factors of Fibromyalgia

• Central Sensitization causes increased excitability of neurons in the central nervous system (CNS)
• Amplified pain signals occur and dysregulated Pain Modulation causes decreased activity of pain-inhibiting pathways
• Neurotransmitter Imbalance is from increased substance P (pain perception)
• Low serotonin and norepinephrine (reduced pain inhibition) and glutamate excess (excitotoxicity and chronic pain) occur
• HPA Axis Dysfunction and blunted cortisol responses lead to poor stress adaptation
• Abnormal Sleep Patterns are characterised by a lack of deep sleep and worsen pain and fatigue

Depression & Fibromyalgia

• Shared Neurotransmitter Deficiencies are what makes low levels of serotonin and norepinephrine contribute to both conditions
• Chronic Pain from Psychological Distress: Persistent pain leads to emotional exhaustion, anxiety, and depression
• HPA Axis Dysfunction reduces cortisol levels, impairing stress resilience
• Disrupted Sleep Patterns: Poorer sleep causes mood disturbances and depression

Estrogen Deficiency

• Estrogen normally inhibits osteoclast activity by reducing RANKL expression and increasing osteoprotegerin (OPG)
• After menopause, increased osteoporosis leads to excessive osteoclast activity
• OPG levels decrease, reducing bone protection
• Bone resorption exceeds formation, leading to bone loss
• Oxidative stress damages osteoblasts and inflammatory cytokines promote osteoclast activity

Testosterone Deficiency

• Testosterone is a precursor for estrogen, which protects bone via aromatization, which when low leads to
• Reduced osteoblast activity, lower bone formation and increased osteoclast activity due to decreased estrogen levels
• Muscle atrophy occurs, resulting in weaker bones
• Low Calcium & Vitamin D weakens bones and causes High Phosphorus impairs calcium absorption

Osteoporosis & Diet

• Excessive Alcohol inhibits osteoblasts, reducing calcium absorption
• High Sodium Intake promotes calcium excretion while low protein diets cause decreased collagen synthesis
• Excessive Caffeine interferes with calcium absorption

Prednisone & Osteoporosis

• Glucocorticoids Inhibit Osteoblast Activity which suppresses bone formation
• Increased Bone Resorption upregulates RANKL which also reduces Calcium Absorption & Excretion
• This results in decreased intestinal absorption of calcium, which causes increased renal excretion, leading to negative calcium

RANKL/RANK/OPG in Osteoporosis

• RANKL - produced by osteoblasts and binds to RANK receptors on osteoclast precursors
• This stimulates osteoclast differentiation
• The OPG Osteoprotegerin acts a decoy receptor which prevents this
• Osteoporosis when ↑ RANKL / ↓ OPG balance leads to excessive bone resorption
• Estrogen deficit increases OPG and surprises RANKL

Iron Deficiency Anemia

• Required for hemoglobin (Hgb) synthesis, which is essential for oxygen transport in red blood cells (RBCs)
• Without sufficient iron, RBCs become microcytic (small) and hypochromic (pale), reducing their oxygen-carrying capacity

High Risk Populations

• Infants and young children due to high iron demand for growth and inadequate dietary intake
• Pregnant women, increased iron demand due to fetal development
• Menstruating women who experience blood loss during menstruation
• Individuals with chronic blood loss from GI ulcers, malignancies, or heavy menstrual bleeding
• Vegetarians and vegans consume less heme iron while elderly may suffer deficiencies

Iron Deficiency Laboraroty Values

• Hgb and Ferritin (the most critical test) and decreased MCH, MCV indicate low iron
• TIBC is high
• Following treatment reticulocyte increases

Thalassemia Trait

• Genetic mutation in a- or ß-globin chains leads to abnormal hemoglobin synthesis
• RBCs are microcytic and hypochromic, similar to IDA

Thalassemia ferratin

• Causes ineffective erythropoiesis (increased iron absorption in the gut)
• Transfusions cause hemochromatosis which cause complications through iron overload

Differences between Anemia

• Iron deficiency Hgb is low
• Thalassemia - LOW MCV
• IDA - Ferritin is low

Risk of Nutritional Anemia

• Older due to low B12
• Vegans - B12 is primary found (crohns' or celiac)
• Folate deficiency Pregnant women =increased demand

Folate Deficiency

• Causes folate to be used up more rapidly
• B12 takes years

Hemolysis of Erthrocytes

• Increased bilirubin
• Increased haemoglobin/haemoglobinuria increased reticuloid count

Autoimmune Anemia

• Autoantibodies bind RBCs, which is either IgM or igG

G6PD

• Inapbilty of red blood cells to hand oxidative stress

SC Genetics

• Autosomal Ressecive disorder caused by mutation In the BETA Chain Globin

SCD Causes

• Abnormal hemoglobin
• Cells become rigid

SICKLE CELL CRISIES

• Sickles rbc's block blood vessles that causs severs pain and organ damage
• Aplastis due to parvovirus B infection surpressed bone merror - can casue pallor or Fatique

Haemolytic

• Increased billirubin

Homeophelia

• Is caused by a generic disorder in the factor 8 gene Is an x link receciv genetic mutstion cauinf factor 8 defiency This disripts colagulatoin cascade

Willebrad Factor

• Stabilized factor 8
• Deficiencies means platelets fail so cant coagulate

Thrombocatypenic Porperea

• Follow viral ifections in children BInd to surge antigen that destriys platelet

Causes of TTP

A dam13 can cleave and a defiency will cause clotting Excessive platke agrigatoisn leads to end organ danage

Uremic Synfrome

• Kidney Damage - causes brain damage Petechia and pulpura due to plate detruction

Causes of TPT

• Microvascluar destruciton in platelets causes bleeding Microagropathiv hemoytics occurs and causes bilirubin

Shiga toxin

• Causes damage to endolithiel cells of children