B Pharmacy Sem 3: Pathophysiology I
Subject 5 : Pathophysiology I
1. Cell Injury, Adaptation & Death
2. Acute & Chronic Inflammation
3. Hemodynamic Disorders: Edema, Thrombosis & Shock
4. Disorders of Blood Cells: Anemias & Leukemias
5. Immune Mechanisms & Hypersensitivity Reactions
6. Introduction to Infectious Disease Pathology
Unit 1: Cell Injury, Adaptation & Death
This unit explores how cells respond to stress, the mechanisms by which they adapt or succumb, and the biochemical and morphological hallmarks of reversible and irreversible injury culminating in cell death.
1.1 Cellular Homeostasis & Stressors
Homeostasis: Dynamic equilibrium of the cellular environment, maintained by ATP‑dependent ion pumps, redox balance, and macromolecular turnover.
Stressors: Hypoxia, toxins, free radicals, infection, physical trauma, nutritional deficiencies.
1.2 Adaptive Responses
| Adaptation Type | Definition | Mechanism & Examples |
|---|---|---|
| Hypertrophy | ↑ Cell size to meet increased functional demand | ↑ synthesis of cytoskeletal proteins (e.g., cardiac muscle in hypertension) |
| Hyperplasia | ↑ Cell number via mitosis | Hormonal (endometrial proliferation), compensatory (liver regeneration) |
| Atrophy | ↓ Cell size and function under diminished demand | Ubiquitin‑proteasome degradation of proteins (e.g., disuse muscle atrophy) |
| Metaplasia | Reversible change of one differentiated cell type to another | Chronic irritation in smokers: columnar → squamous epithelium |
1.3 Mechanisms of Reversible Injury
ATP Depletion: Impairs Na⁺/K⁺‑ATPase → cellular swelling; Ca²⁺ pump failure → intracellular Ca²⁺ rise.
Membrane Alterations: Increased permeability, blebbing, detachment of ribosomes.
Mitochondrial Swelling: Due to permeability transition pore opening; reversible if brief.
ER Swelling & Ribosomal Detachment: ↓ protein synthesis; clumping of chromatin.
1.4 Mechanisms of Irreversible Injury & Cell Death
1.4.1 Necrosis
Morphology: Loss of membrane integrity, enzymatic digestion, inflammation.
Patterns:
Coagulative (ischemic heart)—preserved architecture, “ghost cells.”
Liquefactive (brain infarct, abscess)—tissue softens into liquid.
Caseous (TB)—cheese‑like necrotic debris.
Fat (pancreatitis)—fat saponification in peripancreatic fat.
Gangrenous—extremity ischemia, may be wet (superinfection) or dry.
1.4.2 Apoptosis
Morphology: Cell shrinkage, chromatin condensation, membrane blebs, apoptotic bodies phagocytosed without inflammation.
Pathways:
Intrinsic (Mitochondrial): BAX/BAK activation → cytochrome c release → caspase‑9 → caspase cascade.
Extrinsic (Death Receptor): FasL or TNF binds receptor → DISC formation → caspase‑8 activation.
Physiological Roles: Embryogenesis, lymphocyte selection, hormone‑dependent involution.
Pathological Roles: DNA damage (p53‑mediated), viral cytotoxicity, cancer therapeutics.
1.5 Role of Reactive Oxygen Species (ROS)
Sources: Mitochondrial leakage, NADPH oxidase, xanthine oxidase, P450 metabolism.
Targets: Lipid peroxidation, protein oxidation, DNA strand breaks.
Defense Mechanisms: Superoxide dismutase, catalase, glutathione peroxidase.
Pathological Implications: Ischemia–reperfusion injury, chemical toxicity (e.g., CCl₄), chronic inflammation.
1.6 Cellular Calcium Overload
Mechanism: Increased cytosolic Ca²⁺ activates phospholipases, proteases, endonucleases, ATPases.
Consequences: Membrane damage, cytoskeletal degradation, nuclear fragmentation.
1.7 Key Molecular Events in Cell Death
Mitochondrial Dysfunction → ATP depletion & ROS.
Membrane Damage → loss of osmotic balance.
Proteolysis & DNA Fragmentation → caspase activation (apoptosis) or lysosomal enzymes (necrosis).
1.8 Key Points for Exams
Differentiate reversible vs. irreversible injury by listing two morphological and two biochemical criteria each.
Compare necrosis and apoptosis in terms of mechanism, morphology, and inflammatory response.
Outline the intrinsic apoptotic pathway, naming at least three key proteins.
Explain how ROS generation contributes to cellular injury and name two antioxidant defenses.
Describe an example of cellular adaptation (e.g., hypertrophy) and its physiological trigger.
Unit 2: Acute & Chronic Inflammation
This unit examines the body’s inflammatory responses—rapid acute inflammation and prolonged chronic inflammation—detailing their cellular and molecular mechanisms, morphological features, outcomes, and therapeutic modulation.
2.1 Overview & Classification
Inflammation: Host response to tissue injury or infection, aiming to eliminate the cause, clear debris, and initiate repair.
Types:
Acute: Rapid onset, short duration (minutes–days), predominated by vascular changes and neutrophil influx.
Chronic: Insidious, prolonged (weeks–years), characterized by mononuclear cell infiltration, tissue destruction, and repair with fibrosis.
2.2 Acute Inflammation
2.2.1 Vascular Events
Vasodilation: Mediated by histamine, nitric oxide → increased blood flow → erythema and heat.
Increased Vascular Permeability: Endothelial contraction (histamine, bradykinin), direct injury, leukocyte‑mediated damage → protein‑rich exudate (edema).
2.2.2 Cellular Events
Margination & Rolling: Neutrophils tether and roll along endothelium via selectins (E‑, P‑selectin).
Adhesion & Transmigration: Integrins (LFA‑1) bind ICAM‑1; neutrophils migrate through interendothelial junctions.
Chemotaxis: Directed migration along gradients of IL‑8, C5a, LTB₄.
Phagocytosis & Killing: Recognition (opsonins: IgG, C3b), engulfment into phagolysosomes, microbial killing by ROS and lysosomal enzymes.
2.2.3 Chemical Mediators
| Mediator | Source | Actions |
|---|---|---|
| Histamine | Mast cells, basophils | Vasodilation, ↑ permeability |
| Prostaglandins | COX‑derived from arachidonic acid | Vasodilation, pain, fever |
| Leukotrienes | 5‑LOX pathway | Chemotaxis (LTB₄), bronchospasm (LTC₄, LTD₄, LTE₄) |
| Cytokines (TNF, IL‑1) | Macrophages, endothelial cells | Fever, endothelial activation, acute‑phase protein synthesis |
| Complement (C3a, C5a) | Plasma | Anaphylatoxin (C3a), chemotaxis/opsonization (C5a) |
| Platelet‑Activating Factor | Leukocytes, endothelium | Vasodilation, permeability, leukocyte activation |
2.2.4 Outcomes of Acute Inflammation
Complete Resolution: Removal of stimulus, restoration of tissue architecture.
Suppuration & Abscess Formation: Localized pus collection if neutrophils predominate.
Chronic Inflammation: Persistence of injurious agent or inability to degrade debris.
Fibrosis & Scarring: When injury is severe or in tissues incapable of regeneration.
2.3 Chronic Inflammation
2.3.1 Cellular Composition & Morphology
Mononuclear Infiltrate: Macrophages, lymphocytes, plasma cells.
Tissue Destruction: Mediated by persistent offending agents and inflammatory cells.
Repair & Fibrosis: Angiogenesis and fibroblast activation lead to collagen deposition.
2.3.2 Granulomatous Inflammation
Definition: Focal collection of activated (epithelioid) macrophages often with multinucleated giant cells and a lymphocyte collar.
Types:
Immune Granulomas: Driven by Th1 response and IFN‑γ (e.g., tuberculosis).
Foreign Body Granulomas: Induced by inert material (sutures, talc) without T‑cell involvement.
2.3.3 Mediators & Regulation
Macrophage‑Derived: IL‑1, TNF, IL‑12 promote inflammation and granuloma formation.
T‑Cell‑Derived: IFN‑γ activates macrophages; IL‑4, IL‑13 promote alternative (wound‑healing) macrophage phenotype.
Matrix Metalloproteinases (MMPs): Secreted by macrophages to remodel extracellular matrix.
2.4 Systemic Manifestations (Acute‑Phase Response)
Fever: Pyrogens (IL‑1, TNF) act on hypothalamus via PGE₂.
Leukocytosis: Neutrophilia in acute, lymphocytosis in chronic.
Acute‑Phase Proteins: Hepatic synthesis of CRP, fibrinogen, serum amyloid A.
Sepsis & SIRS: Dysregulated cytokine storm leading to hypotension, coagulopathy, organ dysfunction.
2.5 Pharmacological Modulation
| Drug Class | Targets | Clinical Use |
|---|---|---|
| NSAIDs | COX‑1/2 inhibitors | Analgesia, antipyresis, mild anti‑inflammatory |
| Glucocorticoids | NF‑κB inhibition; cytokine suppression | Autoimmune diseases, asthma, transplant rejection |
| Anti‑TNF Agents | Neutralize TNF‑α (e.g., infliximab) | Rheumatoid arthritis, IBD |
| Leukotriene Modifiers | 5‑LOX inhibitors (zileuton), receptor antagonists (montelukast) | Asthma |
| Anti‑histamines | H₁ receptor antagonists | Allergies |
2.6 Key Points for Exams
Compare vascular vs. cellular events in acute inflammation, naming one mediator for each.
Outline the steps of leukocyte extravasation and the adhesion molecules involved.
Describe granuloma structure and name two causes of granulomatous inflammation.
List three acute‑phase proteins and their functions.
Explain how corticosteroids attenuate both acute and chronic inflammation.
Unit 3: Hemodynamic Disorders – Edema, Thrombosis & Shock
This unit examines disturbances in normal blood flow and fluid balance—namely edema, thrombus formation, and shock—detailing their pathophysiology, clinical manifestations, and therapeutic approaches.
3.1 Fundamentals of Hemodynamics
Normal Fluid Compartments:
Intravascular (plasma), interstitial, and intracellular spaces.
Plasma volume ≈ 5 L; interstitial ≈ 10–12 L; intracellular ≈ 25 L.
Starling Forces govern fluid exchange across capillaries:
Hydrostatic Pressure (P) pushes fluid out of the capillary.
Oncotic (Colloid Osmotic) Pressure (π) draws fluid into the capillary (primarily albumin).
Net Filtration = (Pc – Pi) – (πc – πi).
Small shifts in any component can cause abnormal fluid accumulation (edema).
3.2 Edema
3.2.1 Definition & Types
Edema: Excess fluid in the interstitial or serous cavities.
Localized (e.g., inflammatory edema, lymphatic obstruction).
Generalized (Anasarca): systemic (heart failure, nephrotic syndrome).
3.2.2 Pathogenetic Mechanisms
| Mechanism | Cause Examples |
|---|---|
| ↑ Capillary Hydrostatic Pressure | Heart failure, venous obstruction (DVT, cirrhosis) |
| ↓ Plasma Oncotic Pressure | Hypoalbuminemia (nephrotic syndrome, malnutrition) |
| ↑ Capillary Permeability | Inflammation, burns, allergic reactions |
| Lymphatic Obstruction | Surgical removal (mastectomy), filariasis |
| Sodium & Water Retention | Renal failure, excess aldosterone |
3.2.3 Clinical Features & Sites
Pitting Edema: Pressing leaves a pit (e.g., CHF).
Non‑Pitting Edema: Lymphatic (e.g., lymphedema).
Effusions:
Pleural (hydrothorax), pericardial (hydropericardium), peritoneal (ascites).
3.3 Thrombosis
3.3.1 Definition & Virchow’s Triad
Thrombus: Intravascular coagulum of platelets, fibrin, erythrocytes.
Virchow’s Triad:
Endothelial Injury: Atherosclerosis, trauma, hypertension.
Abnormal Blood Flow: Stasis (immobility), turbulence.
Hypercoagulability: Genetic (Factor V Leiden), acquired (malignancy, OCPs).
3.3.2 Thrombus Formation & Growth
Initiation: Platelet adhesion to exposed subendothelium.
Propagation: Fibrin deposition, recruitment of red cells (“red thrombus”) or platelets (“white thrombus”).
Fate:
Propagation: enlarges thrombus.
Embolization: detaches → travels to distant site.
Dissolution: fibrinolysis (plasmin).
Organization & Recanalization: ingrowth of endothelium and smooth muscle.
3.3.3 Clinical Consequences
Arterial Thrombosis: MI, stroke, limb ischemia.
Venous Thrombosis: DVT → pulmonary embolism.
Microvascular Thrombosis: DIC → multi‑organ failure.
3.4 Shock
3.4.1 Definition & Classification
Shock: Global hypoperfusion leading to cellular dysfunction and organ failure.
Types:
Hypovolemic: ↓ intravascular volume (hemorrhage, dehydration).
Cardiogenic: Pump failure (MI, arrhythmias).
Distributive: Maldistribution of flow (septic, anaphylactic, neurogenic).
Obstructive: Impeded flow (cardiac tamponade, massive PE).
3.4.2 Pathophysiology & Stages
Initial: Compensation via tachycardia, vasoconstriction, RAAS activation.
Progressive: Tissue hypoxia → anaerobic metabolism → lactic acidosis, cell injury.
Irreversible: Widespread cellular death, multi‑organ dysfunction, refractory hypotension.
3.4.3 Cellular & Molecular Changes
Mitochondrial Dysfunction → ↓ ATP, ROS generation.
Endothelial Activation → ↑ permeability, leukocyte adhesion.
Inflammatory Mediators (TNF, IL‑1) amplify injury in septic shock.
3.5 Therapeutic Approaches
| Disorder | Treatment Strategies |
|---|---|
| Edema | Diuretics (furosemide, spironolactone); compression; salt restriction |
| Thrombosis | Anticoagulants (heparin, warfarin, DOACs); antiplatelets (aspirin, clopidogrel); thrombolytics (tPA) |
| Shock |
Hypovolemic: Crystalloids, blood products, correct hemorrhage
Cardiogenic: Inotropes (dobutamine), diuretics, revascularization
Septic: Broad‑spectrum antibiotics, fluid resuscitation, vasopressors (norepinephrine)
Anaphylactic: Epinephrine IM, antihistamines, corticosteroids |
3.6 Key Points for Exams
Explain Starling forces and how each imbalance leads to edema.
List Virchow’s triad components and give one example of each.
Compare arterial vs. venous thrombi in composition and clinical outcome.
Outline the compensatory mechanisms in early shock and their failure in progressive shock.
Match each shock type with its primary therapeutic intervention.
Unit 4: Disorders of Blood Cells – Anemias & Leukemias
This unit covers the pathophysiology, classification, clinical features, laboratory evaluation, and therapeutic approaches to common disorders of red and white blood cells—specifically anemias and leukemias.
4.1 Overview of Hematopoiesis
Sites:
Fetal: Yolk sac → liver/spleen → bone marrow.
Adult: Bone marrow of vertebrae, ribs, pelvis, proximal long bones.
Lineages:
Erythroid: Erythrocytes.
Myeloid: Granulocytes, monocytes, megakaryocytes (platelets).
Lymphoid: B‑ and T‑lymphocytes, NK cells.
Regulation:
Erythropoietin (EPO) from kidney stimulates erythroid progenitors.
Cytokines (GM‑CSF, G‑CSF, IL‑3) for myeloid/megakaryocytic lines.
Thrombopoietin (TPO) for platelets.
4.2 Anemias
4.2.1 Definition & Classification
Anemia: ↓ Hemoglobin (Hgb), Hematocrit (Hct), or RBC count below age/gender norms.
By Size (MCV):
Microcytic (<80 fL): Iron deficiency, thalassemia, anemia of chronic disease (late).
Normocytic (80–100 fL): Acute blood loss, anemia of chronic disease (early), hemolysis.
Macrocytic (>100 fL): Megaloblastic (B₁₂/folate deficiency), non‑megaloblastic (liver disease).
4.2.2 Iron‑Deficiency Anemia
Etiology: Chronic blood loss (menstrual, GI bleeding), inadequate intake, malabsorption.
Pathogenesis: ↓ iron → impaired heme synthesis → microcytic, hypochromic RBCs.
Lab Findings:
↓ Serum ferritin; ↑ TIBC; ↓ serum iron; ↓ transferrin saturation.
Peripheral smear: microcytosis, anisopoikilocytosis, pencil cells.
Clinical: Fatigue, pallor, glossitis, koilonychia, pica.
Treatment: Oral ferrous sulfate; IV iron for malabsorption or severe.
4.2.3 Megaloblastic Anemia
Etiology: Vitamin B₁₂ (pernicious anemia, malabsorption) or folate deficiency.
Pathogenesis: Impaired DNA synthesis → nuclear‑cytoplasmic asynchrony; megaloblasts in marrow.
Lab Findings:
Macrocytosis, hypersegmented neutrophils, target cells.
↑ MCV, ↑ LDH, ↑ bilirubin; low B₁₂/folate levels.
Schilling test historically for B₁₂ absorption.
Clinical: Glossitis, GI symptoms, neurologic (B₁₂): paresthesias, ataxia, dementia.
Treatment:
B₁₂: IM cyanocobalamin or high‑dose oral; folate: oral folic acid (avoid in B₁₂ deficiency alone).
4.2.4 Hemolytic Anemias
Intrinsic: RBC membrane (spherocytosis), enzyme defects (G6PD), hemoglobinopathies (sickle cell).
Extrinsic: Immune (warm/cold AIHA), microangiopathic (DIC, TTP), infections (malaria).
Pathogenesis: Premature RBC destruction → ↑ LDH, ↑ indirect bilirubin, ↑ reticulocyte count.
Clinical: Jaundice, splenomegaly, gallstones.
Treatment:
Remove cause (stop drug, treat infection).
Splenectomy (hereditary spherocytosis), immunosuppression (AIHA), hydroxyurea (sickle cell).
4.3 Leukemias
4.3.1 Definition & Classification
Leukemia: Clonal malignancy of hematopoietic progenitors circulating in blood and marrow.
Acute vs. Chronic:
Acute: Immature blasts predominate; rapid onset.
Chronic: Mature cells accumulate; often indolent.
Lineage:
Myeloid (AML, CML)
Lymphoid (ALL, CLL)
4.3.2 Acute Leukemias
ALL (Acute Lymphoblastic Leukemia):
Common in children; t(12;21) favorable; t(9;22) poor prognosis.
Presentation: Bone pain, fever, lymphadenopathy, CNS involvement.
Labs: >20% lymphoblasts in marrow, TdT⁺, CD10/CD19 markers.
Treatment: Multiagent chemo (vincristine, corticosteroids, asparaginase), intrathecal MTX, BMT.
AML (Acute Myeloid Leukemia):
Median age ~65; subtypes M3 (APL) t(15;17) responds to ATRA.
Presentation: Fatigue, bleeding, chloromas.
Labs: >20% myeloblasts, Auer rods, MPO⁺.
Treatment: Cytarabine + anthracycline induction; ATRA for APL; BMT for high‑risk.
4.3.3 Chronic Leukemias
CML (Chronic Myelogenous Leukemia):
t(9;22) BCR‑ABL → constitutive tyrosine kinase; splenomegaly, leukocytosis.
Phases: Chronic → accelerated → blast crisis.
Treatment: Imatinib (TKI), dasatinib, allogeneic BMT in refractory.
CLL (Chronic Lymphocytic Leukemia):
Elderly; often asymptomatic lymphocytosis; smudge cells.
CD5⁺ B cells; hypogammaglobulinemia.
Treatment: Observation if indolent; fludarabine, rituximab for symptomatic.
4.4 Diagnostic & Monitoring Tools
Complete Blood Count (CBC) with differential.
Peripheral Blood Smear: Cell morphology, blast identification, hemolysis markers.
Bone Marrow Biopsy: Cellular morphology, blast percentage, cytogenetics.
Flow Cytometry: Immunophenotyping for lineage and clonality.
Molecular Studies: BCR‑ABL PCR, FLT3 mutations, JAK2 V617F.
4.5 Key Points for Exams
Classify anemias by MCV and give one example of each category.
Describe pathogenesis and lab findings in iron‑deficiency vs. megaloblastic anemia.
Outline Virchow’s triad in the context of thrombosis vs. malignant transformation in marrow (leukemia).
Differentiate ALL vs. AML by cytogenetic markers, cell surface antigens, and therapy.
List one targeted therapy for CML and one for APL, including mechanism of action.
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Unit 5: Immune Mechanisms & Hypersensitivity Reactions
This unit examines the cellular and molecular bases of host defense—innate and adaptive immunity—and the pathogenesis, classification, and clinical features of hypersensitivity reactions types I–IV.
5.1 Overview of Immune Responses
5.1.1 Innate Immunity
First line: Physical barriers (skin, mucosa), antimicrobial peptides.
Cellular components:
Phagocytes: Neutrophils (short‑lived, rapid responders), macrophages (tissue‑resident, antigen presentation).
NK cells: Recognize and kill virus‑infected or transformed cells via perforin/granzyme.
Soluble mediators: Complement (C3b opsonization, MAC formation), acute‑phase proteins (CRP).
5.1.2 Adaptive Immunity
Humoral: B‑lymphocytes differentiate into plasma cells secreting antigen‑specific antibodies (IgM, IgG, IgE, IgA, IgD).
Cell‑mediated:
CD4⁺ T helper (Th) cells: Th1 (IFN‑γ → macrophage activation), Th2 (IL‑4/5/13 → B‑cell class switching, eosinophils).
CD8⁺ cytotoxic T lymphocytes: Kill infected cells via perforin–granzyme and Fas–FasL.
Antigen presentation: Dendritic cells process and present peptides on MHC I (all nucleated cells) and MHC II (APCs) to T cells.
5.2 Hypersensitivity Classification
| Type | Mechanism | Time Course | Key Mediators | Clinical Examples |
|---|---|---|---|---|
| I (Immediate) | IgE‑mediated mast cell degranulation | Minutes | Histamine, leukotrienes, PGD₂ | Allergic rhinitis, anaphylaxis, asthma |
| II (Cytotoxic) | IgG/IgM binding to cell surface antigen → complement or ADCC | Hours | Complement, NK cells, macrophages | Hemolytic anemia, Goodpasture’s syndrome |
| III (Immune complex) | Deposition of antigen–antibody complexes in tissues → complement activation | 3–10 hours | C3a/C5a anaphylatoxins, neutrophils | Serum sickness, SLE, post‑streptococcal GN |
| IV (Delayed) | T cell–mediated: Th1 macrophage activation (IVa), CTL cytotoxicity (IVc) | 48–72 hours | IFN‑γ, TNF, CD8⁺ T cells | Contact dermatitis, tuberculin skin test, graft rejection |
5.3 Type I Hypersensitivity (Immediate)
5.3.1 Sensitization & Effector Phases
Sensitization: First antigen exposure → Th2 polarization → IL‑4/13 drive B cells to class‑switch to IgE. IgE binds FcεRI on mast cells and basophils.
Effector: Re‑exposure → antigen cross‑links bound IgE → degranulation → release of preformed (histamine, tryptase) and newly synthesized mediators (LTB₄, PAF).
5.3.2 Clinical Manifestations
Local: Urticaria (hives), allergic rhinitis (“hay fever”), bronchoconstriction in asthma.
Systemic: Anaphylaxis—laryngeal edema, hypotension, bronchospasm.
5.3.3 Diagnostic Tests & Treatments
Tests: Skin prick testing, serum specific IgE (RAST).
Therapies:
Acute: Epinephrine (α/β agonist), antihistamines (H₁ antagonists), β₂‑agonists.
Chronic: Allergen immunotherapy, anti‑IgE monoclonal (omalizumab).
5.4 Type II Hypersensitivity (Antibody‑Mediated Cytotoxic)
5.4.1 Mechanisms
Complement-dependent: IgG/IgM binds cell surface antigens → C1q activation → MAC lysis (e.g., transfusion reactions).
ADCC: NK cells recognize Fc on target cells → release perforin/granzyme.
Opsonization & Phagocytosis: Splenic macrophages clear opsonized RBCs in autoimmune hemolytic anemia.
5.4.2 Examples
Hemolytic disease of the newborn: Maternal anti‑Rh(D) IgG crosses placenta.
Goodpasture’s syndrome: Anti‑GBM IgG against type IV collagen → rapidly progressive GN and pulmonary hemorrhage.
Myasthenia gravis: Anti‑AChR IgG blocks neuromuscular transmission.
5.4.3 Diagnostics & Management
Tests: Direct and indirect Coombs’ tests.
Treatments: Plasmapheresis, immunosuppression (steroids, rituximab), IVIG.
5.5 Type III Hypersensitivity (Immune Complex–Mediated)
5.5.1 Pathogenesis
Circulating Ag–Ab complexes deposit in vessel walls, glomeruli, joints → complement activation → C5a‑mediated neutrophil chemotaxis and release of lysosomal enzymes.
5.5.2 Examples
Serum sickness: Immune complexes to non‑human serum proteins → fever, rash, arthralgias.
Arthus reaction: Localized skin necrosis after intradermal antigen in immunized individual.
SLE: Anti‑dsDNA complexes deposit in kidneys → lupus nephritis.
5.5.3 Diagnostics & Therapy
Tests: Low serum C3/C4 levels, elevated ESR, biopsy with granular “lumpy-bumpy” immunofluorescence.
Treatments: Avoidance of antigen, steroids, cyclophosphamide in severe cases.
5.6 Type IV Hypersensitivity (Cell‑Mediated)
5.6.1 Subtypes
IVa: Th1‑macrophage mediated (tuberculin skin test).
IVb: Th2‑eosinophil mediated (chronic asthma).
IVc: CTL‑mediated cytotoxicity (contact dermatitis, Stevens–Johnson syndrome).
IVd: T cell–neutrophil mediated (acute generalized exanthematous pustulosis).
5.6.2 Examples
Contact dermatitis: Poison ivy (urushiol) hapten → T cell sensitization → dermatitis on re‑exposure.
Granulomatous inflammation: TB (type IVa) with caseating granulomas.
Graft rejection: Host T cells recognize donor MHC → destroy graft cells.
5.6.3 Diagnostics & Management
Tests: Mantoux test (PPD), patch testing for contact allergens.
Therapies: Topical/systemic corticosteroids, calcineurin inhibitors (tacrolimus), avoidance of triggers.
5.7 Key Points for Exams
Differentiate the four hypersensitivity types by mechanism, time course, and primary effector cells.
List one clinical example and one treatment strategy for each type.
Describe the cascade from IgE cross‑linking to mediator release in type I reactions.
Explain how immune complex deposition leads to tissue damage in type III.
Outline the role of Th1 vs. Th2 cells in driving type IV hypersensitivity subtypes.
Unit 6: Introduction to Infectious Disease Pathology
This unit provides a foundational framework for understanding how microbial pathogens cause disease, the host responses they elicit, key diagnostic approaches, and principles of antimicrobial therapy.
6.1 Classification of Infectious Agents
| Agent Type | Characteristics | Examples |
|---|---|---|
| Bacteria | Prokaryotic, cell wall (Gram ±), unicellular | Staphylococcus aureus, E. coli |
| Viruses | Obligate intracellular, nucleic acid (DNA/RNA) in protein capsid (± envelope) | Influenza virus, HIV |
| Fungi | Eukaryotic, cell wall (chitin), unicellular (yeasts) or multicellular (molds) | Candida albicans, Aspergillus |
| Parasites | Eukaryotic protozoa or multicellular helminths | Plasmodium falciparum, Schistosoma |
| Prions | Proteinaceous infectious particles without nucleic acid | Creutzfeldt–Jakob disease agent |
6.2 Pathogenesis & Virulence Factors
Adherence & Colonization:
Bacterial adhesins (pili, fimbriae), viral attachment proteins (gp120 in HIV).
Invasion & Spread:
Enzymes (hyaluronidase), cytoskeletal manipulation by intracellular bacteria (e.g., Listeria).
Toxin Production:
Exotoxins (e.g., diphtheria toxin ADP‑ribosylates EF‑2), endotoxin (LPS) triggering septic shock.
Immune Evasion:
Capsule formation (e.g., Streptococcus pneumoniae), antigenic variation (influenza hemagglutinin drift/shift), inhibition of phagolysosomal fusion (Mycobacterium tuberculosis).
Host Damage:
Direct cytopathic effects, collateral damage from immune response (e.g., type III immune complexes in post‑streptococcal GN).
6.3 Patterns of Tissue Response
| Response Type | Features & Examples |
|---|---|
| Suppurative (Purulent) | Neutrophil‐rich exudate forming abscesses (e.g., S. aureus skin infection) |
| Mononuclear/Persistent | Lymphocytes/macrophages predominating (e.g., viral hepatitis) |
| Granulomatous | Epithelioid macrophages and giant cells (e.g., tuberculosis, histoplasmosis) |
| Necrotizing | Widespread tissue death with little inflammation (e.g., anthrax) |
| Cytopathic‑Cytoproliferative | Viral‐induced cell lysis and atypia (e.g., HSV with ground‑glass nuclei) |
6.4 Host Defense Mechanisms
Barrier Defenses: Skin, mucociliary clearance in respiratory tract, gastric acid.
Innate Immunity: Phagocytosis by neutrophils and macrophages, NK cells, complement activation (C3b opsonization, MAC).
Adaptive Immunity:
Humoral: Neutralizing antibodies (IgA at mucosa, IgG in blood).
Cell‑Mediated: CD8⁺ T cells kill infected cells; Th1 macrophage activation via IFN‑γ for intracellular pathogens.
6.5 Diagnostic Techniques
| Method | Principle | Pathogen Examples |
|---|---|---|
| Microscopy & Stains | Gram, Ziehl–Neelsen, India ink | Bacteria, mycobacteria, Cryptococcus |
| Culture | Growth on selective media | Blood cultures for sepsis, fungal cultures |
| Serology | Detection of specific antibodies | ELISA for HIV, HBsAg for hepatitis B |
| Molecular | PCR, nucleic acid amplification | PCR for Chlamydia, SARS‑CoV‑2 |
| Antigen Detection | Rapid immunochromatography assays | Streptococcal rapid test, influenza swab |
| Histopathology | Tissue biopsy with special stains | PAS for fungi, GMS for Pneumocystis |
6.6 Principles of Antimicrobial Therapy
Antibacterial Agents:
Cell‑Wall Synthesis Inhibitors: β‑lactams (penicillins), glycopeptides (vancomycin).
Protein Synthesis Inhibitors: Aminoglycosides (30S), macrolides (50S).
DNA‑Replication Inhibitors: Fluoroquinolones (DNA gyrase).
Antiviral Agents:
Reverse Transcriptase Inhibitors (AZT), neuraminidase inhibitors (oseltamivir), protease inhibitors (ritonavir).
Antifungal Agents:
Ergosterol‑Targeting: Polyenes (amphotericin B), azoles (fluconazole).
Antiparasitic Agents:
Antimalarials: Chloroquine, artemisinin.
Antihelminthics: Praziquantel, albendazole.
Resistance Mechanisms:
Enzymatic drug inactivation (β‑lactamases), target modification (MRSA’s PBP2a), efflux pumps (tetracycline resistance), decreased uptake.
6.7 Infection Control & Prevention
Standard Precautions: Hand hygiene, personal protective equipment.
Isolation Practices: Contact, droplet, airborne precautions.
Vaccination: Active immunization strategies (live‑attenuated, inactivated, subunit, conjugate vaccines).
Antimicrobial Stewardship: Appropriate selection, dosing, and duration to limit resistance.
6.8 Key Points for Exams
Classify pathogens by cellular structure and list one key diagnostic stain for each.
Explain how endotoxin (LPS) induces septic shock via cytokine release.
Differentiate suppurative vs. granulomatous inflammation in response to infection.
List two mechanisms by which bacteria develop antibiotic resistance.
Outline the steps in PCR‑based pathogen detection and its advantages over culture.