Why do CD8+ T cells target the skin in a patient with an allergy to amoxicillin (amoxicillin) after exposure to amoxicillin?

From the Guidelines

Exposure to amoxicillin in someone with an amoxicillin allergy can lead to CD8+ T cells targeting the skin due to a specific type of delayed hypersensitivity reaction, as the skin has a high density of immune cells and amoxicillin can accumulate in skin tissues, making it a primary site for immune surveillance. When amoxicillin binds to proteins in the body, it creates drug-protein complexes that are recognized as foreign by the immune system 1. In allergic individuals, these complexes are processed by antigen-presenting cells and presented to CD8+ T cells, which become activated and target the skin specifically. The skin is particularly vulnerable because it serves as an interface between the body and the environment, making it a primary site for immune surveillance.

Some key points to consider include:

• The skin test has a negative predictive value approaching 100%, and patients who do not react to skin prick tests (SPTs) or intradermal tests (IDTs) are unlikely to have a severe immediate reaction 1.
• The positive predictive value of skin tests is generally accepted to be <50%, and the interpretation of a positive skin test is less well defined 1.
• The British Society for Allergy and Clinical Immunology recommends testing patients against PPL, MDM, amoxicillin, and the index penicillin if known, and penicillin G (benzylpenicillin) if this is not contained in the PPL/MDM reagent kits 1.
• The drug-modified proteins in skin cells become targets for cytotoxic CD8+ T cells, which release inflammatory mediators and directly kill cells displaying these modified proteins, resulting in the characteristic skin manifestations of drug allergies such as rashes, hives, or more severe reactions like Stevens-Johnson syndrome.

The skin-directed immune response occurs because the drug-protein complexes are most abundant in skin tissues and because skin-resident immune cells are particularly efficient at presenting these antigens to T cells. This is supported by the fact that skin tests for penicillin have a high negative predictive value, and patients who do not react to SPT or IDT are unlikely to have a severe immediate reaction 1.

From the FDA Drug Label

5. 2 Severe Cutaneous Adverse Reactions

Amoxicillin may cause severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) If patients develop skin rash they should be monitored closely, and amoxicillin discontinued if lesions progress.

The skin is targeted because severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are known to occur with amoxicillin use, especially in patients with a history of penicillin hypersensitivity.

• CD8+ T cells are involved in the pathogenesis of these reactions, as they play a key role in the immune response to drugs, including amoxicillin.
• The exact mechanism of why the skin is targeted is not explicitly stated in the label, but it is likely due to the immune system's response to the drug, which can lead to an overactive immune response and tissue damage in the skin 2.

From the Research

Mechanism of CD8+ T cells targeting the skin

• The study 3 found that CD8+ T cells mediate skin allergy to amoxicillin in a mouse model, where amox-specific CD8+ T cells were recruited to the skin upon challenge.
• The recruitment of CD8+ T cells to the skin is likely due to the presentation of amoxicillin-containing epitopes by major histocompatibility complex (MHC) class I molecules, as suggested by the study 4.
• The study 4 also found that T-cell recognition of amoxicillin is HLA-DR restricted and does not require antigen processing, which may contribute to the targeting of CD8+ T cells to the skin.

Why the skin is targeted in particular

• The skin is a common site for delayed allergic reactions to drugs, including amoxicillin, as noted in the study 3.
• The study 5 reported cases of immediate and non-immediate allergic reactions to amoxicillin, with varied onset of symptoms, including skin reactions.
• The skin's role as a barrier and its exposure to external substances may make it more susceptible to allergic reactions, including those mediated by CD8+ T cells, as discussed in the study 6.

Role of CD8+ T cells in allergic reactions

• The study 3 demonstrated that CD8+ T cells are effectors of the allergic skin reaction to amoxicillin, and that depleting anti-CD8 mAbs can abrogate the skin inflammatory reaction.
• The study 6 reviewed the role of CD8+ T cells in the pathogenesis of allergic disease, suggesting that changes in CD8+ T-cell function may represent key events in successful T-cell immunotherapy.
• The study 7 found that oral graded challenges to amoxicillin without prior skin testing may be safe for patients with non-life-threatening historical reactions to penicillin, highlighting the importance of understanding the mechanisms of allergic reactions, including the role of CD8+ T cells.