Anatomy & Physiology · 2026–27 Flashcards

Three shelf-like projections (superior, middle, inferior) on the lateral walls of the nasal cavity that create turbulent airflow, maximizing contact of air with the vascular mucosa to filter, warm, and humidify inspired air. The inferior concha is a separate bone; the superior and middle conchae are parts of the ethmoid bone.

The only complete ring of cartilage in the entire airway, located inferior to the thyroid cartilage. It is shaped like a signet ring (narrow anteriorly, broad posteriorly). Because it forms a complete ring, swelling inside the cricoid is especially dangerous — the rigid ring cannot expand to accommodate edema.

The airway defense mechanism in which pseudostratified ciliated columnar epithelium and goblet cells work together: goblet cells secrete mucus that traps inhaled particles, and coordinated ciliary beating propels the mucus-laden debris upward toward the pharynx to be swallowed or expectorated. It is one of the respiratory system's most important innate defense mechanisms.

Type I pneumocytes: squamous (flat), cover ~95% of alveolar surface, site of gas exchange, thin for diffusion. Type II pneumocytes: cuboidal, cover ~5% of alveolar surface, produce surfactant (DPPC) to reduce surface tension, can divide to regenerate Type I cells after injury.

Right lung: 3 lobes (superior, middle, inferior), 2 fissures (horizontal fissure separates superior from middle; oblique fissure separates middle from inferior); shorter and wider. Left lung: 2 lobes (superior, inferior), 1 fissure (oblique); longer and narrower; has the cardiac notch and lingula on its superior lobe.

Quiet inspiration (active): diaphragm (75% of work) + external intercostals. Quiet expiration (passive): elastic recoil only, no muscles. Forced inspiration adds: scalenes, sternocleidomastoid, pectoralis minor. Forced expiration adds: internal intercostals + abdominal muscles (rectus abdominis, etc.).

Intrapleural pressure (Pip) is the pressure in the pleural cavity between visceral and parietal pleurae. It is always negative relative to atmospheric (~−4 mmHg at rest, ~−6 mmHg during inspiration) because two opposing forces create a slight vacuum: the lungs' inward elastic recoil vs. the chest wall's outward spring. This negative pressure keeps the lungs expanded.

Boyle's Law: P₁V₁ = P₂V₂ (at constant temperature, pressure and volume are inversely related). During inspiration: diaphragm/intercostals expand the thorax → lung volume increases → intrapulmonary pressure drops below atmospheric (~−1 mmHg) → air flows in. During expiration: thorax recoils → volume decreases → pressure rises above atmospheric (~+1 mmHg) → air flows out.

Surfactant is a phospholipoprotein mixture (primary component: DPPC — dipalmitoylphosphatidylcholine) produced by Type II pneumocytes. It reduces surface tension at the air-water interface inside alveoli, preventing alveolar collapse (atelectasis). It is especially critical for small alveoli (per LaPlace's Law: P = 2T/r, smaller radius = higher collapse pressure without surfactant).

TV (Tidal Volume): ~500 mL — air moved per normal breath. IRV (Inspiratory Reserve Volume): ~3,100 mL — extra air forcibly inhaled above TV. ERV (Expiratory Reserve Volume): ~1,200 mL — extra air forcibly exhaled below TV. RV (Residual Volume): ~1,200 mL — air remaining after maximum forced expiration (cannot be measured by spirometry).

IC (Inspiratory Capacity) = TV + IRV ≈ 3,600 mL. FRC (Functional Residual Capacity) = ERV + RV ≈ 2,400 mL (resting lung volume after normal expiration). VC (Vital Capacity) = IRV + TV + ERV ≈ 4,800 mL (maximum volume exhaled after maximum inhalation). TLC (Total Lung Capacity) = VC + RV ≈ 6,000 mL.

FEV₁/FVC is the fraction of vital capacity exhaled in the first second of a forced breath. Normal: ≥0.75–0.80. Obstructive disease (asthma, COPD): FEV₁ reduced more than FVC → ratio <0.70 (hallmark). Restrictive disease (pulmonary fibrosis): both FEV₁ and FVC reduced proportionally → ratio remains normal or elevated (>0.80).

Kussmaul breathing is deep, rapid, and regular breathing (hyperpnea without pauses) that is the body's compensatory response to severe metabolic acidosis — most classically diabetic ketoacidosis (DKA). By hyperventilating, the body blows off CO₂ to raise blood pH and compensate for excess acid.

Atmosphere: PO₂ ≈ 159 mmHg, PCO₂ ≈ 0.3 mmHg. Alveoli: PO₂ ≈ 104 mmHg, PCO₂ ≈ 40 mmHg. Arterial blood: PO₂ ≈ 100 mmHg, PCO₂ ≈ 40 mmHg. Venous blood: PO₂ ≈ 40 mmHg, PCO₂ ≈ 45 mmHg. (Alveolar O₂ is lower than atmospheric due to humidification and CO₂ dilution.)

~98.5% bound to hemoglobin (reversibly attached to Fe²⁺ in heme groups; ~197 mL O₂/L blood at full saturation). ~1.5% dissolved in plasma (obeying Henry's Law; ~3 mL O₂/L at PO₂ of 100 mmHg). Only dissolved O₂ contributes to PO₂ and drives diffusion; hemoglobin acts as a reservoir.

Hemoglobin is a quaternary protein with four polypeptide subunits (2α + 2β chains in adult HbA), each containing one heme group with Fe²⁺ at its center. Each molecule can carry 4 O₂. Cooperative binding: binding of the first O₂ causes a conformational shift (T→R state) that increases affinity for subsequent O₂ molecules, producing the sigmoidal O₂-Hb dissociation curve.

The Bohr effect is the decrease in hemoglobin's affinity for O₂ caused by increased CO₂ and/or decreased pH. Mechanism: CO₂ from active tissues enters RBCs → carbonic anhydrase converts it to H₂CO₃ → dissociates into H⁺ + HCO₃⁻ → H⁺ binds hemoglobin, stabilizing its T (deoxy) state → right shift of dissociation curve → O₂ released more readily at tissues. Significance: oxygen delivery is automatically enhanced where metabolism is highest.

Right shift (↑P₅₀, ↓O₂ affinity, enhanced unloading): caused by ↑CO₂, ↓pH, ↑temperature, ↑2,3-BPG — conditions present in metabolically active tissues. Left shift (↓P₅₀, ↑O₂ affinity, impaired unloading): caused by ↓CO₂, ↑pH, ↓temperature, ↓2,3-BPG, fetal hemoglobin (HbF), carbon monoxide poisoning. CO is dangerous because it produces extreme left shift and occupies Hb, blocking O₂ binding.

~70% as bicarbonate ions (HCO₃⁻) dissolved in plasma — the major form, produced in RBCs via carbonic anhydrase reaction: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. ~23% as carbaminohemoglobin (CO₂ bound to amino groups of globin protein). ~7% dissolved in plasma as CO₂ gas.

The chloride shift is the exchange of HCO₃⁻ and Cl⁻ across the RBC membrane during CO₂ loading (at tissues) and unloading (at lungs). At tissues: CO₂ enters RBCs → converted to HCO₃⁻ → HCO₃⁻ leaves RBC in exchange for Cl⁻ entering (via band-3 antiporter), preventing charge imbalance and allowing more CO₂ to be transported as bicarbonate in the plasma.

The Haldane effect states that deoxygenated hemoglobin (deoxyhemoglobin) carries more CO₂ than oxygenated hemoglobin. At tissues, hemoglobin releases O₂ and becomes deoxyhemoglobin, which binds CO₂ more readily as carbaminohemoglobin AND has greater buffering capacity for H⁺ (stabilizing pH). At the lungs, O₂ binding displaces CO₂ for exhalation. Deoxy-Hb is a better CO₂ carrier.

VRG (Ventral Respiratory Group): primary rhythm generator (pre-Bötzinger complex), contains both inspiratory and expiratory neurons, drives the basic breathing pattern; expiratory neurons activate during forced breathing. DRG (Dorsal Respiratory Group): primarily integrates sensory input (from peripheral chemoreceptors, lung stretch receptors); relays inspiratory signals to VRG and spinal motor neurons.

Pneumotaxic center (upper pons): sends continuous inhibitory signals to inspiratory neurons → limits duration of inspiration → controls breathing rate. Apneustic center (lower pons): sends excitatory signals to inspiratory neurons → prolongs inspiration. Normally inhibited by pneumotaxic center. Damage to pneumotaxic center with intact apneustic center → apneustic breathing (prolonged gasping inspirations).

Central chemoreceptors: on ventral medulla surface, bathed in CSF; respond primarily to CSF pH (proxy for PaCO₂); CO₂ crosses blood-brain barrier freely; most powerful driver of normal breathing. Peripheral chemoreceptors: carotid bodies (CN IX) and aortic bodies (CN X); respond to ↓PaO₂ (especially <60 mmHg), ↑PaCO₂, ↓pH; primary O₂ sensors; hypoxia is the dominant stimulus in patients with chronic hypercapnia.

A pulmonary stretch reflex in which slowly adapting stretch receptors in bronchiolar smooth muscle send signals via the vagus nerve (CN X) to the medullary respiratory centers when the lungs are sufficiently inflated. The result is inhibition of further inspiration, preventing over-inflation. Primarily active during large tidal volumes (>1 L) in adults; plays a more prominent role in infants.

V̇E = Tidal Volume (VT) × Respiratory Rate (f). At rest: ~500 mL × 12 breaths/min = ~6 L/min. During maximal exercise: ~3,000 mL × 40–50 breaths/min = 100–150 L/min. VT increases first during light-to-moderate exercise; respiratory rate increases more at higher intensities.

1. ↓Atmospheric PO₂ → ↓PaO₂ → peripheral chemoreceptors stimulated. 2. Hypoxic ventilatory response (HVR): ↑respiratory rate and depth. 3. Respiratory alkalosis (CO₂ blown off, pH rises). 4. Renal compensation: kidneys excrete HCO₃⁻ to normalize pH (takes 2–3 days). 5. EPO released by kidneys → ↑RBC production (polycythemia, over days–weeks). 6. ↑2,3-BPG in RBCs → right shift of O₂-Hb curve → better O₂ unloading at tissues.

Chronic bronchitis: conducting zone — mucus hypersecretion, goblet cell hyperplasia, ciliary destruction, airway inflammation and wall thickening; defined clinically (productive cough ≥3 months/year for ≥2 years). Emphysema: respiratory zone — protease-mediated alveolar wall destruction, ↓surface area, ↓elastic recoil, air trapping and barrel chest. Both: FEV₁/FVC < 0.70 (obstructive pattern), with FEV₁ reduced more than FVC.

Sensitization: first allergen exposure → allergen-specific IgE produced → IgE binds Fc receptors on mast cells (no symptoms). Re-exposure: allergen cross-links IgE → mast cell degranulation → histamine, leukotrienes, prostaglandins released → (1) bronchoconstriction (smooth muscle contraction), (2) airway edema (↑vascular permeability), (3) mucus hypersecretion. Late-phase (hours later): eosinophil recruitment, chronic inflammation. All reversible with treatment (distinguishes asthma from COPD).

CFTR gene mutation (most common: ΔF508, ~70% of alleles) → absent/dysfunctional CFTR Cl⁻ channel on airway epithelium → Cl⁻ not secreted → ENaC (Na⁺ channel) upregulated → Na⁺ and water reabsorbed → periciliary liquid layer dehydrated and collapsed → cilia immobilized → thick, sticky mucus accumulates → chronic bacterial infections (esp. Pseudomonas aeruginosa) → neutrophilic inflammation → progressive bronchiectasis and lung destruction.

Autosomal recessive: requires two defective CFTR alleles (one from each parent). Carrier frequency in Caucasians: ~1 in 25. Diagnosis: sweat chloride test (elevated sweat Cl⁻ >60 mmol/L is diagnostic, because non-functional CFTR in sweat glands fails to reabsorb Cl⁻). Also confirmed by genetic testing for CFTR mutations. Newborn screening via immunoreactive trypsinogen (IRT) is standard in the US.

1. Hypoxic hypoxia: ↓PaO₂ (lungs fail to oxygenate blood) — causes: altitude, hypoventilation, V/Q mismatch. 2. Anemic hypoxia: normal PaO₂ but ↓O₂-carrying capacity — causes: anemia, CO poisoning. 3. Stagnant/circulatory hypoxia: normal blood O₂ content but ↓blood flow to tissues — causes: heart failure, shock. 4. Histotoxic hypoxia: normal O₂ delivery but cells cannot use O₂ — cause: cyanide poisoning (blocks cytochrome oxidase). Distinguishing clue: histotoxic produces bright red venous blood.

Mycobacterium tuberculosis (acid-fast bacillus) inhaled as droplet nuclei (<5 μm) → deposited in alveoli → phagocytosed by alveolar macrophages but survives by inhibiting phagosome-lysosome fusion → macrophages recruit Th1 cells → IFN-γ activates macrophages → granuloma forms (tubercle): epithelioid macrophages + Langhans giant cells + lymphocyte cuff + central caseous (cheese-like) necrosis → contains infection. Primary complex = granuloma + Ghon focus (calcified scar) + hilar lymph node involvement.

Filiform: most numerous, threadlike, give tongue rough texture, NO taste buds. Fungiform: mushroom-shaped, scattered on anterior 2/3, have taste buds. Circumvallate (vallate): large, arranged in a V-row at the posterior tongue, have taste buds — most numerous per papilla. Foliate: leaflike folds on lateral margins, have taste buds. Only filiform papillae lack taste buds.

Parotid: largest, anterior/inferior to ear, drains via Stensen's duct (opens near upper 2nd molar) — serous only (watery, rich in salivary amylase). Submandibular: floor of mouth/medial mandible, drains via Wharton's duct (opens at sublingual caruncle) — mixed (~60% serous, 40% mucous); dominant contributor to resting saliva. Sublingual: smallest, directly under tongue, drains via ducts of Rivinus — predominantly mucous.

Phase 1 — Voluntary (buccal): tongue pushes bolus against hard palate and propels it into the oropharynx. Phase 2 — Pharyngeal (involuntary): soft palate/uvula elevate to close nasopharynx, epiglottis folds over laryngeal inlet, vocal folds adduct, larynx elevates, UES relaxes → bolus enters esophagus. Phase 3 — Esophageal (involuntary): sequential peristaltic contractions move bolus to stomach; LES relaxes for entry.

Parietal cells: HCl (activates pepsinogen, kills bacteria) + intrinsic factor (required for vitamin B₁₂ absorption). Chief cells: pepsinogen (zymogen → activated to pepsin by HCl). G cells: gastrin (hormone that stimulates gastric secretion). D cells: somatostatin (inhibits gastrin and HCl secretion). Mucous neck/foveolar cells: mucus (protects gastric lining from acid).

1. Plicae circulares (circular folds): permanent transverse folds of mucosa and submucosa visible to the naked eye; most prominent in jejunum; increase surface area ~3×. 2. Villi: finger-like projections of mucosa (1–4 mm) with central lacteal and capillary network; increase surface area ~10×. 3. Microvilli (brush border): densely packed projections on enterocytes (electron-microscopic level); increase surface area ~20×. Combined effect: ~200 m² total surface area.

1. Teniae coli: three narrow longitudinal bands of smooth muscle (condensed outer longitudinal layer) running the length of the colon; their continuous contraction is what creates haustra. 2. Haustra: the characteristic pocket-like sacculations between teniae coli. 3. Epiploic appendages (appendices epiploicae): small fat-filled pouches of peritoneum hanging from the serosal surface of the colon.

1. Mucosa: innermost layer; epithelium + lamina propria + muscularis mucosae; directly contacts luminal contents; lining varies by organ. 2. Submucosa: dense connective tissue with Meissner's (submucosal) nerve plexus controlling secretions. 3. Muscularis externa: inner circular + outer longitudinal smooth muscle layers with Auerbach's (myenteric) plexus between them controlling motility/peristalsis. 4. Serosa (or adventitia): outermost layer; peritoneal covering (serosa) for intraperitoneal organs; fibrous connective tissue (adventitia) for retroperitoneal segments.

The liver receives blood from two sources simultaneously: (1) Hepatic artery proper (~25% of flow): oxygenated blood from the aorta via celiac trunk → hepatic artery. (2) Hepatic portal vein (~75% of flow): nutrient-rich (but relatively deoxygenated) blood from the GI tract, spleen, and pancreas. Both vessels enter at the porta hepatis and flow through sinusoids around hepatocytes. Hepatic veins drain into the IVC. This dual supply allows the liver to sample everything absorbed from the gut before it enters systemic circulation.

The lobule is the functional unit of the liver — a hexagonal structure of hepatocyte plates radiating from a central vein. At the six corners are portal triads (portal vein branch + hepatic artery branch + bile ductule). Blood flow: portal triads → sinusoids (lined by Kupffer cells) → central vein → hepatic veins → IVC (centripetal flow). Bile flow: the opposite direction — hepatocytes → bile canaliculi → bile ductules at portal triads (centrifugal flow).

Hepatocytes → bile canaliculi → bile ductules (canals of Hering) → interlobular bile ducts → right and left hepatic ducts → common hepatic duct → (+ cystic duct from gallbladder) → common bile duct → (joins main pancreatic duct) → hepatopancreatic ampulla (ampulla of Vater) → major duodenal papilla → duodenum. Sphincter of Oddi controls the final release into the duodenum.

Bile is a yellow-green alkaline fluid (~500–1,000 mL/day) containing bile salts (from cholesterol), bilirubin (from heme breakdown), cholesterol, phospholipids (lecithin), and bicarbonate. Two digestive roles: (1) Emulsification of fats — bile salts break large fat globules into tiny droplets (micelles), vastly increasing surface area for pancreatic lipase. (2) Micelle formation — bile salts + monoglycerides + fatty acids form mixed micelles that carry lipid products to the brush border for absorption.

Fasting state: sphincter of Oddi is closed; newly produced bile backs up into the gallbladder via the cystic duct; gallbladder concentrates bile up to 10–20× by absorbing water and ions. Fed state: fatty acids and amino acids in the duodenum stimulate I cells to release CCK (cholecystokinin) → CCK causes gallbladder smooth muscle to contract + sphincter of Oddi to relax → concentrated bile squirts into the duodenum via the common bile duct and ampulla of Vater.

Cholelithiasis is the formation of solid concretions in the gallbladder. Two main types: (1) Cholesterol stones (~80% in Western populations): form when bile is supersaturated with cholesterol or deficient in bile salts/lecithin; risk factors: obesity, female sex, rapid weight loss, pregnancy. (2) Pigment stones (~20%): composed of calcium bilirubinate; associated with hemolytic anemias (excess bilirubin production) and liver cirrhosis. Stones can obstruct the cystic or common bile duct, causing biliary colic or jaundice.

Pancreatic amylase: polysaccharides → disaccharides/oligosaccharides (active as secreted). Pancreatic lipase (+ colipase): triglycerides → fatty acids + monoglycerides (active). Proteases (zymogens): trypsinogen → trypsin (activated by enterokinase/enteropeptidase on brush border); trypsin then activates chymotrypsinogen → chymotrypsin, procarboxypeptidase → carboxypeptidase, proelastase → elastase. Nucleases (DNase, RNase): nucleic acids (active). Duct cells secrete bicarbonate to neutralize acidic chyme.

Secretin: released from S cells in the duodenal mucosa in response to acidic chyme (low pH) → stimulates pancreatic duct cells to secrete bicarbonate-rich juice (neutralizes chyme). CCK (cholecystokinin): released from I cells in the duodenum in response to fats and proteins → stimulates acinar cells to secrete digestive enzymes + triggers gallbladder contraction. Both hormones work synergistically.

Alpha (α) cells (~15–20%, periphery): secrete glucagon → raises blood glucose (glycogenolysis + gluconeogenesis). Beta (β) cells (~65–80%, central core): secrete insulin → lowers blood glucose (↑glucose uptake, glycogenesis); most abundant. Delta (δ) cells (~5–10%): secrete somatostatin → inhibits both insulin and glucagon (paracrine brake). PP cells (F cells): secrete pancreatic polypeptide → inhibits pancreatic secretion and gallbladder contraction after a meal.

Type 1 DM: autoimmune destruction of beta cells → absolute insulin deficiency; typically onset in childhood/young adults; requires exogenous insulin. Type 2 DM: peripheral insulin resistance (cells don't respond to insulin) + progressive beta cell dysfunction → relative insulin deficiency; associated with obesity, sedentary lifestyle; initially managed with lifestyle changes and oral medications (e.g., metformin). Both result in hyperglycemia.

Ampulla of Vater: the short flask-shaped common channel formed by the union of the common bile duct and the main pancreatic duct (duct of Wirsung) just before their opening into the duodenum through the major duodenal papilla. Sphincter of Oddi: a complex of smooth muscle sphincters surrounding the terminal common bile duct, pancreatic duct, and ampulla; keeps the ampulla closed between meals and relaxes (via CCK/VIP) during digestion to allow bile and pancreatic juice to flow.

Resistance is inversely proportional to the fourth power of radius (r⁴). If radius is halved, resistance increases 16-fold (2⁴ = 16). Airflow = ΔP / Resistance. Clinical implications: even modest bronchoconstriction (e.g., in asthma) dramatically increases airway resistance, explaining why patients struggle to breathe despite normal respiratory muscle effort. Bronchodilators work by widening radius to reduce resistance.

Trachea: 16–20 C-shaped hyaline cartilage rings, pseudostratified ciliated columnar epithelium. Primary bronchi → secondary (lobar) → tertiary (segmental) bronchi: cartilage rings → irregular cartilage plates. Bronchioles: no cartilage (maintained by radial traction), smooth muscle predominates, epithelium becomes cuboidal. Terminal bronchioles: smallest purely conducting airways; simple cuboidal epithelium with Clara (club) cells; no goblet cells. Progressive decrease: lumen diameter, cartilage, goblet cells, ciliated cells. Progressive increase: number of branches, smooth muscle proportion, surface area.

1. Surface area: ~70 m² in healthy adults; reduced in emphysema (alveolar wall destruction) and pneumonia (consolidation). 2. Membrane thickness: normally ~0.5 μm; increased in pulmonary edema or fibrosis → slows diffusion. 3. Partial pressure gradient: steeper gradient = faster diffusion; reduced at altitude or with V/Q mismatch. 4. Gas solubility (Henry's Law): CO₂ is ~20× more soluble than O₂ in water, explaining why CO₂ transport problems are rare despite CO₂ having a smaller driving gradient.

OSA (~84% of cases): upper airway physically collapses (pharyngeal muscle tone ↓ during sleep; genioglossus fails to maintain patency) despite continued respiratory effort by chest/abdominal muscles → airflow stops. Key: continued thoracic effort with no airflow. CSA: brainstem fails to send respiratory drive signals → both airflow AND respiratory effort absent simultaneously. Key: flat effort belts on polysomnography. Both diagnosed by AHI ≥5 events/hour. OSA treated with CPAP (positive pressure splints airway open).

Cardia: narrow region around the lower esophageal sphincter (cardiac sphincter); prevents acid reflux. Fundus: dome-shaped superior region above the gastroesophageal junction; stores gas and food before mixing begins. Body (corpus): largest region; primary site of gastric secretion and mixing. Pylorus: inferior narrowing; pyloric antrum (mixes/grinds chyme) + pyloric canal + pyloric sphincter (metered valve releasing chyme into duodenum). Also: rugae (folds) allow stomach to expand to ~1.5 L when full.

Duodenum (~25 cm): C-shaped, retroperitoneal; receives chyme, bile, and pancreatic juice at the major duodenal papilla; most chemical digestion initiated here. Jejunum (~2.5 m): highly vascularized, thickest walls, most prominent plicae circulares; site of bulk nutrient digestion and absorption. Ileum (~3.5 m): thinner walls, more goblet cells; specialized absorption of bile salts and vitamin B₁₂ (requires intrinsic factor from parietal cells); has Peyer's patches (lymphoid tissue); ends at ileocecal valve.

Kupffer cells are the liver's resident macrophages, lining the sinusoids of hepatic lobules. They are strategically positioned where all portal blood (carrying gut-absorbed material) must pass. Functions: (1) Phagocytosis of bacteria, endotoxins (LPS), fungi, parasites, and cellular debris from the portal circulation. (2) Phagocytosis of senescent RBCs → heme → bilirubin (sent to hepatocytes for conjugation). (3) Release cytokines (IL-1, TNF-α, IL-6) during infection → acute phase response. (4) In chronic disease: can activate stellate cells → liver fibrosis/cirrhosis.

Emphysema: elastin in alveolar walls destroyed by proteases (esp. elastase from neutrophils) → ↑compliance (lungs stretch too easily, over-inflate) but ↓elastic recoil → passive expiration severely impaired → air trapping → barrel chest. Spirometry: obstructive pattern (FEV₁/FVC <0.70), ↑TLC, ↑RV. Pulmonary fibrosis: excess collagen/scar tissue stiffens lungs → ↓compliance (lungs resist inflation) → restrictive pattern (↓TLC, ↓VC, normal/↑FEV₁/FVC ratio). Work of breathing dramatically increased.

During swallowing (deglutition): (1) Larynx elevates (pulled upward by suprahyoid muscles — you can feel this with a finger on your throat). (2) Epiglottis (leaf-shaped elastic cartilage attached to inner thyroid cartilage) folds posteriorly over the laryngeal inlet, deflecting the bolus toward the esophagus. (3) True vocal folds adduct (close), sealing the rima glottidis as a secondary barrier. (4) False vocal folds also adduct. All three mechanisms prevent aspiration of food/liquid into the trachea.

Mouth: salivary amylase cleaves α-1,4 bonds in starch → maltose + α-dextrins (active at pH 6.7–7.0, inactivated in stomach). Duodenum: pancreatic amylase continues hydrolysis → maltose + α-dextrins + maltotriose. Brush border: maltase (maltose → 2 glucose), α-dextrinase/isomaltase (α-1,6 branch points → glucose), sucrase (sucrose → glucose + fructose), lactase (lactose → glucose + galactose). Absorption: glucose/galactose via SGLT1 (Na⁺-coupled secondary active transport) into enterocyte → GLUT2 into portal blood; fructose via GLUT5 (facilitated diffusion) → GLUT2 → portal blood.

Glucose and galactose: absorbed via SGLT1 (sodium-glucose linked transporter 1) on the apical membrane — secondary active transport that co-transports Na⁺ and one monosaccharide, driven by the Na⁺ gradient established by the basolateral Na⁺/K⁺-ATPase. Exit via GLUT2 on basolateral membrane into capillary blood. Fructose: absorbed via GLUT5 on the apical membrane — facilitated diffusion (no energy, no Na⁺ coupling, moves down its concentration gradient). Exit also via GLUT2 basolaterally. Key difference: glucose/galactose absorption is energy-dependent and can work against a concentration gradient; fructose absorption is passive and slower.

Enterokinase (enteropeptidase) is a brush border enzyme produced by duodenal enterocytes. It is the master switch because it activates trypsinogen → trypsin by cleaving a specific hexapeptide from the N-terminus. Trypsin then activates all other pancreatic zymogens: chymotrypsinogen → chymotrypsin, procarboxypeptidase → carboxypeptidase, proelastase → elastase, and additional trypsinogen (autocatalytic positive feedback). Without enterokinase, the entire pancreatic protease cascade remains inactive and protein digestion in the small intestine fails.

Long-chain fatty acids (≥12 C): diffuse into enterocytes from micelles at brush border → re-esterified to triglycerides in smooth ER → packaged with cholesterol, phospholipids, and apolipoprotein B-48 into chylomicrons → exocytosed into the central lacteal of the villus → enter lymphatic system → thoracic duct → left subclavian vein (bypasses portal circulation). Short/medium-chain fatty acids (<12 C): diffuse directly into enterocytes → pass through without re-esterification → enter capillary blood → portal vein → liver. Key difference: long-chain FAs take the lymphatic route; short/medium-chain FAs take the portal route.

Micelles are tiny (~4–7 nm) aggregates formed by bile salts surrounding the products of lipid digestion (fatty acids, 2-monoglycerides, cholesterol, fat-soluble vitamins). Bile salts are amphipathic — their hydrophobic face points inward toward the lipids and their hydrophilic face points outward toward the aqueous environment. Micelles shuttle water-insoluble lipid digestion products through the unstirred water layer to the brush border of enterocytes, where the lipids dissociate and diffuse across the apical membrane. Micelles are not absorbed — they recycle back to pick up more lipid products. Without micelles, fat absorption drops drastically (steatorrhea).

Peristalsis: coordinated wave of circular muscle contraction behind the bolus + relaxation ahead of it → net forward propulsion of contents toward the large intestine. Controlled by myenteric plexus. Segmentation: rhythmic, alternating contractions of non-adjacent circular muscle segments → chyme is pushed back and forth without net forward movement → primary function is mixing chyme with digestive enzymes and increasing contact with absorptive surface. Most common motility pattern in the fed state. Segmentation frequency decreases distally (12/min duodenum → 8/min ileum), creating a slow net aboral movement.

The migrating motor complex (MMC) is a cyclical pattern of strong peristaltic waves that sweeps through the stomach and small intestine during the fasting (interdigestive) state, approximately every 90–120 minutes. Often called the 'intestinal housekeeper,' the MMC clears residual food, sloughed cells, bacteria, and debris from the upper GI tract between meals, preventing bacterial overgrowth. It is regulated by the hormone motilin (released from Mo cells of the duodenal/jejunal mucosa) and abolished by feeding — eating switches motility from the MMC pattern to the fed-state segmentation pattern.

Gastrin: G cells (stomach antrum); stimulus = protein/peptides, distension, vagal stimulation; actions = stimulates HCl secretion, promotes gastric motility, trophic to gastric mucosa. Secretin: S cells (duodenum); stimulus = acidic chyme (pH <4.5); actions = stimulates pancreatic bicarbonate secretion, inhibits gastric acid secretion. CCK (cholecystokinin): I cells (duodenum/jejunum); stimulus = fatty acids and amino acids; actions = stimulates pancreatic enzyme secretion, gallbladder contraction, sphincter of Oddi relaxation, inhibits gastric emptying. GIP (glucose-dependent insulinotropic peptide): K cells (duodenum/jejunum); stimulus = glucose and fatty acids; actions = stimulates insulin release (incretin effect), inhibits gastric acid secretion.

Cephalic phase (~30% of secretion): triggered by sight, smell, thought, or taste of food; mediated by vagus nerve (parasympathetic) → stimulates parietal cells (HCl), chief cells (pepsinogen), and G cells (gastrin). Gastric phase (~60% of secretion): triggered by food entering the stomach — distension activates stretch receptors, peptides/amino acids stimulate G cells; positive feedback: gastrin → HCl → pepsin → more peptides → more gastrin. Intestinal phase (~10%): initial excitatory phase when chyme first enters duodenum; quickly becomes inhibitory — acidic/fatty chyme triggers enterogastric reflex + secretin/CCK/GIP release → inhibits gastric motility and secretion (negative feedback to prevent duodenal overload).

Iron: primarily duodenum (Fe²⁺ absorbed via DMT1 transporter; Fe³⁺ must first be reduced by ferrireductase; exported via ferroportin, regulated by hepcidin). Calcium: primarily duodenum and proximal jejunum (transcellular pathway regulated by vitamin D/calcitriol via calbindin). Vitamin B₁₂: exclusively terminal ileum (absorbed as B₁₂-intrinsic factor complex via cubilin receptor; intrinsic factor from gastric parietal cells is essential). Bile salts: terminal ileum (active reabsorption via ASBT transporter — enterohepatic circulation returns ~95% of bile salts to the liver). Water: ~8–9 L absorbed daily; most in jejunum (osmotically follows solute absorption), remainder in ileum and colon.

H. pylori is a spiral-shaped, gram-negative bacterium that colonizes the gastric mucosa. Survival: it produces the enzyme urease, which converts urea → ammonia + CO₂, creating a locally alkaline microenvironment that neutralizes surrounding acid. Pathogenesis: ammonia is directly toxic to gastric epithelial cells; the bacterium triggers chronic inflammation (neutrophils, macrophages, IL-8, TNF-α) that damages the mucosal barrier over years; virulence factors (CagA, VacA) further disrupt epithelial integrity. H. pylori causes 70–90% of duodenal ulcers and 60–80% of gastric ulcers. Treatment: triple therapy — PPI + two antibiotics (e.g., clarithromycin + amoxicillin) for 14 days.

H. pylori: bacterial infection → urease-mediated acid neutralization for survival → chronic mucosal inflammation → barrier disruption; causes most duodenal and gastric ulcers; diagnosed by urea breath test, stool antigen, or biopsy; treated with triple therapy (PPI + 2 antibiotics). NSAIDs (aspirin, ibuprofen, naproxen): inhibit cyclooxygenase (COX-1) → decreased prostaglandin synthesis → prostaglandins normally stimulate mucus/bicarbonate secretion, maintain mucosal blood flow, and promote epithelial repair → without prostaglandins, the mucosal barrier weakens → acid-pepsin digestion of exposed mucosa. NSAIDs cause ~25% of gastric ulcers. Prevention: co-prescribe PPI or misoprostol (prostaglandin analog) with chronic NSAID use.

Osmotic diarrhea: non-absorbable osmotically active substance remains in the lumen → draws water in by osmosis. Key example: lactose intolerance (undigested lactose acts as osmotic agent). Distinguishing feature: stops with fasting (removing the offending substance removes the osmotic drive). Secretory diarrhea: intestinal epithelial cells actively secrete fluid and electrolytes into the lumen, overwhelming colonic absorptive capacity. Key example: cholera toxin permanently activates adenylyl cyclase → ↑cAMP → massive Cl⁻ secretion → water follows → up to 20 L/day of watery stool. Distinguishing feature: does NOT stop with fasting (secretion is toxin-driven, independent of luminal contents).

Lactase non-persistence is the ancestral (normal) condition: lactase expression declines after weaning, resulting in reduced ability to digest lactose in adulthood. Affects ~65–70% of the global adult population. Lactase persistence: a regulatory variant (most commonly C/T-13910 near the LCT gene) maintains high lactase expression into adulthood. This mutation arose independently in multiple populations that domesticated cattle and relied on dairy. Prevalence varies: >90% in Northern Europeans, <10% in East Asians and most sub-Saharan Africans. Lactose intolerance = clinical symptoms (bloating, gas, osmotic diarrhea) from lactase non-persistence when dairy is consumed.

Hepatitis A (HAV): fecal-oral transmission (contaminated food/water); acute self-limited only, never chronic; lifelong immunity after infection; vaccine available (inactivated virus). Hepatitis B (HBV): bloodborne/sexual/vertical (mother-to-child) transmission; 5–10% of adults develop chronic infection (>90% of infected neonates become chronic); chronic HBV → cirrhosis and hepatocellular carcinoma risk; vaccine available (recombinant HBsAg). Hepatitis C (HCV): primarily bloodborne (IV drug use, contaminated blood products); ~75–85% become chronic; leading cause of liver transplantation; no vaccine available; now curable with direct-acting antivirals (DAAs, e.g., sofosbuvir/ledipasvir) achieving >95% sustained virologic response.

GERD: transient lower esophageal sphincter (LES) relaxations or chronic LES incompetence → gastric acid and pepsin reflux into the esophagus → esophageal squamous epithelium (not designed for acid exposure) is damaged → inflammation (reflux esophagitis) → symptoms: heartburn, regurgitation, dysphagia. Risk factors: obesity, hiatal hernia, pregnancy, smoking. Barrett's esophagus: chronic acid exposure triggers metaplasia — normal stratified squamous epithelium of the distal esophagus is replaced by intestinal-type columnar epithelium with goblet cells. Barrett's is a premalignant condition: metaplasia → dysplasia → esophageal adenocarcinoma (risk ~0.5%/year). Requires endoscopic surveillance with biopsy. Treated with PPIs; dysplasia may require ablation or resection.

Crohn's disease: can affect any part of GI tract (mouth to anus), most commonly terminal ileum and colon; transmural inflammation (full thickness through all layers); skip lesions (discontinuous patches of disease alternating with normal bowel); granulomas on biopsy; complications: fistulas, strictures, abscesses, malabsorption. Ulcerative colitis: limited to colon and rectum; inflammation confined to mucosa and submucosa only; continuous pattern (starts at rectum, extends proximally without gaps); crypt abscesses on biopsy; complications: toxic megacolon, significantly increased colorectal cancer risk. Both: chronic relapsing-remitting course, extraintestinal manifestations (arthritis, uveitis, skin lesions), treated with 5-ASA, corticosteroids, immunomodulators, biologics (anti-TNF).

Celiac disease is an autoimmune disorder triggered by ingestion of gluten (specifically gliadin peptides from wheat, barley, rye) in genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8 alleles. Mechanism: gliadin peptides cross the intestinal epithelium → tissue transglutaminase (tTG) deamidates gliadin → deamidated gliadin is presented on HLA-DQ2/DQ8 to CD4⁺ T cells → Th1 inflammatory response + anti-tTG and anti-gliadin antibodies → villous atrophy, crypt hyperplasia, and lymphocytic infiltration of the small intestinal mucosa → malabsorption of nutrients. Diagnosis: serologic anti-tTG IgA antibodies + duodenal biopsy showing villous atrophy. Treatment: strict lifelong gluten-free diet.

Antacids (calcium carbonate, Mg(OH)₂, Al(OH)₃): directly neutralize existing acid in the stomach lumen → rapid but short-lived relief; do not reduce acid secretion. H₂-receptor blockers (famotidine, ranitidine, cimetidine): competitively block histamine H₂ receptors on parietal cells → reduce histamine-stimulated acid secretion; effective for mild-moderate suppression; can develop tolerance (tachyphylaxis). Proton pump inhibitors/PPIs (omeprazole, lansoprazole, pantoprazole): irreversibly inhibit H⁺/K⁺-ATPase (the proton pump) on parietal cells → most potent acid suppression available; reduce acid secretion by ~95%; drug of choice for GERD, PUD, Barrett's, and Zollinger-Ellison syndrome. Long-term PPI risks: ↓Ca²⁺/Mg²⁺ absorption, C. difficile infection, B₁₂ deficiency.

The adenoma-carcinoma sequence is the stepwise progression: normal colonic epithelium → hyperproliferative epithelium → small benign adenomatous polyp → dysplastic (pre-cancerous) polyp → invasive carcinoma. This process typically takes 10–15 years, which is why colonoscopy screening is effective — polyps can be detected and removed before malignant transformation. Key genetic mutations (accumulate in order): (1) Loss of APC tumor suppressor gene (early — initiates polyp formation); (2) Activation of KRAS oncogene (promotes growth); (3) Loss of SMAD4 (TGF-β pathway disruption); (4) Loss of TP53 tumor suppressor (late — enables invasion). CRC is the 3rd most common cancer and 2nd leading cause of cancer death in the US.

First line: physical/chemical barriers (skin, mucous membranes, stomach acid, lysozyme, defensins) — always in place, non-specific, prevents pathogen entry. Second line: innate immune response — rapid (minutes to hours), non-specific, no memory; includes phagocytes (neutrophils, macrophages), NK cells, complement system, inflammation, fever, interferons. Third line: adaptive immune response — slow to engage initially (7–17 days for primary response), exquisitely specific (targets particular molecular signatures), generates immunological memory; includes B cells (humoral/antibody-mediated) and T cells (cell-mediated). Key difference: only adaptive immunity has memory and specificity.

Red bone marrow: birthplace of all blood cells (hematopoiesis from hematopoietic stem cells). Site of B cell maturation and selection — B cells complete their entire development here; self-reactive B cells are eliminated (clonal deletion = central tolerance). Also produces myeloid cells (neutrophils, monocytes, eosinophils, basophils, mast cells). Located in proximal femur, ilium, sternum, ribs, vertebrae in adults. Thymus: site of T cell maturation and selection. T cell precursors migrate from bone marrow to thymus. Positive selection (cortex): T cells must recognize self-MHC to survive. Negative selection (medulla): T cells that react too strongly to self-antigens are deleted (AIRE protein enables expression of tissue-specific antigens). Only 2–5% of thymocytes survive. Involutes with age.

Spleen: filters blood (~350 L/day); red pulp (macrophages destroy old/damaged RBCs, stores platelets); white pulp (PALS = T cell zone around central arteriole, lymphoid follicles = B cell zone with germinal centers); no afferent lymphatics. Marginal zone captures blood-borne antigens. Lymph nodes: filter lymph; cortex (B cell follicles, primary and secondary with germinal centers), paracortex (T cell zone, dendritic cells present antigens), medulla (plasma cells, macrophages); afferent lymphatic vessels bring lymph in, efferent vessel exits at hilum. Both: sites where mature naive lymphocytes encounter antigens and launch adaptive immune responses.

Peyer's patches are aggregations of lymphoid tissue in the mucosa and submucosa of the ileum (small intestine), forming part of the gut-associated lymphoid tissue (GALT). They contain B cell follicles with germinal centers and T cell zones, and serve as immune surveillance sites for the intestinal lumen. M cells (microfold cells) are specialized epithelial cells in the follicle-associated epithelium overlying Peyer's patches. M cells have a flattened apical surface (no microvilli) and a deep basolateral pocket containing immune cells. They transcytose antigens, bacteria, and particles from the intestinal lumen directly to underlying dendritic cells and lymphocytes, initiating mucosal immune responses without the antigen entering the blood.

Neutrophils (50–70%): first responders to bacterial infection; phagocytosis, NETs, respiratory burst. Lymphocytes (20–40%): B cells (antibody production), T cells (cell-mediated immunity), NK cells (kill virus-infected/tumor cells). Monocytes (2–8%): circulate then differentiate into macrophages (phagocytosis, APC) or dendritic cells in tissues. Eosinophils (1–4%): defend against parasites; involved in allergic inflammation; release major basic protein. Basophils (0.5–1%): rarest WBC; release histamine and heparin; IgE-mediated responses. Mnemonic for decreasing frequency: Never Let Monkeys Eat Bananas.

NK cells are large granular lymphocytes of the innate immune system (derived from the lymphoid progenitor but do not require prior antigen sensitization). They kill virus-infected cells and tumor cells without needing MHC-restricted antigen presentation. Recognition: NK cells express both activating and inhibitory receptors. Inhibitory receptors (KIRs) recognize self MHC Class I on normal cells → inhibitory signal dominates → cell is spared. Virus-infected or tumor cells often downregulate MHC I to evade CTLs → missing-self hypothesis: absence of MHC I removes the inhibitory signal → activating receptors dominate → NK cell kills the target. Killing mechanism: perforin (forms pores) + granzymes (induce apoptosis), same as CTLs. NK cells also mediate antibody-dependent cellular cytotoxicity (ADCC) via Fc receptors for IgG.

Excess interstitial fluid (~2–4 L/day) enters blind-ended lymphatic capillaries (flap-valve endothelium, anchoring filaments pull open during edema) → lymph flows into collecting lymphatic vessels (have valves + smooth muscle for propulsion) → passes through lymph nodes (afferent vessels in, efferent vessel out at hilum — immune surveillance occurs here) → collects into lymph trunks → two major ducts: thoracic duct (drains left side of body + everything below diaphragm; begins at cisterna chyli at L1-L2; empties into left venous angle/left subclavian vein) and right lymphatic duct (drains right arm, right thorax, right head/neck; empties into right venous angle). Lymph flow driven by: skeletal muscle pump, respiratory pump, smooth muscle in vessel walls, arterial pulsations.

1. Chemotaxis: phagocyte migrates along chemical gradient (fMLP, C5a, IL-8, LTB4) toward infection site. 2. Adherence (recognition): phagocyte binds pathogen via pattern recognition receptors (TLRs, mannose receptors) or via opsonins coating the pathogen (IgG via Fc receptors, C3b via CR1 — opsonization dramatically enhances binding). 3. Ingestion: pseudopods extend around and engulf the pathogen into a membrane-bound vesicle called a phagosome. 4. Killing/digestion: phagosome fuses with lysosome → phagolysosome; contents destroyed by respiratory burst (NADPH oxidase → ROS: superoxide, H₂O₂, hypochlorite), defensins, lysozyme, and acidic pH (~4.5). 5. Exocytosis: indigestible residues expelled; fragments presented on MHC II to T cells (links innate to adaptive immunity).

1. Rubor (redness): local arteriolar vasodilation → increased blood flow to the area. 2. Calor (heat): increased blood flow brings warm blood from the core to the surface. 3. Tumor (swelling): increased vascular permeability → protein-rich exudate leaks into interstitium. 4. Dolor (pain): prostaglandins and bradykinin sensitize nociceptors (lower pain threshold); swelling also compresses nerve endings. 5. Functio laesa (loss of function): added by Virchow — combination of pain, swelling, and tissue damage impairs normal use of the affected area. Key mediators: histamine (from mast cells) drives vasodilation and permeability; prostaglandins sustain inflammation and cause pain; TNF-α and IL-1 amplify the response systemically.

1. Margination: leukocytes (especially neutrophils) move to the periphery of the blood vessel as blood flow slows due to vasodilation and increased permeability. 2. Rolling: leukocytes loosely bind to endothelial selectins (E-selectin, P-selectin) via carbohydrate ligands → they roll along the vessel wall. Selectins are upregulated by TNF-α and IL-1 from activated macrophages. 3. Firm adhesion: chemokines (IL-8/CXCL8) activate leukocyte integrins (LFA-1, Mac-1) → integrins bind firmly to endothelial ICAMs → leukocyte stops rolling and adheres tightly. 4. Diapedesis (transmigration): leukocyte squeezes between endothelial cells (paracellular migration) by binding PECAM-1 (CD31) → enters tissue → follows chemotactic gradient to infection site.

Mechanism: exogenous pyrogens (e.g., bacterial LPS) stimulate macrophages → release endogenous pyrogens (IL-1, IL-6, TNF-α) → travel via blood to the hypothalamus → induce COX-2 → prostaglandin E₂ (PGE₂) produced → PGE₂ raises the hypothalamic thermostat set point → body perceives current temperature as 'too cold' → activates heat-generating responses: vasoconstriction (conserve heat), shivering (produce heat) → core temperature rises to new set point (chills/rigor phase). When set point resets: vasodilation and sweating occur (crisis/defervescence). Benefits: ↑metabolic rate of immune cells, ↑phagocyte activity, ↑interferon production, ↓bacterial iron availability (sequestration), ↓pathogen replication (many bacteria/viruses grow best at 37°C). NSAIDs (aspirin, ibuprofen) reduce fever by inhibiting COX → blocking PGE₂.

Classical pathway: activated by antigen-antibody complexes (IgM or IgG bound to pathogen) → C1q binds Fc regions → activates C1r/C1s → cleaves C4 and C2 → forms C3 convertase (C4b2a). Lectin (MBL) pathway: mannose-binding lectin (MBL) binds mannose residues on pathogen surfaces (no antibodies needed) → MASP-1/MASP-2 activated → cleaves C4 and C2 → same C3 convertase (C4b2a). Alternative pathway: spontaneous hydrolysis of C3 (C3 tickover) → C3b deposits on pathogen surface → binds Factor B → Factor D cleaves Factor B → C3 convertase (C3bBb) stabilized by properdin. All three pathways converge at C3 → C3a + C3b. Three effector outcomes: opsonization (C3b), inflammation (C3a, C5a anaphylatoxins), and membrane attack complex/MAC (C5b-C9 pore → lysis).

The MAC is the terminal effector of the complement cascade, assembled from complement proteins C5b, C6, C7, C8, and multiple C9 molecules. Formation: C5 convertase cleaves C5 → C5a (anaphylatoxin) + C5b → C5b binds C6, C7 (complex inserts into pathogen membrane) → C8 joins and partially penetrates the lipid bilayer → C9 polymerizes (10–16 C9 molecules) to form a transmembrane pore ~10 nm in diameter. Result: the pore disrupts the pathogen's osmotic balance → uncontrolled influx of water and ions → cell swelling and lysis. MAC is most effective against gram-negative bacteria (thin cell wall). Gram-positive bacteria and mycobacteria are resistant due to thick peptidoglycan/waxy cell walls. Host cells are protected by CD59 (protectin), which prevents C9 polymerization.

PAMPs (Pathogen-Associated Molecular Patterns) are conserved molecular structures shared by broad classes of pathogens, absent from mammalian cells, and essential for pathogen survival. TLRs (Toll-Like Receptors) are pattern recognition receptors (PRRs) on innate immune cells that detect PAMPs and trigger inflammatory signaling (via NF-κB → cytokine production). Three key PAMP-TLR pairs: (1) TLR4 recognizes LPS (lipopolysaccharide) from gram-negative bacteria — the most potent innate immune activator; (2) TLR3 recognizes dsRNA (double-stranded RNA) from viruses (endosomal); (3) TLR2 recognizes peptidoglycan and lipoteichoic acid from gram-positive bacteria. Also: TLR5 → flagellin; TLR9 → CpG DNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, and epithelial cells.

Type I (IFN-α, IFN-β): produced by virus-infected cells (IFN-β from any nucleated cell, especially fibroblasts; IFN-α from plasmacytoid dendritic cells); triggered by detection of viral nucleic acids (dsRNA via TLR3, ssRNA via TLR7). Function: bind IFNAR on neighboring uninfected cells → activate JAK-STAT pathway → induce antiviral state (produce PKR which inhibits viral protein synthesis, activate RNase L which degrades viral RNA, upregulate MHC I). Also activate NK cells. Type II (IFN-γ): produced by Th1 cells and NK cells (not by virus-infected cells); triggered by antigen stimulation and IL-12. Function: potent macrophage activator (enhances phagocytosis, respiratory burst, antigen presentation via ↑MHC II); promotes Th1 differentiation; class switch to IgG in B cells. IFN-γ is the key link between innate and adaptive immunity.

Dendritic cells (DCs) are stellate (star-shaped) innate immune cells found in tissues that interface with the external environment (skin as Langerhans cells, mucosal surfaces, lymphoid organs). They are called professional antigen-presenting cells (APCs) because they: (1) constantly sample their environment via phagocytosis and macropinocytosis; (2) upon capturing antigen, mature and migrate via lymphatic vessels to the T cell zones of regional lymph nodes; (3) express high levels of MHC Class II (present to CD4⁺ T cells) and MHC Class I (cross-present to CD8⁺ T cells); (4) express co-stimulatory molecules (B7/CD80/CD86) required for T cell activation (Signal 2). DCs are the most potent activators of naive T cells — they are the critical bridge between innate and adaptive immunity.

1. Lysozyme (in tears, saliva, nasal secretions, breast milk): hydrolyzes peptidoglycan in bacterial cell walls → lysis. 2. Stomach acid (HCl, pH 1.5–3.5): denatures proteins and kills most ingested bacteria. 3. Defensins (in skin, neutrophil granules, Paneth cells of small intestine): small cationic peptides that form pores in bacterial/fungal membranes. 4. Sebum (from sebaceous glands): lipid-rich secretion that lowers skin pH to 3–5, creating hostile conditions for pathogens. 5. Lactoferrin (in breast milk, mucus, neutrophil granules): binds iron, depriving bacteria of this essential nutrient (iron sequestration). Also: complement proteins, collectins (surfactant proteins SP-A, SP-D in lungs), and the normal microbiota (competitive exclusion).

Eosinophils: circulate in blood (1–4% WBCs), migrate to tissues (GI tract, respiratory tract); granules contain major basic protein (MBP), eosinophil peroxidase, cationic protein; primary role: defense against parasitic helminths (too large to phagocytose — eosinophils degranulate toxic proteins onto the parasite surface); also contribute to allergic inflammation and tissue damage in asthma. Basophils: rarest circulating WBC (0.5–1%); granules contain histamine and heparin; express high-affinity IgE receptors (FcεRI); role: similar to mast cells but blood-borne; contribute to Type I hypersensitivity. Mast cells: tissue-resident (skin, mucosae, connective tissue near blood vessels); granules contain histamine, heparin, proteases, TNF-α; express FcεRI; role: sentinel cells that initiate inflammation and allergic responses upon IgE crosslinking → degranulation.

Chief cells secrete pepsinogen (inactive zymogen). Parietal cells secrete HCl, dropping gastric pH to 1.5–3.5. At low pH: (1) pepsinogen undergoes autocatalytic conversion — the acidic environment unfolds the molecule, exposing its active site → becomes pepsin; (2) active pepsin then cleaves other pepsinogen molecules (positive feedback amplification). Pepsin's optimal pH: 1.5–2.0 (one of the few enzymes active at extremely low pH). Pepsin is an endopeptidase: cleaves peptide bonds within the interior of protein chains → producing large polypeptide fragments. Pepsin is irreversibly denatured when chyme enters the alkaline duodenum (pH ~8), so its action is limited to the stomach.

MHC I: found on ALL nucleated cells; composed of one α chain (with α1, α2, α3 domains) + β₂-microglobulin; presents endogenous peptides (8–10 amino acids) from intracellular proteins (e.g., viral proteins, tumor antigens) to CD8⁺ cytotoxic T cells. Encoded by HLA-A, HLA-B, HLA-C genes. MHC II: found only on professional antigen-presenting cells (dendritic cells, macrophages, B cells); composed of an α chain and a β chain (each with two domains); presents exogenous peptides (13–25 amino acids) from phagocytosed/endocytosed material to CD4⁺ helper T cells. Encoded by HLA-DP, HLA-DQ, HLA-DR genes. Both are polygenic and polymorphic, contributing to transplant rejection.

T cell precursors migrate from bone marrow to the thymus as double-negative (CD4⁻CD8⁻) thymocytes. They rearrange TCR genes and become double-positive (CD4⁺CD8⁺). POSITIVE SELECTION occurs in the thymic cortex: cortical epithelial cells present self-MHC; thymocytes that bind self-MHC with moderate affinity survive (ensures MHC restriction); those that fail to bind undergo death by neglect (~90% die). Surviving cells become single-positive (CD4⁺ or CD8⁺) based on which MHC class they recognized. NEGATIVE SELECTION occurs at the corticomedullary junction and medulla: medullary epithelial cells and dendritic cells present self-antigens (aided by the AIRE transcription factor); thymocytes that bind self-antigens too strongly are deleted by apoptosis (establishes central tolerance). Only ~2–5% of thymocytes survive both selections as mature, self-tolerant, self-MHC-restricted naïve T cells.

Th1: driven by IL-12 and IFN-γ; master TF T-bet; secretes IFN-γ, TNF-β; activates macrophages and promotes cell-mediated immunity against intracellular pathogens. Th2: driven by IL-4; master TF GATA-3; secretes IL-4, IL-5, IL-13; promotes humoral immunity, eosinophil activation, IgE class switching; key in helminth defense and allergies. Th17: driven by IL-6 + TGF-β; master TF RORγt; secretes IL-17A, IL-17F, IL-22; recruits neutrophils, defends against extracellular bacteria and fungi at mucosal surfaces. Tfh (T follicular helper): driven by IL-6 + IL-21; master TF Bcl-6; expresses CXCR5; migrates to germinal centers; provides CD40L and IL-21 to B cells for affinity maturation, class switching, and memory B cell formation. Treg (regulatory): driven by TGF-β + IL-2; master TF FoxP3; expresses CD25; secretes IL-10, TGF-β; suppresses immune responses and maintains peripheral tolerance.

Mechanism 1 — PERFORIN/GRANZYME PATHWAY: CTLs release cytotoxic granules via directed exocytosis toward the target cell. Perforin polymerizes and forms pores (~16 nm) in the target cell membrane, allowing granzymes (serine proteases, especially granzyme B) to enter. Granzyme B cleaves and activates caspase-3 and caspase-7, and also cleaves Bid to tBid (which triggers mitochondrial cytochrome c release), initiating apoptosis. This is the dominant killing mechanism. Mechanism 2 — FAS/FASL (CD95/CD95L) PATHWAY: CTLs express Fas ligand (FasL/CD178) on their surface, which binds Fas (CD95) on target cells. Fas trimerization recruits FADD (Fas-associated death domain), which activates caspase-8 via the DISC (death-inducing signaling complex), triggering the extrinsic apoptosis cascade. Both pathways converge on caspase-3 activation, leading to DNA fragmentation, membrane blebbing, and formation of apoptotic bodies — a non-inflammatory form of cell death (unlike necrosis).

T-DEPENDENT (TD) ACTIVATION: Requires help from Tfh cells. B cell internalizes antigen via BCR, processes it, and presents peptide on MHC II to Tfh cells. Tfh provides Signal 1 (TCR-MHC II interaction), Signal 2 (CD40L on Tfh binds CD40 on B cell), and Signal 3 (cytokines like IL-4, IL-21). This triggers germinal center reactions with somatic hypermutation (point mutations in variable regions at rate ~10⁻³/bp/division), affinity maturation (selection for higher-affinity BCRs by follicular dendritic cells), and class switching (IgM → IgG, IgA, or IgE via switch recombination using AID enzyme). Produces long-lived plasma cells and memory B cells. Most protein antigens are TD. T-INDEPENDENT (TI) ACTIVATION: No T cell help needed. TI-1 antigens (e.g., LPS) are polyclonal B cell activators at high concentration. TI-2 antigens (e.g., bacterial capsular polysaccharides) have repetitive epitopes that extensively crosslink BCRs. Primarily produces short-lived plasma cells secreting IgM. No significant class switching, affinity maturation, or memory cell generation. Weaker, shorter-lived response.

IgG: Most abundant (~75–80% of serum Ig); monomer; 4 subclasses (IgG1–4); only Ig to cross placenta (via FcRn receptor); longest half-life (~23 days); opsonization, complement activation (classical pathway), ADCC, neutralization; dominant in secondary response. IgM: ~10% of serum Ig; pentamer in serum (joined by J chain), monomer as BCR; first antibody produced in primary response; most efficient complement activator (one pentamer can activate C1q); cannot cross placenta; indicates acute infection. IgA: ~15% of serum Ig; monomer in serum, DIMER in secretions (joined by J chain + secretory component from poly-Ig receptor); most abundant Ig in mucosal secretions (saliva, breast milk, tears, gut); prevents pathogen attachment; key in mucosal immunity. IgE: lowest serum concentration (~0.002%); monomer; binds FcεRI on mast cells and basophils with very high affinity; crosslinking by antigen triggers degranulation (histamine release); mediates Type I hypersensitivity (allergies, anaphylaxis) and defense against helminths. IgD: ~0.2% of serum Ig; monomer; co-expressed with IgM on mature naïve B cells as BCR; function in serum poorly understood; may activate basophils and mast cells.

IgG is a Y-shaped glycoprotein (~150 kDa) composed of 4 polypeptide chains: 2 identical heavy chains (H, ~50 kDa each, γ type) and 2 identical light chains (L, ~25 kDa each, κ or λ type), linked by interchain disulfide bonds. Each chain has a VARIABLE (V) region at the N-terminus and CONSTANT (C) regions. Light chains: VL + CL (1 constant domain). Heavy chains: VH + CH1 + hinge + CH2 + CH3. The HINGE REGION between CH1 and CH2 provides flexibility for bivalent antigen binding; rich in proline and cysteine (inter-heavy-chain disulfides). Papain digestion yields 2 Fab fragments + 1 Fc fragment. Pepsin yields 1 F(ab')₂ + degraded Fc. FAB (Fragment antigen-binding): VH + CH1 + VL + CL; contains the antigen-binding site. FC (Fragment crystallizable): CH2 + CH3 of both heavy chains; mediates effector functions (complement binding at CH2, FcR binding, placental transfer). Each V region contains 3 COMPLEMENTARITY-DETERMINING REGIONS (CDR1, CDR2, CDR3) — the hypervariable loops that directly contact the epitope. CDR3 of the heavy chain is most diverse (due to V-D-J recombination and junctional diversity).

PRIMARY RESPONSE: Occurs on first exposure to antigen. Lag period of 5–10 days before detectable antibody. Predominantly IgM produced first (peaks ~day 7–10), with limited later IgG. Lower overall antibody titer (magnitude). Lower average antibody affinity. Shorter duration; antibody levels decline relatively quickly. Activates naïve B and T cells; generates initial memory cells. SECONDARY (ANAMNESTIC) RESPONSE: Occurs on re-exposure to same antigen. Shorter lag period (1–3 days) due to pre-existing memory B and T cells. Predominantly IgG (or IgA/IgE depending on context) — rapid class switching. Much higher antibody titer (10–100× greater magnitude). Higher antibody affinity due to prior somatic hypermutation and affinity maturation in germinal centers. Longer duration; antibody levels remain elevated for months to years. Memory B cells have already undergone class switching and affinity maturation, so they differentiate rapidly into high-affinity plasma cells. This principle underlies vaccination: prime with initial dose, boost to generate robust secondary response.

ACTIVE IMMUNITY: Host's own immune system produces antibodies and memory cells after antigen exposure. Slow onset (days to weeks) but LONG-LASTING due to immunological memory. Natural active: infection/recovery (e.g., getting chickenpox → lifelong immunity). Artificial active: vaccination (e.g., mRNA COVID vaccines, attenuated MMR, inactivated polio, toxoid tetanus/diphtheria). Vaccine types include live attenuated, inactivated/killed, subunit/recombinant, toxoid, conjugate, mRNA, and viral vector. PASSIVE IMMUNITY: Pre-formed antibodies transferred to recipient. Immediate protection but TEMPORARY (weeks to months) — no memory cells generated; antibodies degrade over time (IgG half-life ~23 days). Natural passive: maternal IgG crossing placenta (via FcRn) to fetus; IgA in breast milk (colostrum). Artificial passive: injection of immune serum/antiserum (e.g., anti-rabies immunoglobulin post-exposure, anti-RhD for hemolytic disease of newborn, antivenom for snakebite, IV immunoglobulin therapy, monoclonal antibodies like palivizumab for RSV). Key distinction: Active = memory + slow; Passive = no memory + fast.

ANTIGEN: Any molecule that can bind specifically to an antibody or TCR. IMMUNOGEN: A substance that can provoke an adaptive immune response (all immunogens are antigens, but not all antigens are immunogens). HAPTEN: A small molecule (<1 kDa) that can bind antibodies (antigenic) but cannot independently elicit an immune response (not immunogenic alone). A hapten becomes immunogenic when conjugated to a larger carrier protein — the carrier provides T cell epitopes so Tfh cells can help B cells that recognize the hapten. Example: penicillin acts as a hapten by binding to serum proteins, forming a hapten-carrier complex that can trigger allergic reactions. EPITOPE (ANTIGENIC DETERMINANT): The specific portion of an antigen (~5–15 amino acids or ~5–7 sugar residues) that is recognized and bound by an antibody or TCR. Can be linear/sequential (continuous amino acid sequence) or conformational/discontinuous (formed by protein folding bringing distant residues together). B cells can recognize both; T cells only recognize linear epitopes (processed peptides on MHC). SUPERANTIGEN: Molecules (e.g., Staphylococcal enterotoxins, TSST-1, Streptococcal pyrogenic exotoxins) that bypass normal antigen processing by simultaneously binding MHC II (outside the groove) and TCR Vβ region; activate up to 20% of all T cells (vs. normal 0.0001–0.001%), causing massive cytokine release ('cytokine storm'), leading to toxic shock syndrome.

Type I (Immediate/Anaphylactic): Mediated by IgE antibodies bound to mast cells and basophils. Upon re-exposure to allergen, cross-linking of IgE triggers degranulation releasing histamine, leukotrienes, and prostaglandins. Onset within minutes. Example: anaphylaxis to peanuts, allergic asthma. Type IV (Delayed-Type Hypersensitivity): Mediated by sensitized T cells (CD4+ Th1 and CD8+ cytotoxic T cells), not antibodies. Macrophages are recruited and activated by cytokines (IFN-γ, TNF). Onset 24–72 hours after exposure. Example: contact dermatitis from poison ivy, tuberculin skin test (Mantoux test). Key distinction: Type I is antibody-mediated and immediate; Type IV is cell-mediated and delayed.

Type II (Cytotoxic): IgG or IgM antibodies bind directly to antigens on the surface of host cells or tissues. Damage occurs via complement activation (MAC formation), opsonization and phagocytosis, or antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells. Target is cell-surface or matrix antigens. Examples: hemolytic disease of the newborn (Rh incompatibility), transfusion reactions, autoimmune hemolytic anemia, Goodpasture syndrome (anti-GBM antibodies). Type III (Immune Complex): IgG antibodies form soluble antigen-antibody complexes in the bloodstream. These immune complexes deposit in tissues (blood vessel walls, kidneys, joints), activating complement and recruiting neutrophils. Neutrophil lysosomal enzymes cause local tissue destruction. Examples: serum sickness, systemic lupus erythematosus (SLE), Arthus reaction, post-streptococcal glomerulonephritis. Key distinction: Type II targets cell-bound antigens; Type III involves soluble circulating complexes depositing in tissues.

Molecular mimicry: A microbial antigen shares structural similarity with a self-antigen, causing immune cells primed against the pathogen to cross-react with host tissues. Example: Rheumatic fever — antibodies against Streptococcus pyogenes M protein cross-react with cardiac myosin and heart valve tissue, causing rheumatic heart disease. Epitope spreading: Initial immune attack on one self-antigen causes tissue damage that exposes previously hidden (cryptic) self-epitopes, broadening the autoimmune response to additional self-targets over time. This perpetuates and worsens disease. Example: Multiple sclerosis (MS) — initial T cell attack on one myelin protein (e.g., MBP) damages the myelin sheath, exposing other myelin epitopes (e.g., PLP, MOG), progressively expanding the autoimmune response and demyelination.

Hashimoto's thyroiditis: CD8+ cytotoxic T cells and anti-thyroid antibodies (anti-thyroid peroxidase/anti-TPO, anti-thyroglobulin) destroy thyroid follicular cells. Results in hypothyroidism — decreased T3/T4, elevated TSH. Thyroid gland shows lymphocytic infiltration and follicular destruction. Most common cause of hypothyroidism in iodine-sufficient regions. Graves' disease: Thyroid-stimulating immunoglobulins (TSI), which are IgG autoantibodies, bind and activate the TSH receptor, mimicking TSH. Results in hyperthyroidism — elevated T3/T4, suppressed TSH (negative feedback). Classic triad: diffuse goiter, exophthalmos (bulging eyes from retro-orbital inflammation), pretibial myxedema. Key contrast: Hashimoto's is destructive (Type II/IV hypersensitivity → hypothyroid); Graves' is stimulatory (Type II hypersensitivity with stimulating antibodies → hyperthyroid). Both are organ-specific autoimmune diseases of the thyroid with strong female predominance.

1. Attachment: HIV gp120 envelope protein binds to CD4 receptor on helper T cells (also macrophages and dendritic cells). 2) Co-receptor binding: gp120 undergoes conformational change and binds co-receptor — CCR5 (macrophage-tropic, early infection) or CXCR4 (T cell-tropic, later infection). 3) Fusion: gp41 mediates fusion of viral envelope with host cell membrane, releasing viral core into cytoplasm. 4) Reverse transcription: Viral RNA is converted to double-stranded DNA by reverse transcriptase (RNA-dependent DNA polymerase). This enzyme is error-prone, generating high mutation rates. 5) Nuclear import: Viral dsDNA enters the nucleus via the nuclear pore complex. 6) Integration: Viral integrase inserts the dsDNA into the host genome, forming proviral DNA. The provirus can remain latent or be actively transcribed. This integrated state makes HIV impossible to fully eradicate with current therapies and is why HAART (Highly Active Antiretroviral Therapy) must be lifelong.

HAART (Highly Active Antiretroviral Therapy) is a combination regimen using 3+ antiretroviral drugs from at least 2 different classes to suppress HIV replication. Major drug classes: 1) NRTIs (nucleoside reverse transcriptase inhibitors, e.g., tenofovir, emtricitabine) — compete with natural nucleosides during reverse transcription; 2) NNRTIs (non-nucleoside RTIs, e.g., efavirenz) — bind and inhibit reverse transcriptase allosterically; 3) Protease inhibitors (e.g., ritonavir) — block cleavage of polyproteins needed for virion assembly; 4) Integrase inhibitors (e.g., dolutegravir) — prevent proviral DNA insertion; 5) Entry/fusion inhibitors (e.g., maraviroc blocks CCR5, enfuvirtide blocks gp41 fusion). Multi-drug therapy is essential because HIV reverse transcriptase has no proofreading, producing ~1 mutation per replication cycle. Monotherapy rapidly selects for resistant mutants. Combining drugs targeting different steps makes simultaneous resistance to all drugs statistically near-impossible. HAART reduces viral load to undetectable levels and allows CD4+ T cell recovery.

SCID (Severe Combined Immunodeficiency): Affects both B and T cells (and often NK cells). Most common form is X-linked SCID due to mutation in IL-2 receptor gamma chain (γc), shared by receptors for IL-2, -4, -7, -9, -15, -21. Presents in infancy with severe, recurrent infections by bacteria, viruses, fungi, and opportunistic organisms. Fatal without bone marrow transplant or gene therapy. 'Bubble boy' disease. X-linked Agammaglobulinemia (XLA/Bruton's): Selective B cell deficiency. Mutation in BTK (Bruton's tyrosine kinase) gene on X chromosome blocks B cell maturation at pre-B cell stage. No mature B cells, no immunoglobulins. Presents after 6 months (maternal IgG wanes) with recurrent encapsulated bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae). T cell immunity intact — handle viral infections normally. Treated with lifelong IV immunoglobulin (IVIG). DiGeorge Syndrome: Selective T cell deficiency. Caused by 22q11.2 microdeletion leading to failed development of 3rd and 4th pharyngeal pouches → thymic hypoplasia/aplasia. Absent or hypoplastic thymus means T cells cannot mature. Also causes parathyroid hypoplasia (hypocalcemia/tetany), cardiac defects, and characteristic facial features. Susceptible to viral, fungal, and intracellular bacterial infections. Treated with thymic transplant in severe cases.

Phase 1 — Sensitization (first exposure, no symptoms): 1) Allergen (e.g., pollen) is taken up by dendritic cells and presented to Th2 helper T cells. 2) Th2 cells release IL-4 and IL-13, driving B cell class switching to IgE production. 3) IgE antibodies bind via their Fc region to high-affinity FcεRI receptors on mast cells and basophils, 'arming' them. The individual is now sensitized. Phase 2 — Effector response (re-exposure, symptoms): 1) Same allergen re-enters and cross-links two adjacent surface-bound IgE molecules on mast cells. 2) Cross-linking triggers mast cell degranulation — release of preformed mediators: histamine (vasodilation, increased vascular permeability, bronchoconstriction, itching), tryptase, and heparin. 3) Newly synthesized mediators follow: leukotrienes C4/D4/E4 (prolonged bronchoconstriction, 1000× more potent than histamine), prostaglandin D2, and platelet-activating factor (PAF). 4) Late-phase response (4–8 hours): cytokines recruit eosinophils and Th2 cells, causing sustained inflammation. Anaphylaxis: Systemic mast cell degranulation → massive vasodilation, hypotension, laryngeal edema, bronchospasm → cardiovascular collapse. Treatment: intramuscular epinephrine (activates α1 receptors → vasoconstriction; β2 receptors → bronchodilation; β1 → increased cardiac output).

Live attenuated: Contains weakened but replicating pathogen. Elicits strong, long-lasting humoral and cell-mediated immunity (mimics natural infection). Can revert to virulence rarely. Contraindicated in immunocompromised patients. Example: MMR (measles, mumps, rubella), oral polio (Sabin). Inactivated (killed): Contains whole pathogen killed by heat/chemicals. Cannot replicate — safer but weaker immune response. Primarily humoral (antibody) response. Often requires multiple doses/boosters and adjuvants. Example: inactivated polio (Salk), hepatitis A, rabies. mRNA vaccines: Deliver synthetic mRNA encoding a pathogen protein (e.g., spike protein) encapsulated in lipid nanoparticles. Host ribosomes translate the mRNA into antigen, triggering both humoral and cellular immunity. mRNA degrades quickly, never enters nucleus, cannot integrate into DNA. Example: Pfizer-BioNTech and Moderna COVID-19 vaccines. Viral vector: Uses a harmless virus (e.g., adenovirus) engineered to carry gene for pathogen antigen. Vector infects cells and expresses the antigen, stimulating strong humoral and cellular responses. Pre-existing immunity to the vector can reduce efficacy. Example: Johnson & Johnson COVID-19 vaccine (Ad26), AstraZeneca (ChAdOx1). Additional types: Subunit (purified protein antigen, e.g., hepatitis B HBsAg); Toxoid (inactivated toxin, e.g., tetanus, diphtheria).

Herd immunity (community immunity): When a sufficient proportion of a population is immune to an infectious disease (through vaccination or prior infection), indirect protection is conferred to susceptible individuals because chains of transmission are disrupted. Mathematical basis: The herd immunity threshold (HIT) is calculated as HIT = 1 − (1/R₀), where R₀ is the basic reproduction number (average number of secondary infections from one case in a fully susceptible population). Example: Measles has R₀ ≈ 12–18, so HIT = 1 − 1/15 ≈ 93–95% of the population must be immune. Pertussis (R₀ ≈ 12–17) requires ~92–94%. Polio (R₀ ≈ 5–7) requires ~80–86%. Critical importance: Herd immunity protects those who cannot be vaccinated — infants too young for vaccines, immunocompromised patients (e.g., chemotherapy, organ transplant recipients, SCID), pregnant women (for live vaccines), and the elderly with waning immunity. When vaccination rates drop below HIT, outbreaks occur in susceptible pockets (e.g., measles outbreaks in under-vaccinated communities). Herd immunity does NOT require 100% vaccination — it works by reducing the effective reproduction number (Rₑ) below 1, causing the epidemic to decline.