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Topic 6

Part of the FMGE study roadmap. Botany topic pathol-006 of Botany.

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Immunopathology

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Immunopathology — Key Facts for FMGE Core concept: Immune system dysfunction leads to hypersensitivity reactions, autoimmune diseases, and immunodeficiency High-yield point: Type I hypersensitivity (IgE-mediated) causes anaphylaxis, asthma, hay fever; Type IV (cell-mediated) causes TB skin test positivity ⚡ Exam tip: Know which hypersensitivity type matches each disease — this is frequently tested in FMGE

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Immunopathology — FMGE Study Guide

Immune System Overview

The immune system has two main branches:

Innate immunity (non-specific):

  • Physical barriers (skin, mucosa)
  • Phagocytic cells (neutrophils, macrophages)
  • NK cells, complement, cytokines
  • Inflammation

Adaptive immunity (specific):

  • Humoral (B cell): Antibody-mediated; targets extracellular pathogens
  • Cellular (T cell): Cell-mediated; targets intracellular pathogens, abnormal cells
  • Memory formation

Hypersensitivity Reactions

Type I - Immediate/Anaphylactic

Mechanism: IgE antibodies bound to mast cells/basophils; allergen cross-links IgE → degranulation Mediators: Histamine, leukotrienes, prostaglandins, cytokines Time course: Minutes (immediate)

Examples:

  • Anaphylaxis (bee sting, penicillin, nuts)
  • Allergic asthma (allergen-induced bronchoconstriction)
  • Allergic rhinitis (hay fever)
  • Urticaria (hives), angioedema
  • Atopic dermatitis (eczema)

Clinical features: Urticaria, bronchospasm, hypotension, GI symptoms Treatment: Epinephrine (adrenaline), antihistamines, corticosteroids

Skin testing: Immediate wheal and flare reaction

Type II - Cytotoxic/Antibody-Mediated

Mechanism: IgG or IgM antibodies directed against cell surface or extracellular matrix antigens Effects:

  • Opsonization and phagocytosis
  • Complement activation
  • ADCC (antibody-dependent cellular cytotoxicity)

Examples:

  • Autoimmune hemolytic anemia (cold antibodies - Mycoplasma; warm - idiopathic)
  • Hemolytic disease of newborn (Rh incompatibility)
  • Transfusion reactions (ABO mismatch)
  • Goodpasture syndrome (anti-GBM antibodies → kidney, lungs)
  • Pemphigus vulgaris (anti-desmosome antibodies → skin blistering)
  • Myasthenia gravis (anti-ACh receptor antibodies → muscle weakness)
  • Graves disease (anti-TSH receptor antibodies → hyperthyroidism)
  • Pernicious anemia (anti-intrinsic factor antibodies → B12 deficiency)

Type III - Immune Complex-Mediated

Mechanism: Antigen-antibody complexes deposit in tissues → complement activation → inflammation

Examples:

  • Serum sickness: Fever, urticaria, arthralgias, proteinuria after receiving foreign serum (antithymocyte globulin)
  • Arthus reaction: Localized vasculitis at site of repeated antigen injection
  • Post-streptococcal glomerulonephritis: Type III hypersensitivity; occurs 1-3 weeks after strep infection
  • SLE: DNA-anti-DNA immune complexes deposit in kidney, joints, skin
  • Polyarteritis nodosa: Hepatitis B antigen-antibody complexes
  • Scleroderma: Anti-centromere, anti-Scl-70 antibodies

Features: Low complement levels (C3, C4 consumed), proteinuria

Type IV - Delayed/Cell-Mediated

Mechanism: T cells (not antibodies) recognize antigen → release cytokines → macrophage activation Time course: 24-72 hours (delayed)

Examples:

  • Tuberculin skin test (PPD/Mantoux): Induration at 48-72 hours indicates prior TB exposure
  • Contact dermatitis: Poison ivy (urushiol), nickel, cosmetics
  • Graft rejection: Acute cellular rejection of transplanted organs
  • TB granuloma formation
  • Crohn disease
  • Jones-Mote hypersensitivity

Skin testing: Tuberculin type reaction - induration without immediate wheal

Comparison of Hypersensitivity Types

TypeAntibody/CellTimeExamples
Type IIgEMinutesAnaphylaxis, asthma, allergic rhinitis
Type IIIgG/IgMHoursHemolytic anemia, Goodpasture, MG, Graves
Type IIIImmune complexesHours-daysPost-streptococcal GN, SLE, serum sickness
Type IVT cellsDaysTB skin test, contact dermatitis, graft rejection

Autoimmune Diseases

Systemic (Multiple organs involved)

Systemic Lupus Erythematosus (SLE):

  • Young women (9:1 female predominance)
  • ANA (antinuclear antibody) - most sensitive screening test
  • Anti-dsDNA - highly specific, correlates with disease activity (lupus nephritis)
  • Anti-Smith - most specific for SLE
  • Malar rash (“butterfly rash” - sparing nasolabial folds)
  • Discoid rash, photosensitivity, oral ulcers
  • Serositis (pleuritis, pericarditis)
  • Renal involvement (glomerulonephritis) - Class III/IV lupus nephritis
  • Neuropsychiatric (seizures, psychosis)
  • Hematologic (cytopenias - hemolytic anemia, thrombocytopenia, leukopenia)

Rheumatoid Arthritis:

  • Symmetric polyarthritis of small joints (PIP, MCP), spares DIP
  • Morning stiffness >30 minutes
  • RF (rheumatoid factor) - anti-IgG Fc antibody (80% of patients)
  • Anti-CCP (cyclic citrullinated peptide) - more specific than RF
  • Pannus: Inflamed synovium erodes cartilage and bone
  • Swan neck deformity, ulnar deviation, Boutonniere deformity

Scleroderma (Systemic Sclerosis):

  • Diffuse cutaneous: Skin thickening, Raynaud’s, lung fibrosis, renal crisis
  • Limited cutaneous: CREST syndrome (Calcinosis, Raynaud’s, Esophageal dysmotility, Sclerodactyly, Telangiectasia)
  • Anti-centromere antibodies: Limited form
  • Anti-Scl-70 (anti-topoisomerase I): Diffuse form

Sjögren syndrome:

  • Dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia)
  • Anti-SSA (Ro) and Anti-SSB (La) antibodies
  • 60% associated with other autoimmune diseases (RA, SLE)

Polymyositis/Dermatomyositis:

  • Proximal muscle weakness
  • Heliotrope rash (purple eyelids), Gottron’s papules (knuckles)
  • Anti-Jo-1 antibodies (anti-synthetase)
  • Elevated CK, aldolase

Organ-Specific Autoimmune Diseases

  • Hashimoto thyroiditis: Anti-thyroglobulin, anti-microsomal antibodies; hypothyroidism
  • Graves disease: TSH receptor-stimulating antibodies; hyperthyroidism
  • Addison disease: Anti-adrenal antibodies
  • Type 1 Diabetes: Anti-GAD, anti-islet cell antibodies; insulin-dependent
  • Pernicious anemia: Anti-intrinsic factor, anti-parietal cell antibodies
  • Primary biliary cholangitis: Anti-mitochondrial antibodies (AMA)

Immunodeficiency Disorders

Primary (Genetic/Congenital)

B-cell deficiencies:

  • X-linked agammaglobulinemia (Bruton): Defective BTK (Bruton tyrosine kinase) → no mature B cells → recurrent bacterial infections after 6 months (when maternal IgG wanes). Low all immunoglobulin classes.
  • Selective IgA deficiency: Most common primary immunodeficiency; often asymptomatic or recurrent sinopulmonary infections

T-cell deficiencies:

  • DiGeorge syndrome: 22q11 deletion → thymic hypoplasia/aplasia, T-cell deficiency; also cardiac defects, hypocalcemia
  • IL-12/IFN-γ axis defects: Susceptible to intracellular pathogens (mycobacteria)

Combined immunodeficiencies:

  • SCID (Severe Combined Immunodeficiency): ADA deficiency, IL-2Rγ chain mutations → both T and B cell defects; death within first year if untreated; requires bone marrow transplant
  • Wiskott-Aldrich syndrome: WAS gene mutation → thrombocytopenia, eczema, recurrent infections; X-linked

Phagocytic defects:

  • Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase → cannot produce superoxide → recurrent infections with catalase-positive organisms (Staphylococcus, Aspergillus, Nocardia, Serratia). Diagnosed by negative nitroblue tetrazolium (NBT) test.
  • Chediak-Higashi syndrome: LYST gene mutation → giant granules in neutrophils, partial albinism, recurrent pyogenic infections

Complement deficiencies:

  • C3 deficiency: Severe recurrent pyogenic infections
  • C1 esterase inhibitor deficiency: Hereditary angioedema (bradykinin-mediated swelling)
  • C5-C9 deficiency: Susceptible to Neisseria infections
  • C1q, C2, C4: Increased risk of SLE-like disease

Secondary (Acquired)

  • HIV/AIDS: CD4+ T cell depletion → opportunistic infections (PCP, toxoplasmosis, cryptococcal meningitis, candidiasis)
  • Malnutrition: Protein-calorie deficiency
  • Malignancy: Lymphomas, leukemias
  • Immunosuppressive drugs: Steroids, chemotherapy, cyclosporine
  • Radiation therapy
  • Splenectomy: Overwhelming post-splenectomy infection (encapsulated organisms)

Transplant Rejection

Hyperacute rejection:

  • Preformed antibodies against donor antigens
  • Minutes to hours after transplant
  • Thrombosis, graft necrosis
  • Must remove graft

Acute rejection:

  • Days to weeks after transplant
  • Cellular (Type IV): CD8+ T cells attack graft
  • Humoral (Type II): Antibodies against donor vessels

Chronic rejection:

  • Months to years
  • Vascular changes, fibrosis, gradual organ dysfunction
  • Major cause of late graft failure

Amyloidosis

Definition: Extracellular deposition of misfolded proteins in β-pleated sheet configuration

Types:

  • AL (Primary): Light chain deposition (plasma cell dyscrasias)
  • AA (Secondary): SAA protein deposition (chronic inflammatory conditions - RA, IBD)
  • Familial: Transthyretin (TTR) mutations
  • Dialysis-associated: β2-microglobulin (long-term hemodialysis)

Clinical features: Nephrotic syndrome, hepatomegaly, cardiomyopathy, macroglossia Diagnosis: Congo red stain with apple-green birefringence under polarized light

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