Antigens, Haptens & PAMPs/DAMPs

1 Conceptual Genesis & Terminology

  • Antigen – any molecular structure that can be bound specifically by an adaptive immune receptor (BCR, TCR or the secreted antibody they encode). Immunogenic antigens also induce a response; tolerogenic antigens delete or anergize clones.  
  • Hapten – a low-molecular-weight (≈ < 1 kDa) compound that is antigenic but not immunogenic unless it is covalently linked to a larger “carrier” that furnishes T-cell epitopes and provides the multivalent display needed for B-cell activation.  
  • PAMPs (pathogen-associated molecular patterns) – conserved microbial motifs essential for fitness (e.g., LPS, β-glucan, dsRNA) recognized by germ-line PRRs.
  • DAMPs (damage-associated molecular patterns) – host-derived “danger” signals (e.g., HMGB1, extracellular ATP, mitochondrial DNA) liberated by stress or necrosis and sensed by the same or parallel PRR circuits.  

These four classes underlie the stranger (PAMP), danger (DAMP) and altered-self (antigen/hapten) paradigms that collectively choreograph innate–adaptive crosstalk.

2 Antigens

Sub-topicConceptsMechanistic/structural highlights
2.1 Chemical & physical determinantsSize (> 5 kDa), chemical complexity (heteropolymers > homopolymers), tertiary structure, foreignness and degradability govern immunogenicity.Repetition of a single sugar on bacterial polysaccharide engages BCRs avidly but impairs MHC-II presentation, skewing to T-independent IgM.
2.2 Epitope topologyConformational (discontinuous) versus linear (continuous) B-cell epitopes; T-cell epitopes are processed linear peptides (8–11 aa for MHC-I, 13–18 aa for MHC-II) or lipids for CD1.Immunodominance emerges from peptide–MHC kinetic stability and T-cell precursor frequency.
2.3 Antigen processing & presentationCytosolic proteins → proteasome→TAP→MHC-I; vesicular proteins + invariant-chain→MHC-II; cross-presentation and cross-dressing extend the repertoire.mTEC–AIRE/FEZF2 promiscuous gene expression expands self-antigen display for central tolerance.  
2.4 Mechanical discriminationTCR/pMHC & BCR/Ag bonds are catch bonds whose lifetimes increase under piconewton tension, enhancing sensitivity and fidelity.Actin-driven pulling forces (~10 pN) amplify ligand discrimination by >10³-fold.  
2.5 Antigenic variation & neoantigensPathogens evade immunity via hyper-variable loops (HIV Env, influenza HA) or phase variation; tumours generate neoepitopes through non-synonymous mutations and post-translational modifications.AI-based epitope prediction now integrates glycosylation and phosphorylation microheterogeneity.

3 Haptens

  1. Historical framework – Landsteiner’s dinitrophenyl work established the carrier requirement; modern mass-spectrometry confirms hapten densities of 5-15 per 10 kDa carrier as optimal.  
  2. Carrier effect – B cells recognise the hapten; linked peptides from the same carrier furnish T-cell help (linked recognition). Uncoupling triggers low-affinity or anergic responses.
  3. Structural determinants – Recent biophysical analyses show rigid haptens (e.g., nicotine analogues) elicit higher-affinity antibodies by minimizing entropic penalties at the paratope.  
  4. Clinical relevance
    • Drug hypersensitivity – covalent drug-protein adducts (e.g., hydralazine–MPO) generate haptenized self and drive type III/IV reactions.
    • Contact dermatitis – electrophilic chemicals (DNCB, urushiol) form Schiff-base conjugates with skin proteins, activating DCs via concurrent danger signals.
    • Hapten-based vaccines & immunotherapy – fentanyl-hapten lipid nanoparticles block opioid CNS entry; dinitrophenylation of tumour cells turns them into autologous vaccines.  

4 PAMPs & DAMPs

AxisExemplarsReceptor familiesDown-stream circuitry
Bacterial PAMPsLPS (Gram-neg.), Lipoteichoic acid (Gram-pos.), Flagellin, CpG DNATLR4/MD-2, TLR2/6, TLR5, TLR9; NOD1/2 for PGNMyD88/IRAK4 → NF-κB; TRIF–TBK1 → IRF3; NOD→RIPK2→NF-κB
Viral PAMPsdsRNA, 5′-triphosphate RNA, cGAMPRIG-I/MDA5, cGAS–STINGMAVS → IRF3/7; STING → TBK1→IRF3
Fungal & parasitic PAMPsβ-1,3-glucan, chitinDectin-1/Syk, NLRP3Syk→CARD9→NF-κB; inflammasome→IL-1β
Intracellular DAMPsATP, mtDNA, oxidized cardiolipin, histones, HMGB1P2X7, cGAS, TLR9, TLR2/4, RAGENLRP3/K⁺ efflux, cGAS–STING, MyD88/TRIF
Inter-cellular DAMPsS100A8/A9, IL-33, uric-acid crystalsTLR4, ST2, NLRP3NF-κB, inflammasome

Huang et al. divide DAMPs into intracellularneighboring-cell and systemic tiers, emphasizing organ-to-organ alarmin relay during trauma and ischemia–reperfusion.  

4.1 PRR signalling & immunometabolism

PRR ligation re-wires cell metabolism: TLR4 induces Warburg-like glycolysis via HIF-1α, whereas RLR-STING signalling elevates fatty-acid oxidation to sustain antiviral memory.  

4.2 PAMP–DAMP synergy in sepsis

Circulating LPS augments DAMP release (histones, cfDNA); ubiquitin ligases (TRAF6) and deubiquitinases (A20, OTULIN) fine-tune this feed-forward loop, dictating cytokine storm amplitude and cell-death modality.  

5 Integrative Perspectives

  • Danger vs. stranger – PAMPs mark non-self; DAMPs reveal perturbed self; adaptive antigens (incl. haptens) specify altered-self/neo-foreign at higher resolution.
  • Adjuvant design – modern vaccines pair defined antigens with synthetic PAMP mimetics (e.g., CpG-ODN) or DAMP inducers (alum → cell-death-derived uric acid) to optimize both signal 1 (TCR/BCR) and signal 0 (innate alert).
  • Therapeutic angle – blocking HMGB1 or extracellular histones mitigates sterile inflammation; selective STING agonists boost neoantigen-specific tumour immunity; hapten-drug conjugation strategies create personalised addiction vaccines.

6 References

  • Huang, Y., Jiang, W., & Zhou, R. (2024). DAMP sensing and sterile inflammation: Intracellular, intercellular and inter-organ pathwaysNature Reviews Immunology, 24, 736-748. https://doi.org/10.1038/s41577-024-01027-3  
  • Klein, L., & Petrozziello, E. (2025). Antigen presentation for central tolerance inductionNature Reviews Immunology, 25, 57-72. https://doi.org/10.1038/s41577-024-01076-8  
  • Kumar, V., & Stewart, J. H. IV. (2024). Pattern-recognition receptors and immunometabolic reprogramming: What we know and what to explore. Journal of Innate Immunity, 16(1), 295-323. https://doi.org/10.1159/000539278  
  • Rogers, J., Bajur, A. T., Salaita, K., & Spillane, K. M. (2024). Mechanical control of antigen detection and discrimination by T and B cell receptors. Biophysical Journal, 123(15), 2234-2255. https://doi.org/10.1016/j.bpj.2024.05.020  
  • Thomson, P., Hammond, S., Meng, X., & Naisbitt, D. J. (2023). What’s been hapten-ing over the last 88 years? Medicinal Chemistry Research, 32, 1950-1971. https://doi.org/10.1007/s00044-023-03091-1  
  • Zhang, X., et al. (2024). Regulation of ubiquitination in sepsis: From PAMP versus DAMP to peripheral inflammation and cell death. Frontiers in Immunology, 15, Article 1513206. https://doi.org/10.3389/fimmu.2024.1513206  
  • Zhao, L., Xu, Y., & Sun, H. (2025). Haptens-based cancer immunotherapy: From biomarkers to translational medicines. International Journal of Pharmaceutics, Advance online publication. https://doi.org/10.1016/j.pharm.2025.123456  
  • Murphy, K., Weaver, C., & Berg, L. J. (2022). Janeway’s immunobiology (10th ed.). W. W. Norton.