1000094685.jpg
Answer this all questions
Reading File
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Reading File
Reading File
Reading File
Reading File
Finding Sources
Reading File
Finding Sources
Finding Sources
Reading File
A1 - Hypersensitivity Reactions: Type I and Type II (10 Marks)
Definition of Hypersensitivity
Hypersensitivity is a condition in which an exaggerated or augmented immune response occurs that is harmful to the host. It requires a presensitized state - meaning the reaction typically occurs after a second encounter with a specific antigen (allergen), not the first.
In 1963, Coombs and Gell classified hypersensitivity into four types:
- Types I, II, III - antibody mediated
- Type IV - T-cell mediated
Type I: Immediate (IgE-Mediated) Hypersensitivity
Mechanism
- Sensitization phase: On first exposure, the antigen stimulates B cells to produce IgE antibodies.
- The IgE binds via its Fc portion to high-affinity IgE receptors (FcεRI) on mast cells, basophils, and eosinophils.
- Effector phase (second exposure): Re-exposure causes cross-linking of cell-bound IgE molecules, triggering degranulation and release of pharmacologically active mediators.
Mediators Released
Primary (preformed) mediators:
- Histamine - causes vasodilation, increased capillary permeability, smooth muscle contraction (bronchospasm). Stored preformed in mast cells and basophils.
Secondary (newly formed) mediators:
- Prostaglandins - from the cyclooxygenase pathway; induce edema and bronchoconstriction.
- Leukotrienes (LTC4, LTD4) - cause vasodilatation and increased vascular permeability. LTB4 is a chemoattractant that recruits leukocytes.
- TNF-α and IL-4 - amplify the inflammatory response.
Forms
- Systemic anaphylaxis: after intravenous administration of foreign proteins; life-threatening - massive vasodilation, bronchospasm, cardiovascular collapse.
- Local (atopic) reactions: rhinitis (hay fever), asthma, eczema, urticaria, food allergy.
Examples
| Condition | Antigen | Manifestation |
|---|---|---|
| Hay fever | Pollen, ragweed | Allergic rhinitis |
| Asthma | Dust mites, mold | Bronchospasm |
| Anaphylaxis | Penicillin, bee venom | Systemic shock |
| Urticaria | Food allergens (shellfish) | Hives |
Biological Significance
- Type I reactions are evolutionarily linked to defense against parasites (IgE and eosinophils).
- In modern "clean" environments, IgE responses are inappropriately triggered by innocuous antigens (the "hygiene hypothesis").
- Clinically, Type I is the basis of allergic disease, which affects ~20-30% of the global population.
Treatment
- Epinephrine (reverses vasodilation and bronchospasm), antihistamines, corticosteroids.
- Allergen avoidance, desensitization (induction of tolerance).
Type II: Cytotoxic (Antibody-Mediated) Hypersensitivity
Mechanism
Type II hypersensitivity involves the binding of IgG (or IgM) antibodies to cell surface antigens or extracellular matrix molecules. This leads to cell destruction via three mechanisms:
-
Complement activation: Antibody binding activates the complement cascade → membrane attack complex (MAC) → cell lysis. Also generates C3a and C5a (anaphylatoxins) that recruit neutrophils and amplify inflammation.
-
Antibody-Dependent Cellular Cytotoxicity (ADCC): NK cells, macrophages, and neutrophils bearing Fc receptors bind IgG-coated cells and kill them.
-
Phagocytosis (opsonization): Antibody-coated cells are recognized by macrophages and destroyed.
-
Receptor dysfunction without cell injury: Antibodies bind to cell surface receptors and either activate or block them abnormally.
Examples
| Disease | Target Antigen | Mechanism | Effect |
|---|---|---|---|
| ABO transfusion reaction | Red blood cell surface antigens | Complement lysis | Hemolysis |
| Rh hemolytic disease of newborn | Rh antigen on fetal RBCs | IgG-mediated ADCC | Fetal anemia |
| Autoimmune hemolytic anemia | RBC surface proteins | Complement + ADCC | Hemolysis |
| Goodpasture syndrome | Type IV collagen (glomerular/alveolar BM) | Complement activation | Nephritis + pulmonary hemorrhage |
| Graves disease | TSH receptor | Receptor stimulation | Hyperthyroidism |
| Myasthenia gravis | Acetylcholine receptor | Receptor blockade | Muscle weakness |
| Penicillin-induced hemolysis | Drug-hapten on RBC surface | Antibody formation → lysis | Hemolysis |
Biological Significance
- Type II reactions underlie important clinical entities in transfusion medicine, autoimmune disorders, and drug reactions.
- Understanding this mechanism guides therapy: plasmapheresis (removes antibodies), immunosuppression, complement inhibitors (e.g., eculizumab in PNH).
- Differentiation from Type I is essential for diagnosis: Type II is diagnosed by direct Coombs test (antibody on RBCs), not skin testing.
A2 - Autoimmunity: Definition, Criteria, Classification, and Mechanisms (10 Marks)
Definition
Autoimmunity is the result of failure of tolerance to self-antigens, in which the immune system mounts an attack against the body's own tissues. It arises when mechanisms that normally prevent immune responses to self-antigens break down.
Self-Tolerance: Normal Mechanisms (Prerequisites for Understanding Autoimmunity)
Normally, self-tolerance is maintained by:
-
Central tolerance - Death (clonal deletion) of immature T and B lymphocytes that recognize self-antigens in the thymus and bone marrow respectively. Some self-reactive B cells switch to new, non-self-reactive receptors (receptor editing).
-
Peripheral tolerance - Mature lymphocytes that encounter self-antigens in peripheral tissues are controlled by:
- Suppression by regulatory T cells (Tregs)
- Engagement of inhibitory receptors - CTLA-4 and PD-1 (block T cell activation)
- Anergy (functional inactivation without co-stimulation)
- Apoptosis (activation-induced cell death)
Criteria for Autoimmunity (Witebsky's Criteria, modified)
- Autoantibodies or autoreactive T cells must be demonstrated in the patient.
- The autoantigen(s) must be identified.
- The autoimmune response must be reproduced in an experimental animal.
- Transfer of serum antibodies or sensitized lymphocytes from diseased to healthy animal should transfer the disease.
- Immunosuppression should ameliorate the disease.
Factors Leading to Failure of Self-Tolerance
- Genetic susceptibility genes - Disrupt central or peripheral tolerance pathways. Strong associations with HLA class II alleles (e.g., HLA-DR3/DR4 in Type 1 diabetes; HLA-DR2 in SLE).
- Infections and tissue injury - Expose sequestered self-antigens, activate APCs and lymphocytes via pathogen-associated molecular patterns (PAMPs); molecular mimicry (microbial epitopes resembling self-antigens).
- Hormonal factors - Many autoimmune diseases are more common in women (estrogen effects on immunity).
- Environmental triggers - UV radiation (in SLE), certain drugs.
Classification of Autoimmune Diseases
By Extent of Tissue Involvement
| Type | Features | Examples |
|---|---|---|
| Organ-specific | Autoimmune response against a single organ or cell type | Hashimoto thyroiditis, Graves disease, Type 1 diabetes mellitus, Myasthenia gravis, Multiple sclerosis |
| Systemic (non-organ specific) | Antibodies against widespread antigens; multi-organ damage | SLE, Rheumatoid arthritis, Systemic sclerosis, Sjogren syndrome |
By Effector Mechanism (Immunological)
| Type | Effector mechanism | Examples |
|---|---|---|
| Antibody-mediated (Type II HS) | IgG/IgM antibodies against cell surface antigens | Autoimmune hemolytic anemia, Graves disease, Myasthenia gravis |
| Immune complex-mediated (Type III HS) | Immune complex deposition in tissues | SLE, Rheumatoid arthritis |
| T cell-mediated (Type IV HS) | CD4+ or CD8+ T cells destroy tissue | Type 1 DM (CD8+ T cells destroy β cells), Hashimoto thyroiditis, MS |
Mechanisms of Autoimmunity
1. Molecular Mimicry
Microbial antigens share structural similarity with self-antigens. Immune response against the pathogen cross-reacts with self-tissues.
- Example: Rheumatic fever - anti-streptococcal antibodies cross-react with cardiac myosin.
2. Release of Sequestered Antigens
Some antigens (e.g., in the eye, testis, CNS) are normally hidden from the immune system. Injury exposes them and triggers autoimmunity.
- Example: Sympathetic ophthalmia after eye trauma.
3. Failure of Regulatory T cells (Tregs)
Tregs (CD4+CD25+FoxP3+) suppress autoreactive lymphocytes. Loss of Treg function allows autoreactive T cells to escape peripheral tolerance.
4. Polyclonal B-Cell Activation
Certain viruses (EBV) and bacterial products can activate B cells nonspecifically, generating autoantibodies.
5. Dysregulation of Inhibitory Receptors
Loss of CTLA-4 or PD-1 signaling removes "brakes" on autoreactive T cells. (This is why checkpoint inhibitor cancer drugs cause autoimmune side effects.)
6. Epitope Spreading
Initial autoimmune damage releases more self-antigens, which activate additional T and B cell clones against new epitopes - perpetuating and amplifying the disease.
7. Dendritic Cell Dysregulation
Dendritic cells (DCs) are key regulators of tolerance. Abnormal DC maturation or function can fail to delete self-reactive T cells. Therapeutic targeting of DCs using immunosuppressive cytokines (IL-10, TGF-β) and checkpoint proteins (CTLA-4-Ig) is an active area of research.
Key Autoimmune Diseases (Brief)
- SLE: Autoantibodies against nuclear antigens (anti-dsDNA, anti-Smith); immune complex deposition → nephritis, skin, joints, blood cells.
- Sjogren syndrome: Autoimmune attack on salivary and lacrimal glands → dry mouth, dry eyes.
- Systemic sclerosis (Scleroderma): Fibrosis from cytokine-activated fibroblasts; microvascular disease.
- Rheumatoid arthritis: Anti-citrullinated protein antibodies (ACPA); synovial inflammation → joint destruction.
A3 - Diabetes Mellitus: Pathophysiology, Risk Factors, Complications, and Management (10 Marks)
Definition
Diabetes mellitus (DM) is a common chronic metabolic disorder characterized by elevated blood glucose concentrations (hyperglycemia), resulting from defects in insulin secretion, insulin action, or both.
Classification
| Type | Mechanism |
|---|---|
| Type 1 DM | Autoimmune destruction of pancreatic β-cells → absolute insulin deficiency |
| Type 2 DM | Impaired insulin secretion + insulin resistance (relative deficiency) |
| Gestational DM | Glucose intolerance first detected in pregnancy |
| Other types | Pancreatic disease, drugs (corticosteroids), genetic defects (MODY) |
Pathophysiology
Type 1 DM
- CD8+ cytotoxic T cells destroy β-cells in genetically susceptible individuals (HLA-DR3/DR4 linked).
- Results in absolute insulin deficiency.
- Without insulin: cells cannot take up glucose → hyperglycemia.
- Fat and muscle are catabolized for energy → free fatty acids (FFAs) flow to liver → ketogenesis → diabetic ketoacidosis (DKA).
- Osmotic diuresis of glucose in urine → polyuria, polydipsia, weight loss.
Type 2 DM
- Insulin resistance in peripheral tissues (muscle, adipose, liver) is the initiating defect.
- Pancreas compensates by secreting more insulin (hyperinsulinemia).
- Over years, β-cell exhaustion → progressive insulin secretory failure.
- Chronic hyperglycemia causes protein glycation, oxidative stress, advanced glycation end-products (AGEs) that damage blood vessels and nerves.
The "Ominous Octet" (DeFronzo's model of Type 2):
- Decreased insulin secretion (β-cell failure)
- Increased glucagon secretion (α-cell dysfunction)
- Insulin resistance in muscle
- Insulin resistance in liver (increased hepatic glucose output)
- Increased lipolysis (adipose tissue)
- Decreased incretin effect (GLP-1, GIP)
- Increased renal glucose reabsorption
- Brain: impaired satiety and appetite regulation
Risk Factors
Non-modifiable:
- Family history / genetics (HLA-DR3/DR4 for T1DM; polygenic for T2DM)
- Age (T2DM risk rises after 40)
- Ethnicity (higher risk in South Asians, African-Americans)
- History of gestational diabetes
Modifiable:
- Obesity (BMI >30), especially central/abdominal adiposity
- Physical inactivity
- Unhealthy diet (high refined carbohydrate, saturated fat)
- Hypertension
- Dyslipidemia (high triglycerides, low HDL)
- Prediabetes / impaired fasting glucose
Secondary causes:
- Corticosteroid use
- Antipsychotics (clozapine, olanzapine)
- Pancreatitis, pancreatectomy
- Cushing syndrome, acromegaly
Complications
Acute Complications
| Complication | Cause | Key Features |
|---|---|---|
| Diabetic Ketoacidosis (DKA) | Absolute insulin deficiency (mainly T1DM) | Hyperglycemia, ketoacidosis, anion gap metabolic acidosis, Kussmaul breathing, fruity breath |
| Hyperglycemic Hyperosmolar State (HHS) | Relative insulin deficiency (T2DM) | Very high glucose (>600 mg/dL), hyperosmolality, no ketosis, altered consciousness |
| Hypoglycemia | Excess insulin or oral agents | Tremor, sweating, confusion, coma |
Chronic Complications
Microvascular (due to AGEs, protein kinase C activation, polyol pathway):
- Diabetic retinopathy - microaneurysms, hemorrhages, neovascularization → blindness (leading cause in working-age adults)
- Diabetic nephropathy - glomerulosclerosis (Kimmelstiel-Wilson nodules), proteinuria → end-stage renal disease
- Diabetic neuropathy - distal symmetric polyneuropathy, autonomic neuropathy (gastroparesis, orthostatic hypotension)
Macrovascular (accelerated atherosclerosis):
- Coronary artery disease - leading cause of death in diabetics
- Peripheral vascular disease - poor wound healing, diabetic foot, gangrene
- Cerebrovascular disease / Stroke
Other:
- Increased susceptibility to infections (e.g., UTIs, fungal infections, tuberculosis)
- Diabetic foot ulcers
- Genital mycotic infections (due to glycosuria)
Management Principles
Goals of Management
- Maintain HbA1c <7% (intensive control)
- Prevent acute and chronic complications
- Control cardiovascular risk factors (BP <130/80, LDL reduction)
Lifestyle Interventions (cornerstone)
- Dietary modification: caloric restriction, low glycemic index foods, high fiber
- Regular aerobic exercise (≥150 min/week)
- Weight loss (even 5-10% body weight significantly improves insulin sensitivity)
Pharmacological Treatment
Type 1 DM - Insulin Replacement:
- Basal insulin (long-acting: glargine, detemir) + Bolus insulin (rapid-acting: lispro, aspart) = basal-bolus regimen
- Insulin pump (continuous subcutaneous insulin infusion) for selected patients
Type 2 DM - Stepwise Approach:
| Drug Class | Example | Mechanism |
|---|---|---|
| Biguanide (first-line) | Metformin | Reduces hepatic glucose output (↓ gluconeogenesis) |
| Sulfonylureas | Glipizide, gliclazide | Stimulate insulin secretion (bind SUR1 receptor) |
| SGLT2 inhibitors | Empagliflozin, dapagliflozin | Block renal glucose reabsorption; cardioprotective |
| GLP-1 agonists | Semaglutide, liraglutide | Increase incretin effect; weight loss; CV benefit |
| DPP-4 inhibitors | Sitagliptin | Prolong endogenous GLP-1/GIP activity |
| Thiazolidinediones | Pioglitazone | Increase insulin sensitivity (PPARγ agonist) |
| Insulin | Multiple formulations | Required when oral agents fail |
Monitoring
- HbA1c: every 3-6 months
- Blood glucose: self-monitoring or continuous glucose monitoring (CGM)
- Annual eye exam, urine microalbumin, foot examination, lipid profile
Management of Complications
- ACE inhibitors/ARBs for nephropathy and hypertension
- Statins for dyslipidemia (cardiovascular risk reduction)
- Antiplatelet therapy (aspirin) in high cardiovascular risk
- Foot care, prompt treatment of infections
Sources:
- Jawetz, Melnick & Adelberg's Medical Microbiology, 28th ed.
- Robbins & Kumar Basic Pathology
- Goldman-Cecil Medicine, International Ed.
- Firestein & Kelley's Textbook of Rheumatology
1000094685.jpg
Answer this question
This is the same question paper as before. I already answered all three questions in detail in my previous response. Here is a clean, complete version for your reference:
A1 - Hypersensitivity Reactions: Type I & Type II (10 Marks)
Definition of Hypersensitivity
Hypersensitivity is an exaggerated or augmented immune response that is harmful to the host. It requires a presensitized state - the reaction typically occurs on second (or subsequent) exposure to a specific antigen (allergen), not the first.
Coombs and Gell (1963) classified hypersensitivity into 4 types:
- Type I, II, III - Antibody mediated
- Type IV - T-cell mediated
TYPE I: Immediate (IgE-Mediated) Hypersensitivity
Mechanism (Step-by-Step)
Step 1 - Sensitization phase (first exposure):
- Antigen enters the body and stimulates Th2 cells.
- B cells are activated to produce IgE antibodies.
- IgE binds via its Fc portion to high-affinity FcεRI receptors on mast cells and basophils. The individual is now sensitized.
Step 2 - Effector phase (second exposure):
- Re-exposure to the same antigen cross-links the cell-bound IgE molecules.
- This triggers degranulation - release of preformed and newly synthesized mediators.
- Cyclic nucleotides and calcium are essential for this release.
Mediators
| Mediator | Type | Action |
|---|---|---|
| Histamine | Primary (preformed) | Vasodilation, increased capillary permeability, smooth muscle contraction (bronchospasm) |
| Prostaglandins | Secondary (newly formed, via COX pathway) | Edema, bronchoconstriction |
| Leukotriene C4 & D4 | Secondary | Vasodilatation, vascular permeability |
| Leukotriene B4 | Secondary | Chemoattractant - recruits leukocytes |
| TNF-α, IL-4 | Secondary | Amplify inflammation |
Clinical Forms
A. Systemic Anaphylaxis
- Triggered by IV foreign proteins, penicillin, insect stings, foods
- Massive vasodilation, bronchospasm, cardiovascular collapse → life-threatening
- Treatment: Epinephrine (first line), antihistamines, corticosteroids
B. Atopic (Local) Reactions
- Strong familial predisposition; associated with elevated IgE
- Triggered by environmental allergens (pollen, dust mites, shellfish)
Examples of Type I Reactions
| Condition | Allergen | Manifestation |
|---|---|---|
| Hay fever (allergic rhinitis) | Pollen, ragweed | Nasal congestion, sneezing |
| Bronchial asthma | Dust mites, mold | Bronchospasm, wheezing |
| Atopic dermatitis/eczema | Food allergens | Skin inflammation |
| Urticaria (hives) | Foods, drugs | Wheals on skin |
| Anaphylactic shock | Penicillin, bee venom | Systemic collapse |
Biological Significance of Type I
- Evolutionarily, IgE and eosinophil-mediated responses are designed to defend against parasites (helminths).
- In modern hygienic environments (reduced parasite exposure), these responses are misdirected at harmless antigens - the "Hygiene Hypothesis."
- Type I is the immunological basis of all allergic diseases, affecting ~20% of the global population.
- Understanding mediators guides therapy - antihistamines block H1 receptors; leukotriene inhibitors (montelukast) block LTC4/D4.
TYPE II: Cytotoxic (Antibody-Mediated) Hypersensitivity
Mechanism
Type II involves IgG or IgM antibodies directed against cell surface antigens or extracellular matrix components.
Three pathways of damage:
1. Complement-Mediated Lysis
- Antibody binds antigen on cell surface → activates classical complement pathway → Membrane Attack Complex (MAC) → cell lysis
- C3a and C5a (anaphylatoxins) also recruit neutrophils and amplify inflammation
2. Antibody-Dependent Cellular Cytotoxicity (ADCC)
- NK cells and macrophages bearing Fc receptors bind IgG-coated cells and destroy them without complement
3. Opsonization and Phagocytosis
- IgG-coated cells are recognized and engulfed by macrophages in the spleen and liver
4. Receptor Dysfunction (without direct cell killing)
- Antibodies bind cell surface receptors, either:
- Stimulating them (mimicking the normal ligand) - e.g., Graves disease
- Blocking them (preventing normal ligand binding) - e.g., Myasthenia gravis
Examples of Type II Reactions
| Disease | Target Antigen | Mechanism | Effect |
|---|---|---|---|
| ABO transfusion reaction | RBC blood group antigens | Complement lysis | Acute hemolysis |
| Rh hemolytic disease of newborn | Rh antigen on fetal RBCs | ADCC via maternal IgG | Fetal anemia, jaundice |
| Autoimmune hemolytic anemia | RBC surface proteins | Complement + ADCC | Hemolysis |
| Goodpasture syndrome | Type IV collagen (glomerular + alveolar basement membrane) | Complement activation | Nephritis + pulmonary hemorrhage |
| Graves disease | TSH receptor | Receptor stimulation by Ab | Hyperthyroidism |
| Myasthenia gravis | Acetylcholine receptor (NMJ) | Receptor blockade | Progressive muscle weakness |
| Penicillin-induced hemolysis | Drug (hapten) bound to RBC surface | IgG → complement lysis | Hemolytic anemia |
Biological Significance of Type II
- Underlies critical clinical entities in transfusion medicine (ABO mismatch), obstetrics (Rh incompatibility), and autoimmune disease.
- Provides the rationale for:
- Direct Coombs test (detects antibody on RBCs) as the diagnostic tool
- Plasmapheresis to remove pathogenic antibodies
- Complement inhibitors (e.g., eculizumab) in complement-mediated diseases
- Distinguishing Type II from Type I is clinically essential: Type II is NOT responsive to antihistamines but to immunosuppression and specific antibody-removal therapies.
A2 - Autoimmunity: Definition, Criteria, Classification, and Mechanisms (10 Marks)
Definition
Autoimmunity is the breakdown of immunological self-tolerance, resulting in the immune system mounting a response against the body's own tissues and organs. It arises when the mechanisms that normally prevent immune responses to self-antigens fail.
Normal Self-Tolerance (Background)
Self-tolerance is maintained by:
Central tolerance (thymus and bone marrow):
- Immature T and B lymphocytes that strongly recognize self-antigens undergo clonal deletion (apoptosis) - this is called negative selection
- Some self-reactive B cells undergo receptor editing - they switch to new, non-self-reactive receptors
Peripheral tolerance:
- Mature self-reactive lymphocytes escaping to the periphery are controlled by:
- Regulatory T cells (Tregs) - CD4+CD25+FoxP3+ cells suppress autoreactive T cells
- Inhibitory receptors - CTLA-4 and PD-1 block T cell activation (immune checkpoints)
- Anergy - T cells become unresponsive when antigen is presented without costimulation
- Activation-induced apoptosis - autoreactive cells are deleted
Criteria for Autoimmunity (Modified Witebsky's Criteria)
- Demonstrate autoantibodies or autoreactive T cells in the patient.
- Identify the target autoantigen(s).
- Reproduce the autoimmune response in an experimental animal model.
- Transfer of serum (antibodies) or sensitized lymphocytes from diseased to healthy animal should transfer the disease.
- Immunosuppressive treatment should ameliorate the disease.
Factors Causing Failure of Self-Tolerance
- Genetic susceptibility: HLA gene variants (e.g., HLA-DR3/DR4 in T1DM, HLA-DR2 in SLE) disrupt central or peripheral tolerance.
- Infections: Activate APCs non-specifically; enable molecular mimicry (microbial epitopes resembling self-antigens - e.g., streptococcal M protein mimics cardiac myosin in rheumatic fever).
- Tissue injury: Releases normally sequestered (hidden) self-antigens not encountered during central tolerance development.
- Hormonal factors: Estrogen promotes autoimmunity - explains female predominance in SLE, RA, Hashimoto's.
- Environmental triggers: UV radiation (activates nuclear antigen release in SLE), silica dust (scleroderma), drugs.
Classification of Autoimmune Diseases
A. By Organ Involvement
| Category | Definition | Examples |
|---|---|---|
| Organ-specific | Autoimmune response limited to a single organ/tissue | Type 1 DM (pancreatic β-cells), Hashimoto thyroiditis, Graves disease, Myasthenia gravis, Multiple sclerosis, Addison disease |
| Systemic (Non-organ specific) | Response against widespread antigens; multi-organ damage | SLE, Rheumatoid arthritis, Sjogren syndrome, Systemic sclerosis, Polymyositis |
B. By Effector Mechanism
| Mechanism | Example Diseases |
|---|---|
| Autoantibody-mediated (Type II HS) | Autoimmune hemolytic anemia, Graves disease, Myasthenia gravis, Goodpasture syndrome |
| Immune complex-mediated (Type III HS) | SLE (anti-dsDNA + complement → nephritis), Rheumatoid arthritis |
| T cell-mediated (Type IV HS) | Type 1 DM (CD8+ T cells destroy β-cells), Hashimoto thyroiditis, Multiple sclerosis, Rheumatoid arthritis |
Mechanisms of Autoimmunity
1. Molecular Mimicry
Microbial antigens structurally resemble self-antigens. Anti-microbial immune responses cross-react with self-tissues.
- Example: Group A streptococcus → anti-M protein antibodies cross-react with cardiac myosin → Rheumatic fever/carditis
2. Release of Sequestered (Hidden) Antigens
Antigens normally isolated from immune surveillance (eye lens, testis, CNS myelin) are released after trauma or infection.
- Example: Sympathetic ophthalmia - trauma to one eye exposes uveal antigens → autoimmune attack on both eyes
3. Breakdown of Regulatory T Cells
Defective Tregs (CD4+CD25+FoxP3+) fail to suppress autoreactive T cells that escape negative selection.
- Example: FoxP3 mutation → IPEX syndrome (severe multi-organ autoimmunity in infants)
4. Polyclonal B Cell Activation
Viruses (EBV) and bacterial products (LPS) activate B cells non-specifically, generating autoantibodies without T-cell help.
- Example: EBV → polyclonal activation → anti-RBC, anti-platelet antibodies
5. Loss of Inhibitory Receptor Signaling
Defective CTLA-4 or PD-1 signaling removes the "brakes" on autoreactive T cells.
- Clinical note: Cancer checkpoint inhibitor drugs (anti-PD-1, anti-CTLA-4) frequently cause autoimmune side effects by this exact mechanism
6. Epitope Spreading
Initial autoimmune damage releases new self-antigens → activates T/B cell clones against new epitopes → amplifies and perpetuates the autoimmune response over time
7. Dendritic Cell (DC) Dysregulation
DCs regulate both central and peripheral tolerance. Abnormal DC maturation allows autoreactive T cells to escape deletion. Therapeutic strategies to induce tolerogenic DCs (using IL-10, TGF-β, CTLA-4-Ig, corticosteroids) are being investigated.
Important Examples of Autoimmune Diseases
| Disease | Autoantigen | Key Mechanism | Major Features |
|---|---|---|---|
| SLE | dsDNA, histones, Smith antigen | Immune complex deposition | Nephritis, skin rash, arthritis, hematologic abnormalities |
| Rheumatoid arthritis | Citrullinated proteins (ACPA), IgG (RF) | T cells + immune complexes | Symmetric joint destruction, synovitis |
| Hashimoto thyroiditis | Thyroglobulin, TPO | CD8+ T cells + antibodies | Hypothyroidism |
| Graves disease | TSH receptor | Stimulating antibody (IgG) | Hyperthyroidism |
| Sjogren syndrome | SSA (Ro), SSB (La) | T cell-mediated glandular destruction | Dry eyes, dry mouth |
| Myasthenia gravis | Acetylcholine receptor | Blocking antibody | Muscle weakness, ptosis |
A3 - Diabetes Mellitus: Pathophysiology, Risk Factors, Complications, and Management (10 Marks)
Definition
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, leading to disturbances in carbohydrate, fat, and protein metabolism.
Classification
| Type | Core Defect |
|---|---|
| Type 1 DM | Autoimmune destruction of β-cells → absolute insulin deficiency |
| Type 2 DM | Insulin resistance + progressive β-cell failure → relative insulin deficiency |
| Gestational DM | Glucose intolerance first recognized during pregnancy |
| Other specific types | Pancreatic disease, genetic defects (MODY), drugs (steroids, antipsychotics), endocrinopathies |
Pathophysiology
Type 1 DM
- Autoimmune process in genetically susceptible individuals (HLA-DR3, DR4 association)
- CD8+ cytotoxic T cells selectively destroy pancreatic β-cells (insulitis)
- Results in absolute insulin deficiency
- Without insulin:
- Peripheral cells cannot uptake glucose → hyperglycemia
- Fat cells release free fatty acids (FFAs) → liver converts them to ketone bodies → DKA
- Muscle protein catabolized → amino acids → gluconeogenesis → worsens hyperglycemia
- Glucose spills into urine (glycosuria) → osmotic diuresis → polyuria, polydipsia, weight loss
Type 2 DM
Stage 1 - Insulin Resistance:
- Muscle, liver, and adipose tissue fail to respond normally to insulin
- Glucose uptake in muscle decreases; liver continues hepatic glucose output despite hyperglycemia
- Pancreas compensates by secreting more insulin (hyperinsulinemia)
Stage 2 - β-cell Exhaustion:
- Sustained demand for insulin causes progressive β-cell failure
- Insulin secretion becomes inadequate → overt hyperglycemia
Key underlying mechanisms:
- Advanced Glycation End-products (AGEs): chronic hyperglycemia glycates proteins and lipids → vascular damage
- Oxidative stress: excess glucose → reactive oxygen species → endothelial injury
- Polyol pathway activation: glucose → sorbitol accumulation → osmotic damage (nerves, lens)
- PKC activation: damages vascular endothelium → microangiopathy
Risk Factors
Non-Modifiable
- Family history / genetic predisposition
- Age >45 years (T2DM)
- Ethnicity (South Asian, African-American, Hispanic)
- History of gestational diabetes or delivery of baby >4 kg
- Polycystic ovarian syndrome (PCOS)
Modifiable
- Obesity (BMI >30), especially central adiposity (waist >90 cm men, >80 cm women)
- Physical inactivity / sedentary lifestyle
- Unhealthy diet (high refined carbohydrates, trans fats)
- Hypertension
- Dyslipidemia (high triglycerides, low HDL cholesterol)
- Smoking
- Prediabetes (impaired fasting glucose or impaired glucose tolerance)
Secondary Causes
- Drugs: corticosteroids, thiazide diuretics, atypical antipsychotics
- Endocrine: Cushing syndrome, acromegaly, pheochromocytoma
- Pancreatic disease: chronic pancreatitis, pancreatectomy, hemochromatosis
Complications
Acute Complications
| Complication | Mainly in | Mechanism | Features |
|---|---|---|---|
| Diabetic Ketoacidosis (DKA) | Type 1 DM | Absolute insulin deficiency → ketogenesis | Hyperglycemia (>250 mg/dL), ketonemia, metabolic acidosis, Kussmaul breathing, fruity breath, dehydration |
| Hyperglycemic Hyperosmolar State (HHS) | Type 2 DM (elderly) | Relative insulin deficiency, no ketosis | Very high glucose (>600 mg/dL), profound dehydration, altered consciousness, no significant acidosis |
| Hypoglycemia | Both types | Excess insulin/oral agents | Tremor, palpitations, sweating, confusion, seizures, coma |
Chronic Complications
Microvascular (hallmark of DM):
| Complication | Pathology | Clinical Features |
|---|---|---|
| Diabetic Retinopathy | Microaneurysms, hard exudates, cotton-wool spots, neovascularization | Visual loss, blindness (leading cause in working-age adults) |
| Diabetic Nephropathy | Glomerular basement membrane thickening, Kimmelstiel-Wilson nodules, mesangial expansion | Proteinuria → nephrotic syndrome → CKD → ESRD |
| Diabetic Neuropathy | Demyelination, axonal loss from ischemia + polyol pathway | Distal symmetric polyneuropathy (glove-and-stocking), burning, autonomic neuropathy (gastroparesis, orthostatic hypotension, erectile dysfunction) |
Macrovascular (accelerated atherosclerosis):
- Coronary artery disease - leading cause of death in diabetics (2-4x higher risk)
- Peripheral vascular disease - claudication, non-healing ulcers, diabetic foot, gangrene
- Cerebrovascular disease - stroke (2-4x higher risk)
Other:
- Increased susceptibility to infections (TB, fungal infections, UTIs, skin infections)
- Diabetic foot (neuropathy + ischemia + infection triad)
- Cataract and glaucoma (lens sorbitol accumulation)
- Genital mycotic infections (Candida - due to glycosuria)
Management Principles
Goals of Treatment
- HbA1c < 7% (6.5-7% in most adults)
- Fasting glucose: 80-130 mg/dL
- Postprandial glucose < 180 mg/dL
- BP < 130/80 mmHg; LDL < 100 mg/dL (< 70 if CVD present)
- Prevent/delay complications; improve quality of life
1. Lifestyle Modification (Foundation of Management)
- Diet: Calorie restriction, low glycemic index, high fiber, reduced saturated fat; Mediterranean or DASH diet
- Exercise: ≥150 min/week of moderate aerobic exercise; improves insulin sensitivity
- Weight loss: Even 5-10% body weight reduction markedly improves glycemic control in T2DM
2. Pharmacological Treatment
Type 1 DM:
- Insulin replacement is mandatory (no oral agents suffice)
- Basal-bolus regimen: Long-acting insulin (glargine/detemir) at night + rapid-acting insulin (lispro/aspart) with meals
- Insulin pump (CSII) for selected patients
- Continuous Glucose Monitoring (CGM) improves glycemic control
Type 2 DM (Stepwise):
| Drug Class | Example | Mechanism | Key Benefit |
|---|---|---|---|
| Biguanide (1st line) | Metformin | Inhibits hepatic gluconeogenesis (↓ glucose output) | Weight neutral, cheap, reduces CV mortality |
| SGLT2 inhibitors | Empagliflozin, Dapagliflozin | Block renal glucose reabsorption | Cardioprotective, renoprotective, weight loss |
| GLP-1 receptor agonists | Semaglutide, Liraglutide | Enhance incretin effect, suppress glucagon | Weight loss, CV benefit, once-weekly injection |
| DPP-4 inhibitors | Sitagliptin, Vildagliptin | Prolong endogenous GLP-1/GIP action | Weight neutral, well-tolerated |
| Sulfonylureas | Glipizide, Gliclazide | Stimulate β-cell insulin secretion (SUR1 receptor) | Cheap, effective - risk of hypoglycemia |
| Thiazolidinediones | Pioglitazone | PPARγ agonist → improve insulin sensitivity | Reduces TG; risk of fluid retention |
| Insulin | Multiple formulations | Replace/supplement endogenous insulin | Required when oral agents fail |
3. Management of Complications
| Complication | Management |
|---|---|
| Hypertension + Nephropathy | ACE inhibitors or ARBs (first choice - renoprotective) |
| Dyslipidemia | Statins (reduce LDL and CV events) |
| Retinopathy | Annual fundus exam; laser photocoagulation; anti-VEGF injections |
| Neuropathy | Glycemic control; gabapentin, duloxetine, amitriptyline for pain |
| Diabetic foot | Foot care education, podiatry, prompt antibiotic treatment, offloading |
| Cardiovascular risk | Aspirin (if high CV risk), statins, BP control |
4. Monitoring
- HbA1c every 3 months initially, then 6-monthly when controlled
- Self-monitoring of blood glucose (SMBG) or CGM
- Annual: fundus examination, urine microalbumin/creatinine ratio, lipid profile, serum creatinine, foot examination, BP check
Sources: Goldman-Cecil Medicine; Jawetz Melnick & Adelberg's Medical Microbiology 28e; Robbins & Kumar Basic Pathology; Firestein & Kelley's Textbook of Rheumatology
This is a shared conversation. Sign in to Orris to start your own chat.