Hello My name is Pritam Mistri, I am a 2nd year MBBS student from WBUHS University
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Type 3 hypersensitivity
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Here is a complete, exam-focused breakdown of Type III Hypersensitivity for you, Pritam:
Type III Hypersensitivity - Immune Complex Mediated
Basic Definition
Type III hypersensitivity is caused by the deposition of antigen-antibody (immune) complexes in tissues and vessel walls, leading to complement activation and neutrophil-mediated tissue injury.
- Antibody class involved: IgG (primarily) and IgM
- Not cell-mediated - it is purely antibody + complement driven
Pathogenesis - 3 Sequential Phases
(This is the classic exam sequence from Robbins)
Phase 1 - Formation of Immune Complexes
- Antigen enters the body → stimulates B cells → plasma cells secrete IgG antibodies (~1 week later)
- Antibodies bind circulating antigen → form antigen-antibody (immune) complexes in the blood
Phase 2 - Deposition of Immune Complexes
- Complexes circulate and deposit in vessel walls (or are formed in situ at sites of "planted" antigen)
- Most pathogenic complexes: medium-sized, formed under slight antigen excess
- Preferred deposition sites: kidney (glomeruli), joints, skin, blood vessels - organs where blood is filtered at high pressure
Phase 3 - Inflammation and Tissue Injury
- Deposited complexes activate complement (C3a, C5a = anaphylatoxins)
- C5a is a potent chemoattractant - recruits neutrophils
- Neutrophils try to phagocytose the complexes but cannot (they are fixed in vessel walls) → "frustrated phagocytosis"
- Neutrophils release lysosomal enzymes and reactive oxygen species → tissue destruction
- Platelet aggregation → microthrombi → further ischemia
- Result: Fibrinoid necrosis of vessel walls (smudgy eosinophilic material = necrotic tissue + immune complexes + complement + plasma proteins)
Clinical Features (appear ~10 days after antigen exposure)
- Fever
- Urticaria (hives)
- Joint pain (arthralgia/arthritis)
- Lymph node enlargement
- Proteinuria (glomerular damage)
Important Lab Finding
- Serum C3 levels fall during active disease (complement is consumed)
- Immunofluorescence of kidney biopsy: granular deposits of immunoglobulin + complement = "lumpy-bumpy" pattern
- Electron microscopy: electron-dense deposits along glomerular basement membrane (subendothelial/subepithelial)
Two Forms - HIGH YIELD
| Feature | Systemic Immune Complex Disease | Local (Arthus Reaction) |
|---|---|---|
| Prototype | Serum sickness | Arthus reaction |
| Antigen source | Circulating foreign proteins | Injected intracutaneously into sensitized individual |
| Mechanism | Complexes form in blood, deposit in vessels | Complexes form locally in vessel walls |
| Lesion | Systemic vasculitis, nephritis, arthritis | Localized skin necrosis |
| Time course | ~10 days after first exposure | Hours after re-exposure |
Classic Examples - Must Know for Exams
| Disease | Antigen Involved | Main Manifestation |
|---|---|---|
| SLE | Nuclear antigens (dsDNA, histones) | Nephritis, skin, arthritis |
| Post-streptococcal GN | Streptococcal cell wall antigens | Nephritis |
| Serum sickness | Foreign serum protein (e.g., horse antithymocyte globulin) | Vasculitis, arthritis, nephritis |
| Polyarteritis nodosa | Hepatitis B surface antigen | Systemic vasculitis |
| Reactive arthritis | Bacterial antigens (e.g., Yersinia) | Acute arthritis |
| Arthus reaction | Foreign proteins (experimental) | Cutaneous vasculitis/necrosis |
Comparison of All 4 Hypersensitivity Types - Quick Recap
| Type | Name | Antibody/Cell | Key Molecule | Example |
|---|---|---|---|---|
| I | Anaphylactic | IgE | Mast cells, histamine | Asthma, anaphylaxis |
| II | Cytotoxic | IgG, IgM | Complement/phagocytes | Hemolytic disease, Myasthenia gravis |
| III | Immune Complex | IgG, IgM | Complement + neutrophils | SLE, serum sickness, post-strep GN |
| IV | Delayed (DTH) | None (T cells) | CD4+/CD8+ T cells | TB, contact dermatitis, transplant rejection |
Exam Memory Tips
- "Lumpy-bumpy" = Type III (granular IF pattern in kidney)
- "Linear" = Type II (anti-GBM antibodies in Goodpasture)
- Complement consumption (↓C3) = active Type III disease
- Serum sickness = prototype systemic; Arthus = prototype local
- Medium-sized complexes in slight antigen excess = most pathogenic
Sources: Robbins, Cotran & Kumar - Pathologic Basis of Disease (10th ed.); Robbins & Kumar Basic Pathology
Do you want me to go deeper into any specific aspect - like SLE as a Type III disease, the complement pathway in detail, or the comparison with Type II hypersensitivity? I can also give you MCQs to test yourself!
Short note on Methotrexate
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I have all the information needed. Here is your complete short note on Methotrexate, exam-ready:
Short Note: Methotrexate (MTX)
Drug Class
Antimetabolite / Folate Antagonist - belongs to the DMARD (Disease-Modifying Anti-Rheumatic Drug) category and is also used as a cytotoxic/anticancer agent.
Mechanism of Action
MTX is structurally similar to folic acid. It enters cells via active transport and inhibits dihydrofolate reductase (DHFR) - the enzyme that converts:
Folic acid (FH2) → Tetrahydrofolate (FH4)
- Without FH4, there is no N5,N10-methylene-FH4 available
- This blocks synthesis of: dTMP (thymidine), purines (adenine, guanine), and amino acids (methionine, serine)
- Net result: DNA and RNA synthesis is halted - affecting rapidly dividing cells most
- Cell cycle specific: S phase
- At low (rheumatic) doses, MTX also inhibits AICAR transformylase → accumulation of extracellular adenosine → potent anti-inflammatory effect (suppresses neutrophils, macrophages, lymphocytes)
- MTX is polyglutamated inside cells - retained for prolonged periods = prolonged effect
Pharmacokinetics
| Parameter | Detail |
|---|---|
| Routes | Oral, IV, IM, intrathecal (IT) |
| Oral bioavailability | ~70% (variable at higher doses) |
| Distribution | Intestinal epithelium, liver, kidney; also ascites/pleural effusions |
| BBB penetration | Poor - given intrathecally for CNS malignancy |
| Metabolism | 7-hydroxylation (less water-soluble metabolite - can cause crystalluria) |
| Excretion | Primarily renal (urine) - up to 30% via bile |
| Half-life | 6-9 hours |
Important: Urine must be kept alkaline + patient well-hydrated to prevent crystalluria and renal toxicity.
Therapeutic Uses
Oncology (High-dose MTX)
- Acute Lymphocytic Leukemia (ALL) - most important
- Burkitt lymphoma (children)
- Breast cancer
- Head and neck carcinomas
- Mycosis fungoides
- CNS prophylaxis (intrathecal route)
Non-oncology / Inflammatory Diseases (Low-dose MTX)
- Rheumatoid Arthritis (RA) - anchor drug, 7.5-25 mg/week
- Psoriasis (severe)
- Psoriatic arthritis
- Crohn disease
- SLE, vasculitis, polymyositis, giant cell arteritis
- Juvenile Idiopathic Arthritis (JIA)
- Ectopic pregnancy (IM injection)
Adverse Effects - HIGH YIELD
| System | Effect |
|---|---|
| Bone marrow | Myelosuppression - leukopenia, thrombocytopenia, anemia |
| GI | Nausea, stomatitis (mucositis), GI ulceration - most common |
| Liver | Hepatotoxicity - elevated LFTs; chronic use → hepatic fibrosis/cirrhosis |
| Lung | Pneumonitis / pulmonary fibrosis - hypersensitivity type |
| Kidney | Crystalluria, renal tubular damage (7-OH metabolite) |
| Skin | Alopecia, photosensitivity |
| Teratogenicity | Absolutely contraindicated in pregnancy (Category X) - causes neural tube defects, abortion |
| CNS | Leukoencephalopathy (with high-dose/IT use) |
Leucovorin Rescue - EXAM FAVOURITE
Why needed? In high-dose MTX therapy, toxicity to normal cells is severe.
Leucovorin (Folinic acid = N5-formyl-FH4):
- Bypasses the DHFR block
- Directly replenishes the folate pool
- Rescues normal rapidly dividing cells (GI mucosa, bone marrow) without reversing MTX effect on tumor (given after a timed delay)
- Also given to reduce stomatitis and GI side effects even at low doses
Resistance Mechanisms
- Gene amplification of DHFR gene (cancer cells make more DHFR to overcome inhibition)
- Reduced drug uptake (transporter mutations)
- Impaired polyglutamation
Drug Interactions
- NSAIDs - reduce renal clearance of MTX → increased toxicity
- Probenecid, penicillins - reduce tubular secretion → MTX accumulation
- Folic acid supplements - reduce toxicity but may slightly reduce efficacy by 10-18%
- Hydroxychloroquine - reduces MTX clearance
Contraindications
- Pregnancy (absolute)
- Renal failure (drug accumulates)
- Significant hepatic disease
- Pre-existing myelosuppression
- Active infection
One-Line Summary for Exam
MTX = Folate antagonist → inhibits DHFR → blocks dTMP/purine synthesis → stops DNA replication (S-phase specific). Uses: ALL, RA, psoriasis, ectopic pregnancy. Toxicity: myelosuppression, mucositis, hepatotoxicity, pneumonitis. Antidote: Leucovorin.
Sources: Lippincott Illustrated Reviews - Pharmacology; Katzung's Basic & Clinical Pharmacology (16th ed.)
Want MCQs on Methotrexate, or should we move to another drug or topic, Pritam?
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