# Current perspective of the etiopathogenesis of delayed-type, and T-cell-mediated drug-related skin diseases

Marc Vocanson, Dean J Naisbitt, Jean-François Nicolas

► To cite this version:

Marc Vocanson, Dean J Naisbitt, Jean-François Nicolas. Current perspective of the etiopathogenesis of delayed-type, and T-cell-mediated drug-related skin diseases. Journal of Allergy and Clinical Immunology, 2020, 145 (4), pp.1142 - 1144. 10.1016/j.jaci.2020.01.030. hal-04952186

HAL Id: hal-04952186

https://hal.science/hal-04952186v1

Submitted on 14 Apr 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

Public Domain
# Current perspective of the etiopathogenesis of delayed-type, and T cell-mediated drug related skin diseases

Marc VOCANSON, PhD,<fnref n="1" /> Dean J NAISBITT, PhD,<fnref n="2" /> and Jean-François NICOLAS, MD<fnref n="1" />,<fnref n="3" />

**Affiliations:**

**Correspondence:**

Marc Vocanson, CIRI-INSERM U1111, 21 avenue Tony Garnier 69007 Lyon, France

Tel: +33 437 28 23 48; e-mail address: marc.vocanson@inserm.fr

**Conflict of Interest:** The authors declare that they have no relevant conflict of interest.

**Key words:** Drug hypersensitivity, drug allergy, cytotoxic CD8+ T cells, TCR recognition, genetics, tolerance, danger signals, heterologous immunity

<footnote n="1">¹ CIRI, Centre International de Recherche en Infectiologie; INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; CNRS, UMR 5308, Lyon, France</footnote>

<footnote n="2">² MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, The University of Liverpool, Liverpool, L69 3GE, England</footnote>

<footnote n="3">³ Allergology & Clinical Immunology Department, Lyon-Sud University Hospital, Pierre-Bénite, France</footnote>
Cutaneous adverse drug reactions (cADRs) represent one of the most frequent adverse events induced by drugs, including both classical low-molecular weight chemical drugs or new biological agents (cytokines, monoclonal antibodies, therapeutic proteins).

cADRs are mainly immune-mediated and can be classified based on timing (immediate vs delayed), mechanisms, and pattern of clinical manifestations. cADRs encompass drug hypersensitivity reactions (DHRs), also referred as drug allergies, which comprise several phenotypically distinct clinical entities including B-cell (antibody-mediated, Gell Coombs types I-III) and T-cell (delayed-type, Gell Coombs type IV) mediated reactions. By contrast, most of cADRs are not allergic, but associated with an immunological phenotype due to drug-receptor or drug-enzyme interactions, leading for instance to non-IgE but mas-related G-protein coupled receptor (MRGPRX2)-dependent degranulation of mast cells and urticaria. Those reactions are referred as pseudo-allergic reactions. Finally, a last subset of cADRs includes various autoimmune manifestations induced by the profound immune dysregulation created by certain drug regimens.

In this brief review, we discuss the current perspective and paradigm shifts of cADRs, focusing exclusively on the etiopathogenesis of delayed-type, and T cell-mediated drug-related skin diseases mediated by small chemicals/xenobiotics.

Delayed-type DHRs occur in 1-3% of hospitalized patients exposed to multiple drugs such as anticonvulsants, antibiotics, anti-tuberculosis, non-steroidal anti-inflammatory drugs.... They are mostly benign and present as skin exanthema (such as maculopapular exanthema (MPE) or erythema multiforme (EM)), which last a few days and disappear without sequelae with drug discontinuation. However, a minority of patients develop severe cADRs carrying high mortality and morbidity. These diseases include notably drug-induced hypersensitivity syndrome (DIHS), drug-reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)¹.

## Molecular features of drug-peptide-MHC TCR recognition

Common to the immunopathogenesis of these diseases is the activation of drug-specific cytokine-secreting CD4+ and cytotoxic CD8+ T cells (CTLs), which have been isolated from the blood and the inflamed skin of all DHRs patients¹. Currently, three non-mutually exclusive models describe how a low-molecular weight chemicals/xenobiotics elicit an immune response: (i) the hapten/pro-hapten model, based on the covalent binding of drugs
toward self-proteins, which requires the presentation of drug-modified peptides on MHC
proteins for the priming of specific naïve T cells, as well as for their reactivation in the skin¹;
(ii) the pharmacological interaction (pi) model which postulates that certain offending drugs
bind non-covalently to either the T Cell Receptor (TCR) or MHC protein in a peptide-
independent manner to directly activate T cells²; and (iii) the abacavir altered peptide
repertoire model, in which the drug interferes with certain amino-acids of the MHC peptide
binding groove, changing the chemistry of the peptide binding cleft to promote the
presentation of a new peptide repertoire that elicits a T-cell response³. With the two modes
of non-covalent drug presentation (pi and altered peptide repertoire), drugs selectively but
indifferently (re)activate naïve but also pre-existing memory T-cells. This could explain the
variability of time-to-symptom of certain DHRs, which can occur from as little as 1.5 days (for
antiretroviral abacavir hypersensitivity syndrome) to several weeks after first drug exposure,
as well as the remarkably rapid disappearance of certain symptoms after drug
discontinuation.

However, if our understanding of molecular features of TCR recognition by drugs is
expanding, a major enigmatic issue in the field remains: how sensitization occurs?

Factors predisposing to T cell-mediated drug hypersensitivity

Multiple pharmacogenetic studies have associated increased susceptibility to DHR
with the carriage of specific human leukocyte antigen (HLA) or metabolism risk alleles by
different ethnicity⁴. But intriguingly, most of risk allele positive patients do not develop a
DHR when they are exposed to the culprit drug, indicating that a combination of different
factors are required to prompt the acquisition of sensitization⁴.

One of these factors could be the levels of drug exposure and the accumulation of
MHC drug peptide complexes to activate T cells. Recent works have demonstrated that beta-
lactam antibiotic exposure generate multiple, but relatively comparable numbers of drug
epitopes in the blood of both hypersensitive and tolerant patients⁵, suggesting that if the
level of drug exposure is certainly important, it is not sufficient. Obviously, our technological
capacity to characterize drug epitopes is in its infancy, notably at the skin level, but these
results reinforce the concept of drug tolerance (i.e. drug epitopes fail to induce DHR due to
regulatory mechanisms) rather than ignorance (i.e. drugs generate no / minimal number of
epitopes upon exposure), as a major feature for all drug-exposed patients.
Several past and recent studies have shown that CD4+ regulatory T cells (Tregs) are instrumental to preserve tolerance during drug infusion. Their depletion allows for robust priming of drug-specific or drug-related CTLs both *in vitro*, or in models with subsequent development of skin inflammation⁶. Furthermore, HIV patients who present major Treg defects are particularly predisposed to DHR. Of note, along with Tregs, it is possible that complementary mechanisms such as inhibitory check point receptors (ICRs) further strengthen drug tolerance. The emergence of therapeutic antibodies that target ICRs (like cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1/ligand 1 (PD-1/PD-L1)) has significantly improved outcomes for patients with a variety of malignancies. But they also lead to the appearance of numerous adverse events, including cADRs. Today, it's not known whether these reactions are induced by the revitalization of skin auto-reactive T cells or due to an active sensitization of cancer patients to small chemical co-medications, or both.

*But, how are tolerance mechanisms in hypersensitive patients overwhelmed?*

So far, very few is known about the capacity of drugs to stimulate the innate immune system, and the production of "danger signals", which are key to counter-regulate Tregs and foster the differentiation or reactivation of CTLs. A recent study has shown that blood monocytes from sulfonamide allergic patients are more sensitive to oxidative stress and *in vitro* cytotoxicity than those from drug tolerant patients, suggesting that drug-induced cell damage could form the basis of drug sensitization⁷. This study confirms work reporting of the ability of abacavir and a carbamazepine metabolite, to promote inflammasome activation and IL-1β production in monocytes⁸. But, here, IL-1b secretion was secondary to pro-inflammatory priming by damage-associated molecular patterns or Toll-like receptor stimulation. Hence, it is possible that external cues are provided from the patient's underlying pathology and break immune regulation, thus accelerating drug allergy occurrence. Numerous patients suffering from cADRs are treated for infection, cancer or diverse autoimmune manifestations¹, which may provide or amplify the drug-induced innate immune signals required for efficient T cell sensitization.

Finally, another proposed theory to explain patient sensitization is that of heterologous immunity, whereby hypersensitive patients would possess pre-expanded pools of virus (notably from the Herpes viridae family)-specific memory T cells capable of cross-reacting against the altered peptide repertoire created by certain drug exposure ⁹, initiating
rapid and severe diseases. In the same line, a recent study reported that patients with SJS/TEN to carbamazepine displayed robust expansion of drug-specific T cells bearing the same public TCR<sup>10</sup>, suggesting that a bias in the pre-immune TCR repertoire could have supported disease onset in these patients.

The etiopathogenesis of cARDs to small chemicals/xenobiotics is a highly complex molecular and cellular process, which has not delivered all its secrets. Future HLA-controlled, large patient cohort prospective studies, combining in-depth quantification of blood or skin drug-epitopes, extensive immunophenotyping of danger signals or regulatory cues, and longitudinal monitoring of T cell sensitization are now warranted to move the field forward. Only in this way, we will be able to implement early screening strategies aiming to identify compounds with a high likelihood of eliciting cADRs.

**Figure legend:** The main factors, which influence T cell-mediated drug hypersensitivity reactions.** Drug chemistry, HLA or metabolism genotype, and exposure conditions finely tune the formation of T cell epitopes in both tolerant and hypersensitive patients. Three non-mutually exclusive models describe drug complex - T cell receptor (TCR) interactions: (i) the hapten/pro-hapten model, (ii) the pharmacological interaction (pi) model and (iii) the altered peptide repertoire model. Regulatory mechanisms (Tregs, inhibitory check point receptors...) maintain homeostasis regarding drug epitopes in a large majority of exposed patients. We speculate that the danger signals required to circumvent tolerance mechanisms and promote the differentiation of cytotoxic effector cells (CTLs) are provided by drug-induced cell damages, or by external cues due to underlying diseases. The existence of pre-expanded pools of microbe-specific memory T cells cross-reactive for drug epitopes (heterologous immunity), or the existence of biased pre-immune TCR repertoires, could provide another alternative to circumvent tolerance.
References

1. Chen CB, Abe R, Pan RY, Wang CW, Hung SI, Tsai YG, et al. An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity. J Immunol Res 2018; 2018:6431694.

2. Pichler WJ. Immune pathomechanism and classification of drug hypersensitivity. Allergy 2019; 74:1457-71.

3. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M, et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 2012; 486:554-8.

4. Redwood AJ, Pavlos RK, White KD, Phillips EJ. HLAs: Key regulators of T-cell-mediated drug hypersensitivity. HLA 2018; 91:3-16.

5. Meng X, Al-Attar Z, Yaseen FS, Jenkins R, Earnshaw C, Whitaker P, et al. Definition of the Nature and Hapten Threshold of the beta-Lactam Antigen Required for T Cell Activation In Vitro and in Patients. J Immunol 2017; 198:4217-27.

6. Cardone M, Garcia K, Tilahun ME, Boyd LF, Gebreyohannes S, Yano M, et al. A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity. J Clin Invest 2018; 128:2819-32.

7. Elzagallaai AA, Sultan EA, Bend JR, Abuzgaia AM, Loubani E, Rieder MJ. Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides. J Clin Pharmacol 2019.

8. Toksoy A, Sennefelder H, Adam C, Hofmann S, Trautmann A, Goebeler M, et al. Potent NLRP3 Inflammasome Activation by the HIV Reverse Transcriptase Inhibitor Abacavir. J Biol Chem 2017; 292:2805-14.

9. Almeida CA, van Miert P, O'Driscoll K, Zoet YM, Chopra A, Witt C, et al. Virus-specific T-cell clonotypes might contribute to drug hypersensitivity reactions through heterologous immunity. J Allergy Clin Immunol 2019; 144:608-11 e4.

10. Pan RY, Chu MT, Wang CW, Lee YS, Lemonnier F, Michels AW, et al. Identification of drug-specific public TCR driving severe cutaneous adverse reactions. Nat Commun 2019; 10:3569.
<figure><img src="image_1.png" /></figure>

<figure><img src="image_2.png" /></figure>

## Genetics

MHC molecules (HLA-B*57:01, HLA-B*15:02...)

Metabolism (CYP2C9*3)

## Exposure conditions

Calibrated to reach max plasma levels in all individuals

<figure><img src="image_3.png" /></figure>
**Figure:** The main factors, which influence T cell-mediated drug hypersensitivity reactions. Drug chemistry, HLA or metabolism genotype, and exposure conditions finely tune the formation of T cell epitopes in both tolerant and hypersensitive patients. Three non-mutually exclusive models describe drug complex - T cell receptor (TCR) interactions: (i) the hapten/pro-hapten model, (ii) the pharmacological interaction (pi) model and (iii) the altered peptide repertoire model. Regulatory mechanisms (Tregs, inhibitory check point receptors...) maintain homeostasis regarding drug epitopes in a large majority of exposed patients. We speculate that the danger signals required to circumvent tolerance mechanisms and promote the differentiation of cytotoxic effector cells (CTLs) are provided by drug-induced cell damages, or by external cues due to underlying diseases (infection, inflammation...). The existence of pre-expanded pools of microbe-specific memory T cells cross-reactive for drug epitopes (heterologous immunity), or the existence of biased pre-immune TCR repertoires, could provide another alternative to circumvent tolerance.