Author: V. Dimov, M.D., Allergist/Immunologist, Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D.; A. Bewtra, M.B.B.S., Professor, Creighton University Division of Allergy & Immunology
Recognition of drugs by the immune system
Karl Landsteiner first proposed that multivalency is essential for immune responses to foreign substances.
Drug macromolecules are large with multiple repeating epitopes.
A small molecule can have multiple recurrences of a single epitope that act as ‘complete’ allergens.
Quaternary ammonium epitopes render drugs such as succinylcholine bivalent and related neuromuscular blockers, as multivalent.
Most drugs are simple in structure have a small molecular weight - most do not qualify as drug allergens.
There are 2 ways in which small chemicals (weight lower than 1kDa) can fulfill the requirement for multivalency:
- direct binding with macromolecules to form multivalent hapten-carrier complexes
- reactive intermediates during drug metabolism
What is hapten?
Hapten is a small molecule which can elicit an immune response only when attached to a large carrier such as a protein. The carrier does not elicit an immune response on its own.
Haptenation is neither complete nor irreversible. For penicillins, less than 0.01% of drug is covalently protein-bound in plasma.
Penicillin binds with macromolecules to form multivalent hapten-carrier complexes. Haptenation results in a sufficient density of drug epitopes and a drug-specific immune response ensues.
The β-lactam ring is unstable and acylates lysine residues in proteins. This results in penicilloyl epitope which is immunodominant in penicillin allergy (major determinant).
Other molecular rearrangements allow β-lactams to haptenate through carboxyl and thiol groups, resulting in less dominant or ‘minor’ determinants.
Minor determinant IgE responses are of major clinical importance because of their association with anaphylaxis, whereas penicilloyl IgE responses are associated with urticaria.
Penicillins, cephalosporins, and carbapenems share a bicyclic nucleus, which conveys variable cross-reactivity.
Cross-reactivity among penicillins is virtually complete.
Cephalosporins are similar to penicillins chemically but individual immune responses are variable. Third-generation cephalosporins (e.g., ceftazidime) are less likely to elicit cross-allergic responses than first-generation cephalosporins.
Carbapenems had a similar degree of cross-reactivity to first-generation cephalosporins in some studies.
Monobactams (prototype: aztreonam) are poorly immunogenic and very weakly cross-reactive with other β-lactams, likely due to the absence of a second nuclear ring structure.
Reactive intermediates during drug metabolism
Simple drugs can be converted into reactive intermediates during drug metabolism. Metabolism occurs in the liver by cytochrome P450-associated enzymes, which can produce protein-reactive intermediates.
Intracellular proteins can be haptenated, resulting in multivalent complex secreted from the cells and processed for both T and B lymphocyte activation.
For example, the acetylation and oxidation metabolism of sulfonamides leads to N4-sulfonamidoyl hapten.
Sulfonamide antimicrobials (sulfamethoxazole (SMX), sulfadiazine, sulfacetamide) differ from other sulfonamide-containing medications by having an aromatic amine at the N4 position and a substituted ring at the N1 position - not found in thiazide diuretics and sulfonylureas. Cross-reactivity between these groups of sulfonamides is very rare.
‘p–i concept’ - ‘pharmacological interaction of drugs with immune receptors’
A chemically inert drug, unable to covalently bind to proteins, can activate the immune system by binding to T cell receptors (TCR).
If the drug fits with into some of the more than 10 x 12 different T cell receptors, a stimulation of T cells may follow.
An MHC-augmented interaction with TCR may enhance the signal.
This monovalent drug-TCR interaction is similar to the interaction of drugs with pharmacological receptors. This is different from recognition of hapten-carrier complexes by TCR.
Direct drug binding to TCR can result in:
- tolerance from inhibitory signals
- partial or full activation
Activation may result in a clinical picture indistinguishable from the multivalent pathway.
Clinical manifestations of the p–i mechanism is a T cell orchestrated inflammation and causes drug exanthems (rashes) and drug-induced hepatitis.
Threshold of T cell activation is lowered by generalized immune stimulation of T cells by:
- systemic viral infection (e.g., EBV, CMV, HHV6)
- human immunodeficiency virus (HIV) infection
- autoimmune diseases
These diseases involve broad stimulation of T cells, high cytokine levels and expression of MHC- and co-stimulatory molecules.
The p–i mechanism does not require biotransformation of an inert drug to a chemically reactive compound. It is independent of the generation of hapten-specific antibody response.
The p–i concept can explain some of the ‘bizarre’ features of drug hypersensitivity:
- Rapid symptoms at the first encounter with the drug, without a sensitization phase. If T cells with many TCR respond to the drug, the reaction may appear rapidly.
- Higher risk of drug hypersensitivity in generalized viral infections, which lower the threshold for T cell reactivity.
- Superantigen-like stimulation, leading to a massive overstimulation
- Preferential involvement of the skin in drug allergy. The skin is a repository for an enormous number of T cells, many of which are considered to be primed memory-effector cells which perform sentinel functions and react rapidly. This explains the diffuse involvement of skin in many drug hypersensitivity reactions.
Factors affecting drug immunogenicity
Even with recurrent high-dose exposures, highly immunogenic drugs do not induce immune response in a majority of patients.
For penicillins, the IgG response rate for the major penicilloyl determinant is only 50% among hospitalized patients.
Allergenic drugs can induce the entire spectrum of immunopathologic reactions.
Gell and Goombs classification of hypersensitivity reactions: ACID
Anaphylaxis, angioedema, asthma, type I
Cytotoxic, antibody-mediated, type II, e.g AIHA, ITP, Graves'
Immune complex disease (CIC), type III, e.g. GN, serum sickness, drug fever
Delayed, cell-mediated, type IV, e.g. contact dermatitis
Type I, IgE-mediated drug reactions may involve anaphylaxis or urticaria. Type I reactions occur early or late in a course of therapy and can persist for weeks or months after drug withdrawal.
Type II cytolytic reactions are to rapidly haptenating drugs such as penicillin.
Type III, drug-specific immune complexes result from high-dose, prolonged therapy. They produce drug fever, serum sickness, and cutaneous vasculitis.
Type IV, contact dermatitis occurs with topically applied drugs. Highly sensitizing drugs such as penicillins are no longer provided in a topical form.
What is serum sickness?
From a historical perspective, the term serum sickness means a self-limited immune complex disease caused by exposure to foreign animal proteins or haptens.
Some proteins and large polypeptide drugs (e.g. insulin) can directly stimulate antibody production. However, most drugs act as haptens, binding to proteins, and then stimulating an allergic reaction.
Gell and Coombs classification of drug hypersensitivity was established before T cell subsets were known.
3 antibody-dependent types of reactions require an involvement of helper T cells.
T cell-meditated immunopathology has been subclassified as types IVa-IVd reactions
This subclassification considers the cytokine production and type of cells:
- monocytes (type IVa)
- eosinophils (type IVb)
- cytotoxic activity of both CD4 and CD8 T cells (type IVc)
- neutrophils (type IVd)
Type IVa (Th1)
Th1 cells activate macrophages by secreting large amounts of interferon-gamma.
Th1 cells drive the production of complement-fixing antibodies involved in type II and III reactions (IgG1, IgG3).
TH1 are co-stimulatory for TNF, IL-12 and CD8 T cell responses.
In vivo correlate is monocyte activation - in PPD or granuloma formation in sarcoidosis.
Th1 cells activate CD8 cells, which might explain the common combination of IVa and IVc reactions (e.g., in contact dermatitis).
Type IVb (Th2)
Th2 cells secrete IL-4, IL13, and IL-5, which promote B cell production of IgE and IgG4, mast cells and eosinophils.
There is a link to type I reactions, as Th2 cells boost IgE production by IL-4/IL-13 secretion.
T cells can act as cytotoxic cells. They emigrate to the tissue and kill tissue cells like hepatocytes or keratinocytes in a perforin/granzyme B and Fas ligand dependent manner.
Cytotoxic T cells play an important role in:
- maculopapular and bullous skin diseases
- neutrophilic inflammations (acute generalized exanthematous pustulosis, AGEP)
- contact dermatitis
Type IVc reactions are important in bullous skin reactions like Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), where activated CD8 T cells kill keratinocytes.
Serum granulysin (level greater than 10 ng/mL) predicts Stevens-Johnson syndrome and toxic epidermal necrolysis and the test takes just 5 minutes. J Am Acad Dermatol. 2011;65:65-68.
T cells coordinate sterile neutrophilic inflammation of the skin, in particular AGEP. In this drug-induced disease, T cells recruit neutrophils via CXCL8 release and prevent their apoptosis via GM-CSF.
Such T cell reactions are also found in Behçet disease and pustular psoriasis.
T cell-meditated drug hypersensitivity subclassified as types IVa-IVd:
IVa - 1 = Th1
IVb - 2 = Th2
IVc = cytotoxic CD8 T cells
Drug Allergy. Middleton's Allergy: Principles and Practice, Mosby; 7 edition (November 19, 2008).
Clinical review: ABC of allergies. Adverse reactions to drugs. BMJ 1998;316:1511-1514.
Severe Cutaneous Adverse Reactions to Drugs. Current Opinion in Allergy and Clinical Immunology. Faith L. Chia; Khai Pang Leong. Published on Medscape, 08/2007.
Multiple choice questions
Chapter 57: Drug Allergy. Allergy and Immunology Review Corner: Chapter 57 of Pediatric Allergy: Principles & Practices, edited by Donald Y.M. Leung, et al.