4.2 Hypersensitivity, Autoimmunity & Immunodeficiency

Hypersensitivity: Same Tools, Wrong Target or Magnitude

Hypersensitivity reactions are immune effector mechanisms that damage host tissues. Gell and Coombs types I–IV remain the CBSE framework; each type is defined by mechanism, not by organ alone.

Type I detail

Sensitization produces allergen-specific IgE that binds high-affinity FcεRI on mast cells. Re-exposure cross-links IgE → intracellular calcium → degranulation (histamine → vasodilation, permeability, bronchospasm) and de novo lipid mediators. Systemic distribution causes anaphylaxis (airway edema, hypotension). Epinephrine is first-line clinically because it reverses mast-cell mediators’ physiologic effects; mechanism questions focus on IgE–FcεRI–mast cell, not drug lists alone.

Type II vs III—bound vs soluble

Type II targets antigen fixed on cells or basement membranes (e.g., anti-GBM in Goodpasture attacking type IV collagen in lung and glomerulus). Type III forms lattices of soluble antigen and antibody that deposit in vessels, joints, and glomeruli, activating complement and recruiting neutrophils. Low-grade chronic complex deposition is a major driver of SLE tissue injury.

Type IV

Haptenized skin proteins presented to memory CD4 cells cause contact dermatitis (nickel, poison ivy urushiol). CD8 cells kill virus-infected or allogeneic cells. Granulomatous inflammation (TB, some fungal disease) is a chronic Type IV pattern with macrophage activation under IFN-γ.

Tolerance and Autoimmunity

Central tolerance deletes or edits strongly self-reactive clones: thymic negative selection of T cells (AIRE-dependent tissue antigen expression in medulla) and bone-marrow editing/deletion of B cells. Peripheral tolerance restrains escapees via anergy (signal 1 without costimulation), Tregs (FoxP3, CTLA-4, IL-10, TGF-β), immune privilege, and activation-induced cell death. Autoimmunity arises when these checkpoints fail in a genetically susceptible host (HLA associations) after environmental triggers (infection, smoking, drugs).

Autoimmune vignette mechanisms

Distinguish receptor-modulating Type II (Graves stimulate, myasthenia block/degrade) from cytotoxic Type II (hemolysis, Goodpasture complement/ADCC). HLA links (e.g., HLA-DR3/DR4 with T1DM and other autoimmunity) illustrate genetic risk without being sole causes.

Primary Immunodeficiency: Cluster by Arm

Approach PIDs by which limb fails and which pathogens dominate, then match the named syndrome.

B-cell / antibody defects

Recurrent sinopulmonary pyogenic bacteria (encapsulated organisms), enteroviral risk with agammaglobulinemia, and poor vaccine antibody responses.

T-cell and combined defects

Viral, fungal, Pneumocystis, and live-vaccine dangers; poor delayed-type hypersensitivity.

Phagocyte defects

Complement defects

Putting Vignettes Together

A CBSE stem might describe a boy with abscesses from Aspergillus and a negative oxidative burst → CGD, not SCID. Another shows linear IgG along GBM with lung hemorrhage → Type II anti-GBM, not Type III granular deposits of SLE. A teenager with recurrent Neisseria and low CH50 focused on terminal components → MAC deficiency. Anaphylaxis after peanut with elevated tryptase → Type I. Contact dermatitis 2 days after nickel → Type IV. Reasoning always starts from mechanism → effector → clinical pattern, not from memorizing orphan disease names alone.

Tolerance failure vignettes often add family HLA risk or a trigger (drug-induced lupus with anti-histone; molecular mimicry in rheumatic fever Type II against cardiac myosin-like epitopes). Secondary immunodeficiencies (HIV CD4 loss, iatrogenic immunosuppression, protein-losing states) can mimic PID patterns and should be considered when onset is late or exposure history fits—but primary named syndromes remain high-yield for classic age-of-onset and organism clusters.