Immunopathology — Hypersensitivity, Immunodeficiency & Autoimmunity
🟢 Lite — Quick Review (1h–1d)
Rapid summary for last-minute revision before your exam.
Hypersensitivity types:
- Type I (Immediate/Anaphylactic): IgE + mast cells; Examples: Anaphylaxis, asthma, allergic rhinitis, food allergies; Mediator: Histamine, leukotrienes; Test: Skin prick
- Type II (Cytotoxic Antibody): IgG/IgM antibodies against cell surface antigens; Examples: AIHA (warm), ITP, Goodpasture (anti-GBM), Graves’ (anti-TSH receptor), myasthenia gravis (anti-AChR); Mechanism: Opsonization, complement, ADCC
- Type III (Immune Complex): Antigen-antibody complexes deposit in tissues; Examples: SLE (DNA-anti-DNA), serum sickness, poststreptococcal GN, Arthus reaction; Mechanism: Complement activation → neutrophil recruitment → tissue damage
- Type IV (Delayed/Cell-mediated): T cells (CD4+ Th1, CD8+); Examples: TB skin test (PPD), contact dermatitis (poison ivy — nickel), transplant rejection, granulomas; No antibodies involved; Takes 24–72 hours
⚡ Exam tip: Graves’ disease = Type II (IgG antibodies against TSH receptor → stimulate thyroid). Hashimoto thyroiditis = Type IV (T cell mediated). Myasthenia gravis = Type II (anti-AChR antibodies). Both are autoimmune thyroid diseases but different types!
🟡 Standard — Regular Study (2d–2mo)
Standard content for students with a few days to months.
Hypersensitivity Reactions
Type I Hypersensitivity (Immediate/Anaphylactic)
Mechanism:
- Sensitization: First exposure → APC processes allergen → T helper 2 (Th2) cells produce IL-4, IL-5, IL-13 → B cells class switch → IgE production
- Re-exposure: IgE binds FcεRI receptors on mast cells and basophils (surface-bound IgE is pre-formed)
- Cross-linking: Allergen bridges two IgE molecules → mast cell degranulation
- Mediator release:
- Preformed (immediate): Histamine, tryptase, chymase, heparin, proteases
- Newly synthesized (late): Leukotrienes (LTC4, LTD4, LTE4 = SRS-A), prostaglandins (PGD2), cytokines (IL-4, IL-5, IL-13), chemokines
- Eosinophil recruitment: IL-5 (major eosinophil growth factor), eotaxin
Clinical Examples:
- Systemic: Anaphylaxis — IgE-mediated; most dangerous; laryngeal edema, bronchospasm, hypotension, urticaria; Treatment: IM EPINEPHRINE
- Skin: Urticaria (hives), atopic dermatitis (eczema), pruritus
- Respiratory: Allergic rhinitis (hay fever), asthma (extrinsic/allergic asthma)
- Food allergy: GI symptoms, urticaria, anaphylaxis
Diagnosis: Skin prick test (immediate wheal and flare), serum IgE levels, radioallergosorbent test (RAST)
Type II Hypersensitivity (Cytotoxic/Antibody-Mediated)
Mechanisms:
- Opsonization + complement: Antibodies coat RBC → phagocytosis via Fc receptors + complement C3b
- Complement activation → MAC: Cell lysis (rare, but seen in transfusion reactions, hemolytic disease of newborn)
- ADCC (antibody-dependent cellular cytotoxicity): K cells, NK cells destroy antibody-coated cells
- Receptor dysfunction: Agonist antibodies (Graves’ = stimulate TSH receptor); antagonist antibodies (myasthenia gravis = block AChR)
Examples:
| Disease | Antigen/Target | Mechanism |
|---|---|---|
| Autoimmune hemolytic anemia (warm) | RBC surface (Rh, I antigen) | Opsonization + complement; ADCC |
| Autoimmune hemolytic anemia (cold) | RBC (I antigen) + IgM | Complement activation |
| Hemolytic disease of newborn | Rh(D) antigen on fetal RBC | Maternal anti-Rh IgG crosses placenta |
| Transfusion reactions (ABO) | ABO antigens on donor RBC | Preformed IgM → complement activation |
| ITP | Platelet (GPIIb/IIIa) | Opsonization + splenic destruction |
| Autoimmune neutropenia | Neutrophil antigens | Opsonization |
| Goodpasture syndrome | Type IV collagen (α3 chain) in basement membranes of glomerulus and alveolus | Complement activation; anti-GBM disease |
| Graves’ disease | TSH receptor (agonist antibody) | Stimulates thyroid; hyperthyroidism |
| Myasthenia gravis | Acetylcholine receptor (antagonist antibody) | Blocks neuromuscular transmission |
| Pemphigus vulgaris | Desmoglein 3 (cell adhesion) | Acantholysis; blistering |
| Bullous pemphigoid | BP180 and BP230 (hemidesmosomes) | Subepidermal blisters; tense bullae |
Type III Hypersensitivity (Immune Complex-Mediated)
Mechanism:
- Immune complex formation: Antigen-antibody complexes form in circulation (antigen in slight excess)
- Deposition: Complexes deposit in vessel walls, glomeruli, joints, skin
- Complement activation: C3a, C5a → neutrophil recruitment
- Neutrophil activation: Release of lysosomal enzymes → tissue damage
- Platelet aggregation → microthrombi
Examples:
| Disease | Antigen | Clinical Features |
|---|---|---|
| Systemic lupus erythematosus (SLE) | Nuclear antigens (dsDNA, histones, Sm, U1-RNP) | Multisystem; malar rash, arthritis, nephritis, serositis |
| Poststreptococcal glomerulonephritis | Streptococcal antigens (nephritogenic strains) | Nephritic syndrome; latencode= ‘3 weeks’ post-pharyngitis |
| Serum sickness | Foreign proteins (antitoxin, drugs) | Fever, urticaria, arthralgia, lymphadenopathy; 1–2 weeks after exposure |
| Arthus reaction | Various | Localized vasculitis + tissue necrosis at injection site |
| RA (rheumatoid arthritis) | IgG-Fc (rheumatoid factor) | Chronic polyarthritis; pannus formation |
| Meningococcemia | Bacterial antigens | DIC, purpura fulminans |
| HIV-associated nephropathy (CHAN) | HIV antigens | Collapsing glomerulopathy |
Type IV Hypersensitivity (Delayed/Cell-Mediated)
Mechanisms:
- CD4+ Th1 cells: Recognize antigens on APCs → secrete IFN-γ → activate macrophages → granuloma formation
- CD8+ cytotoxic T cells: Directly kill target cells
- T cells do NOT produce antibodies; takes 24–72 hours (delayed)
Examples:
| Disease | Mechanism | Features |
|---|---|---|
| Tuberculin skin test (PPD/Mantoux) | Th1 cells respond to TB antigens | Induration at 48–72 hours |
| Contact dermatitis (poison ivy, nickel, latex) | CD4+ and CD8+ T cells against hapten-protein complex | Pruritic, vesicular rash at contact site |
| Granuloma (TB, leprosy, schistosomiasis) | Th1 → activated macrophages → epithelioid cells + giant cells | Caseating (TB) or non-caseating |
| Acute transplant rejection | CD8+ CTLs kill donor cells; CD4+ Th1 | Hyperacute (<24h), acute (days-weeks), chronic (months-years) |
| Hashimoto thyroiditis | CD4+ Th1 → cytotoxic T cells + cytokines destroy thyroid | Hypothyroidism |
| Type 1 diabetes mellitus | CD8+ CTLs destroy pancreatic β-cells | Hyperglycemia |
Immunodeficiency Disorders
Primary (Congenital) Immunodeficiencies
B-cell Deficiencies (humoral):
- X-linked agammaglobulinemia (XLA / Bruton agammaglobulinemia): BTK gene mutation → no mature B cells → NO immunoglobulins of any class; presents after 6 months (when maternal IgG wanes); recurrent sinopulmonary infections with encapsulated bacteria (S. pneumoniae, H. influenzae); absent tonsils/lymphoid tissue; treat with IVIG
- Common variable immunodeficiency (CVID): Normal B cells but failed plasma cell differentiation → low IgG, IgA, ± IgM; most common symptomatic primary immunodeficiency; presents after age 2 (often in 20s–30s); recurrent infections; autoimmune disease (ITP, AIHA); granulomatous disease; ↑risk of lymphoma
- IgA deficiency: Most common primary immunodeficiency (1:500); selective IgA deficiency → recurrent mucosal infections (respiratory, GI); some asymptomatic; associated with celiac disease; anti-IgA antibodies can cause anaphylaxis if given blood products
T-cell Deficiencies:
- DiGeorge syndrome (22q11.2 deletion): Thymic hypoplasia/aplasia → T-cell deficiency; cardiac defects (conotruncal abnormalities — truncus arteriosus, TETRALOGY OF FALLOT), abnormal facies (low-set ears, hypertelorism, micrognathia), thymic aplasia, cleft palate, hypocalcemia (parathyroid hypoplasia); mnemonic: CATCH-22 (Cardiac, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia, chromosome 22q11.2); Treatment: Thymus transplant for severe cases
Combined B- and T-cell Immunodeficiencies:
- Severe Combined Immunodeficiency (SCID): Adenosine deaminase (ADA) deficiency OR IL-2 receptor γ-chain (X-linked SCID) → NO functional T cells; presents in first 6 months; recurrent infections (bacterial, viral, fungal, opportunistic — Pneumocystis, CMV, Candida); failure to thrive; absent thymus; X-linked SCID is most common form; treat with bone marrow transplant; WARNING: BCG is CONTRAINDICATED in SCID
- Wiskott-Aldrich syndrome (WAS): X-linked; mutation in WASP gene → cytoskeletal dysfunction in hematopoietic cells; triad: Thrombocytopenia (small platelets = microthrombocytopenia), Eczema, Recurrent infections; increased lymphoma risk; treat with bone marrow transplant
- Hyper-IgM syndrome: X-linked (CD40L deficiency) or AR; IgM is made but no class switching → normal/elevated IgM but low IgG, IgA, IgE; recurrent sinopulmonary infections; susceptible to Pneumocystis, Cryptosporidium; CD40 ligand (CD40L) on T cells is required for B cell class switching
Phagocyte Deficiencies:
- Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase → cannot produce reactive oxygen species → recurrent infections with catalase-positive organisms (S. aureus, Aspergillus, Serratia, Nocardia, Burkholderia cepacia — PLACESS); granuloma formation; NBT test negative (no respiratory burst); DHR flow cytometry (more sensitive); treat with IFN-γ; prophylactic antibiotics
- Leukocyte Adhesion Deficiency (LAD): CD18 (β2 integrin) mutation → neutrophils can’t adhere → delayed umbilical cord separation (>30 days), recurrent infections without pus; neutrophil counts are very high (leukocytosis) but cells can’t reach tissues; treat with bone marrow transplant
Secondary (Acquired) Immunodeficiencies
- HIV/AIDS: CD4+ T cell depletion → opportunistic infections, malignancies
- Malnutrition: Protein-energy malnutrition → impaired cell-mediated immunity
- Malignancy: Lymphoma, leukemia → impaired immunity
- Immunosuppressive drugs: Steroids (impair phagocytes, T cells), chemotherapy, calcineurin inhibitors
- Chronic infections: TB, leprosy → impaired T cell responses
- Splenectomy: Impaired opsonization of encapsulated bacteria
Autoimmunity
General Features
- Female predominance (3:1 to 10:1); female immune system is more robust → more autoantibodies
- Multiple autoimmune diseases can co-exist in same patient (autoimmune polyendocrine syndromes)
- Molecular mimicry: Microbes share epitopes with self → immune response against microbe cross-reacts with self
- Loss of self-tolerance: Failure of central tolerance (thymic deletion of autoreactive T cells) or peripheral tolerance (Treg failure, failed anergy)
Key Autoimmune Diseases and Their Markers
| Disease | Key Autoantibody | Target | Clinical Features |
|---|---|---|---|
| SLE | ANA (anti-dsDNA, anti-Sm) | Nuclear antigens | Malar rash, arthritis, nephritis, serositis, hematologic, CNS |
| Rheumatoid arthritis | Anti-CCP (cyclic citrullinated peptide) | Citrullinated proteins | Symmetric polyarthritis, rheumatoid nodules, pannus |
| Sjögren syndrome | Anti-SS-A (Ro), Anti-SS-B (La) | Salivary/lacrimal glands | Dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia) |
| Graves’ disease | TSI (thyroid-stimulating immunoglobulin) | TSH receptor | Hyperthyroidism, ophthalmopathy, pretibial myxedema |
| Hashimoto thyroiditis | Anti-TPO, Anti-thyroglobulin | Thyroid peroxidase, thyroglobulin | Hypothyroidism, goiter |
| Myasthenia gravis | Anti-AChR, Anti-MuSK | Acetylcholine receptor | Fatigable weakness, ptosis, diplopia; Resolved by edrophonium test |
| Guillain-Barré syndrome | Anti-ganglioside antibodies (Anti-GQ1b) | Peripheral nerve gangliosides | Ascending paralysis, areflexia; post-infectious (Campylobacter) |
| Goodpasture syndrome | Anti-GBM | Type IV collagen (α3) | Pulmonary hemorrhage + rapidly progressive glomerulonephritis |
| Pemphigus vulgaris | Anti-desmoglein 3 | Desmosomes | Flaccid bullae, oral ulcers, positive Nikolsky sign |
| Bullous pemphigoid | Anti-BP180, Anti-BP230 | Hemidesmosomes | Tense bullae, negative Nikolsky sign |
HLA Associations
| HLA | Associated Disease |
|---|---|
| DR3 | Type 1 DM, SLE, Graves’, Hashimoto’s, Addison’s |
| DR4 | Rheumatoid arthritis, Type 1 DM |
| B27 | Ankylosing spondylitis, Reactive arthritis (Reiter’s), Psoriatic arthritis, IBD-associated arthritis |
| DR2 | Multiple sclerosis, narcolepsy, Goodpasture, SLE |
| DQ2/DQ8 | Celiac disease |
| B51 | Behçet disease |
Transplant Immunology
Types of Rejection
| Type | Time | Mechanism | Histology |
|---|---|---|---|
| Hyperacute rejection | Minutes to hours | Preformed antibodies (against ABO or preformed anti-HLA) | Thrombosis, ischemia, necrosis |
| Acute rejection | Days to weeks | T cell-mediated (cellular) + antibody-mediated (humoral) | Lymphocytic infiltrate, vasculitis |
| Chronic rejection | Months to years | Both cellular and humoral; fibrosis and vascular changes | Vascular thickening (“transplant vasculopathy”), fibrosis |
| Graft-versus-host disease (GVHD) | After bone marrow transplant | Donor T cells attack recipient tissues | Skin (rash), liver (jaundice, elevated LFTs), GI (diarrhea) |
🔴 Extended — Deep Study (3mo+)
Comprehensive coverage for students on a longer study timeline.
Anaphylaxis
- Most severe Type I reaction; systemic mast cell and basophil degranulation
- Common causes: Foods (peanuts, shellfish, tree nuts), drugs (penicillin, NSAIDs), insect stings (bee venom), latex
- Clinical: Urticaria, angioedema, laryngeal edema, bronchospasm, hypotension, GI symptoms (cramping, vomiting)
- Treatment: IM EPINEPHRINE (0.3–0.5 mg of 1:1000 in anterolateral thigh); airway, breathing, circulation; antihistamines, corticosteroids (adjuncts); observation for biphasic reaction (recurrence 8–12 hours later)
Systemic Lupus Erythematosus (SLE)
- Prototypical systemic autoimmune disease; ANA positive in >95%
- Pathogenesis: Loss of self-tolerance → autoantibodies against nuclear antigens → immune complex deposition → tissue damage
- Classification criteria (SLICC): ≥4 criteria (clinical + immunological) or lupus nephritis with ANA/anti-dsDNA
- Key antibodies:
- ANA (sensitive but not specific) = screening test
- Anti-dsDNA (specific for SLE; correlates with nephritis)
- Anti-Sm (specific for SLE; not sensitive)
- Anti-histone (drug-induced lupus)
- Anti-U1 RNP (mixed connective tissue disease)
- Lupus anticoagulant, anticardiolipin, anti-β2 GPI (antiphospholipid syndrome — causes thrombosis, miscarriages)
- Clinical: Malar rash (spares nasolabial folds; photosensitive), discoid rash, oral ulcers, arthritis (non-erosive, Jaccoud’s), serositis (pleuritis, pericarditis), nephritis (wire-loop glomerulonephritis), CNS lupus (seizures, psychosis), hematologic (cytopenias)
- Treatment: NSAIDs, hydroxychloroquine (mainstay), corticosteroids, immunosuppressants (azathioprine, mycophenolate, cyclophosphamide, rituximab)
Key NEET PG Pearls
- Type I: IgE + mast cells + histamine → immediate (minutes); anaphylaxis, asthma, allergic rhinitis
- Type II: IgG/IgM antibodies against cell surface; Graves’ = anti-TSH receptor (agonist); Myasthenia gravis = anti-AChR (antagonist); Goodpasture = anti-GBM
- Type III: Immune complex deposition; SLE = anti-dsDNA; poststreptococcal GN; serum sickness
- Type IV: T cell mediated; 24–72 hour delay; TB skin test, contact dermatitis, transplant rejection, Hashimoto’s
- Graves’ disease: Type II (antibody); Hashimoto thyroiditis: Type IV (T cell); both are autoimmune thyroid diseases
- SCID: Most severe combined immunodeficiency; presents <6 months; absent thymus; BCG contraindicated; treat with bone marrow transplant
- DiGeorge syndrome: 22q11.2 deletion; CATCH-22; thymic aplasia → T-cell deficiency; conotruncal cardiac defects
- CGD: NADPH oxidase defect → catalase-positive organisms; NBT test negative; DHR flow cytometry diagnostic
- X-linked agammaglobulinemia: BTK mutation → NO B cells → NO antibodies; presents after maternal IgG wanes (>6 months)
- HLA associations: B27 → ankylosing spondylitis; DR4 → RA; DR3 → DM type 1, SLE; DQ2/DQ8 → celiac disease
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