Hypersensitivity & Immunopathology
Usually weeks 3-5 of an immunology & genetics course, after innate and adaptive immunity are builtThis is where immunology stops being wiring diagrams and starts being patients: the same effector mechanisms you just learned — IgE and mast cells, antibody plus complement, immune complexes, T cells — each become a hypersensitivity type when aimed at the wrong target. Exam questions are almost all pattern-matching: a vignette hands you a timing clue, an antibody, or an infection pattern, and you name the type, the deficiency, or the rejection. Learn each mechanism paired to its ONE classic disease and most questions answer themselves.
This guide is the frame. The exam is written from your lectures— drop this topic's slides on the dashboard to get flashcards and board-style questions from your own course, and quiz them all term (one cumulative exam rewards nothing more than early, repeated self-testing). The immunology & genetics playbook has the weekly loop.
AI-authored study notes, not faculty-reviewed and not medical advice. Verify every mechanism against your course materials and faculty; programs differ in emphasis.
High-Yield Pearl
Every hypersensitivity question is timing plus antigen location: minutes = IgE, hours-days on a fixed cell = II, 1-2 weeks with deposits = III, 48-72 hours with no antibody at all = IV.
What the exam asks
Mechanisms, patterns, and what happens when each one fails.
- Type I — immediate (IgE). Allergen cross-links pre-formed IgE on mast cells and basophils, triggering degranulation of histamine and tryptase within minutes; the late phase (roughly 4-12 hours) is driven by leukotrienes, prostaglandins, and eosinophils. Requires prior sensitization — the first exposure makes IgE (Th2, IL-4 class switching), the second exposure fires. Classic diseases: anaphylaxis, allergic rhinitis, atopic asthma, food and drug allergy.
- Type II — antibody-mediated (cytotoxic). IgG or IgM binds a fixed cell-surface or matrix antigen, killing the cell by complement activation, opsonization/phagocytosis, or ADCC — or dysregulating it by binding a receptor. Examples: hemolytic disease of the newborn (anti-Rh IgG crosses the placenta), autoimmune hemolytic anemia, ITP, Goodpasture, and the receptor variants Graves (stimulating antibody) and myasthenia gravis (antibody that blocks and depletes the acetylcholine receptor).
- Type III — immune complex. Soluble antigen-antibody complexes deposit in vessel walls, glomeruli, joints, and skin, fix complement, and recruit neutrophils — the damage is at deposition sites, not the antigen's home tissue. Serum sickness appears 1-2 weeks after antigen exposure with fever, urticaria, arthralgias, and low complement; SLE nephritis, post-streptococcal GN, and the Arthus reaction are the other stems.
- Type IV — delayed, T-cell-mediated. The only antibody-free type: sensitized Th1 cells recruit and activate macrophages via IFN-gamma (or CD8 cells kill directly), peaking at 48-72 hours. Classic examples: the tuberculin (PPD) skin test, contact dermatitis from poison ivy or nickel, granuloma formation in TB, and the insulitis of type 1 diabetes. Not transferable by serum — only by T cells.
- Mechanisms of autoimmunity. Tolerance fails in defined ways: central tolerance defects (AIRE mutation → APECED), Treg failure (FOXP3 mutation → IPEX), release of sequestered antigens (sympathetic ophthalmia, post-vasectomy), and molecular mimicry (streptococcal M protein → rheumatic fever). HLA associations are the tested genetics: B27 with ankylosing spondylitis and reactive arthritis, DR3/DR4 with type 1 diabetes, DR4 with rheumatoid arthritis.
- Primary immunodeficiencies by compartment. The infection pattern names the defect: no B cells/antibody → recurrent sinopulmonary infections with encapsulated bacteria (Bruton XLA — no CD19+ cells, absent tonsils; CVID — low IgG with normal B-cell numbers, presents later); no T cells → viral, fungal, opportunistic infections (DiGeorge 22q11 deletion — thymic aplasia, hypocalcemia, conotruncal defects; SCID — all of it, plus failure to thrive, no live vaccines); phagocyte defect → catalase-positive organisms (CGD — NADPH oxidase, abnormal dihydrorhodamine test); complement defects → C5-C9 gives recurrent Neisseria, C1 esterase inhibitor deficiency gives hereditary angioedema, early components (C1q/C2/C4) give SLE-like disease.
- Transplant rejection by timeline. Hyperacute: minutes, pre-formed recipient antibodies against donor antigens (ABO, HLA), vessel thrombosis on the table — prevented by crossmatch. Acute: weeks to months, primarily recipient T cells against donor MHC (with an antibody-mediated component), the type immunosuppression targets. Chronic: months to years, vascular smooth-muscle proliferation and fibrosis, largely irreversible. Graft-versus-host: donor T cells attack recipient skin, liver, and gut — seen in bone marrow transplant.
- The transfer experiments. A recurring MCQ device: types I-III transfer with serum (antibody-mediated); type IV transfers only with T cells. Hemolytic disease of the newborn is the physiologic version — maternal IgG (the only isotype that crosses the placenta) attacks fetal Rh+ cells, which is why RhoGAM (anti-D IgG) given to the mother prevents sensitization.
Worth drilling · 25 concepts
Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.
- 1Type I hypersensitivity — IgE cross-linking on mast cells, symptoms in minutes
- 2Anaphylaxis — systemic mast-cell degranulation; treat with IM epinephrine first
- 3Tryptase — the serum marker that confirms mast-cell degranulation after the event
- 4Type II hypersensitivity — IgG/IgM against fixed cell-surface antigen
- 5Hemolytic disease of the newborn — maternal anti-Rh IgG crosses the placenta
- 6Graves disease — stimulating antibody against the TSH receptor
- 7Myasthenia gravis — antibody blocks and depletes the acetylcholine receptor
- 8Type III hypersensitivity — soluble immune complexes deposit in vessels and glomeruli
- 9Serum sickness — fever, rash, arthralgias 1-2 weeks after antigen, low complement
- 10Type IV hypersensitivity — T-cell mediated, no antibody, peaks 48-72 hours
- 11PPD skin test — read at 48-72 hours because the mechanism is delayed-type
- 12Contact dermatitis — hapten plus skin protein sensitizes T cells (nickel, poison ivy)
- 13Molecular mimicry — streptococcal M protein triggering rheumatic fever
- 14HLA-B27 — ankylosing spondylitis and reactive arthritis association
- 15Bruton agammaglobulinemia — X-linked BTK defect, no mature B cells, boys after 6 months
- 16CVID — low immunoglobulins with normal B-cell numbers, presents in teens-adults
- 17DiGeorge syndrome — 22q11 deletion: thymic aplasia, hypocalcemia, cardiac defects
- 18SCID — no functional T cells, failure to thrive, no live vaccines ever
- 19Chronic granulomatous disease — NADPH oxidase defect, catalase-positive infections
- 20Dihydrorhodamine test — flow-cytometry assay for the respiratory burst
- 21Hereditary angioedema — C1 esterase inhibitor deficiency, swelling without urticaria
- 22Terminal complement deficiency — C5-C9 loss brings recurrent Neisseria
- 23Hyperacute rejection — pre-formed antibodies clot the graft within minutes
- 24Chronic rejection — vascular fibrosis over months to years, irreversible
- 25Graft-versus-host disease — donor T cells attack recipient skin, liver, gut
Practice it
Active recall over the drill list — flip and claim, match the pairs, produce the answers cold.
Every concept on the drill list, one card at a time — the name up front, the fact that identifies it on the flip. Claim each card honestly and the deck learns what to lead with next time. Progress lives in this browser only.
What everyone misses
The distinctions that lose points on this material, year after year.
- Timing is the answer, not a detail. Students memorize mechanisms but the vignette usually only gives timing: minutes = type I or hyperacute rejection, 1-2 weeks after new antigen = type III serum sickness, 48-72 hours = type IV. If you skip the clock you argue yourself into the wrong type.
- Type II vs type III both use IgG. The isotype doesn't separate them — the antigen's location does. Fixed on a cell or membrane = type II (damage where the antigen lives); soluble in blood = type III (damage wherever complexes deposit, classically glomeruli, joints, skin).
- Graves and myasthenia are hypersensitivity — type II. Receptor-binding antibodies count as type II even when nothing is destroyed; students file them under 'autoimmune, therefore type III.' Stimulating vs blocking the receptor is still antibody against a fixed surface antigen.
- CVID is not Bruton presenting late. Bruton has absent B cells (no CD19+ cells, no tonsils) in infant boys; CVID has normal B-cell numbers that fail to become plasma cells, low IgG, and presents in adolescence or adulthood. B-cell count is the discriminator MCQs hang on.
- Contact dermatitis is NOT IgE allergy. Poison ivy and nickel are type IV — hapten-modified proteins presented to T cells, blistering at 48-72 hours. Choosing 'IgE-mediated' because the stem says 'allergic reaction' is the classic trap; antihistamines barely help and skin-prick testing is the wrong test (patch testing is right).
- GVHD flips the direction of rejection. In solid-organ rejection the recipient attacks the graft; in GVHD the graft's donor T cells attack the recipient. Stems about bone marrow transplant plus rash, diarrhea, and jaundice are asking for donor-versus-host, and the answer choice 'host T cells' is wrong.
- Early vs terminal complement deficiency. They point opposite directions: early components (C1q, C2, C4) → lupus-like disease from poor immune-complex clearance; terminal components (C5-C9) → Neisseria. Students collapse both into 'more infections.'
Clinical correlations
Where this topic shows up again — in clinic, on rotations, and on the boards.
- Anaphylaxis management. Hypotension, wheeze, and urticaria minutes after the sting or drug: IM epinephrine into the anterolateral thigh is first-line, before antihistamines or steroids, because only epinephrine reverses the mast-cell-driven vasodilation and bronchospasm. Watch for the biphasic recurrence hours later.
- RhoGAM prophylaxis. An Rh-negative mother carrying an Rh-positive fetus gets anti-D immune globulin at 28 weeks and after delivery; the passive antibody clears fetal Rh+ cells before her immune system is sensitized, preventing type II hemolysis in the NEXT pregnancy — the first Rh+ baby is usually fine.
- Lupus flare with low complement. A malar rash, arthralgias, and new proteinuria with falling C3/C4 is immune-complex (type III) disease consuming complement in the glomeruli; complement levels and anti-dsDNA titers track disease activity, which is why they're rechecked at every flare.
- The infection pattern is the immunodeficiency workup. Recurrent otitis, sinusitis, and pneumonia with strep and Haemophilus → check quantitative immunoglobulins and B cells; thrush, PJP, and disseminated viral infection → count T cells; recurrent Staph aureus, Serratia, and Aspergillus abscesses → dihydrorhodamine test for CGD; the second episode of meningococcemia → CH50 for terminal complement.
- Live vaccines and T-cell defects. SCID and other severe T-cell deficiencies can be killed by live attenuated vaccines (MMR, varicella, rotavirus, BCG) — the attenuated organism disseminates. Newborn screening (TRECs) exists to find SCID before the first live vaccine and before infections destroy the window for curative stem-cell transplant.
- Recurrent angioedema without hives. Face, lips, airway, or bowel-wall swelling with NO urticaria and no response to antihistamines or epinephrine points to hereditary angioedema — bradykinin-mediated from C1 esterase inhibitor deficiency (low C4 is the screen). ACE inhibitors cause the same picture pharmacologically by blocking bradykinin breakdown.
- Crossmatch before transplant. Hyperacute rejection is prevented, not treated: ABO typing and a lymphocyte crossmatch detect pre-formed anti-donor antibodies before the anastomosis is ever sewn. A graft that mottles and thromboses on the table is the vignette's way of saying the crossmatch was missed.