How immunology is tested on Step 1

Questions connect a defect or drug to the immune step it affects.

InnateNeutrophils, macrophages, NK cellsComplement, epithelial barriersToll-like receptors recognize PAMPsMinutes to hoursNo memoryAdaptiveT cells and B cellsAntibodiesAntigen-specific receptorsDays on first exposureMemory: faster second responsevs
Innate vs adaptive. Dendritic cells link the two by carrying antigen to lymph nodes and activating naive T cells.
FeatureMHC IMHC II
Expressed onAll nucleated cellsAntigen-presenting cells (dendritic cells, macrophages, B cells)
PresentsIntracellular (endogenous) peptides, e.g., viralExtracellular (exogenous) peptides
Recognized byCD8 cytotoxic T cellsCD4 helper T cells
LoadingEndoplasmic reticulum via TAPAcidified endosome; invariant chain removed
Partner chainβ2-microglobulinα and β chains

Memory aid: CD8 × MHC I = 8 and CD4 × MHC II = 8.

T cells

Two signals start a response; cytokines shape it.

Naive CD4 T cellTh1IL-12 → IFN-γ;macrophagesTh2IL-4 → IL-4, 5, 13;IgETh17IL-17; neutrophilsTregFOXP3; IL-10, TGF-β
Helper subsets. IFN-γ from Th1 cells inhibits Th2 cells, and IL-4 from Th2 cells inhibits Th1 cells.
  • Signal 1: peptide on MHC binds the T-cell receptor (with CD4 or CD8).
  • Signal 2: B7 (CD80/86) on the APC binds CD28 on the T cell. Without it, the T cell becomes anergic.
  • CD8 cytotoxic T cells kill infected and tumor cells with perforin and granzymes or Fas ligand.
  • NK cells kill cells that lack MHC I (missing self) and mediate antibody-dependent cytotoxicity through CD16.

Antibodies and cytokines

Class switching requires help from CD4 T cells through CD40–CD40 ligand.

AntibodyKey features
IgMFirst made; pentamer; best complement activator; B-cell surface receptor (monomer)
IgGMost abundant; crosses the placenta; opsonizes; fixes complement
IgADimer in secretions and breast milk; protects mucosa
IgEBinds mast cells and basophils; allergy and helminths
IgDB-cell surface receptor; function uncertain

Isotype switching (IgM to IgG, IgA, or IgE) is driven by cytokines and CD40–CD40L signaling.

IL-1, IL-6, TNF-αFever and acute phase response; TNF-α also causesseptic shock and cachexiaIL-8Neutrophil chemotaxisIL-2T-cell growth (target of calcineurin inhibitors)IL-4 and IL-5IgE switching; eosinophils and IgAIFN-γActivates macrophages; increases MHC expressionIL-10, TGF-βAnti-inflammatory, regulatory
Cytokines. Interferon-α and -β are produced by virus-infected cells and induce an antiviral state in neighbors.

Complement

Three pathways converge on C3.

  • Classical pathway: C1 binds antibody (IgG or IgM) on an antigen.
  • Alternative pathway: spontaneous activation on microbial surfaces.
  • Lectin pathway: mannose-binding lectin binds microbial sugars.
  • Functions: C3b opsonization; C3a, C4a, and C5a as anaphylatoxins; C5a neutrophil chemotaxis; C5b–9 membrane attack complex (lyses Neisseria).
  • Regulators: C1 esterase inhibitor (deficiency → hereditary angioedema, avoid ACE inhibitors); DAF (CD55) and CD59 (deficiency → paroxysmal nocturnal hemoglobinuria).

Worked example

Connect a drug to an immune signal.

functions Worked example — after a kidney transplant

A transplant recipient takes tacrolimus. Which T-cell step does the drug block, and what toxicity is classic?

  1. Tacrolimus binds FKBP and inhibits calcineurin.
  2. Without calcineurin, NFAT is not dephosphorylated and cannot enter the nucleus.
  3. IL-2 transcription falls, so T cells do not proliferate after signals 1 and 2.
  4. Like cyclosporine, it is nephrotoxic; it also causes neurotoxicity and hyperglycemia.

Answer. It blocks calcineurin-dependent IL-2 production; nephrotoxicity is the classic toxicity.