Current Immunology Reviews (Discontinued) - Volume 10, Issue 1, 2014

As developed by the leading experts in the field who contributed this “Thematic Issue” on the immune mechanisms of severe cutaneous reactions to medications, tremendous advances were done in the past 10 years. These theoretical advances suggest that severe drug reactions involve original pathways of immune response. Such findings open new and fascinating fields for research, but also already have some practical impact on the management of these terrible diseases. After more than 50 years of efforts we can reasonably expect that the burden of SCAR will decrease tremendously in the next decade.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions with a high morbidity and mortality. Although these reactions are rare, their medical, social and financial impact is great. Many cases require intensive care treatment in the acute stage of the disease and long lasting sequelaein survivors may occur. The majority of cases are caused by medications, whereas infections, autoimmune diseases and unknown causes may be responsible as well. Risk estimates for medications have been provided by epidemiologic studies, but they are often not reflected in drug dictionaries and textbooks. Investigations have shown that specific medications taken bypatients with a predefined genetic predisposition and certain ethnic origin may lead to SJS/TEN. However, a test to detect such a higher risk is not available for most drugs. Litigations concerning these reactions consume substantial resources, probably far greater than the resources devoted to research that could improve treatment and reduce the risk of these reactions.

Drugs may stimulate the immune system by forming stable new antigenic complexes consisting of the drug or drug metabolite which is covalently bound to a protein or peptide (hapten-carrier complex). Both, B- and T-cell immunity may arise, the latter directed to hapten modified peptides presented by HLA molecules. Beside this immunological stimulation, drugs can also stimulate the immune system through binding by non-covalent bonds to proteins like immune receptors. This so-called “pharmacological interaction with immune receptors” concept (“p-i concept”) may occur with HLA or TCR molecules themselves (p-i HLA or p-i TCR), and not the immunogenic peptide. It is a type of “off-target” activity of the drug on immune receptors, but more complex as various cell types, cell interactions and functionally different T cells are involved. In this review the conditions which lead to activation of T cells by p-i are discussed: important factors for a functional consequence of drug binding is the location of binding (p-i HLA or p-i TCR); the exact site within these immune receptors; the affinity of binding and the finding that p-i HLA can stimulate the immune system like an allo-allele. The p-i concept is able to solve some puzzles of drug hypersensitivity reactions and are a basis to better treat and potentially avoid drug hypersensitivity reactions. Moreover, the p-i concept shows that in contrast to previous beliefs small molecules do interact with immune receptors with functional consequence. But these interactions are not based on “immune recognition”, are at odds with some immunological concepts, but may nevertheless open new possibilities to understand and even treat immune reactions.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions (SCARs) characterized by necrotic changes of the epidermis. Recent studies suggest that skin damage fromSJS and TEN is mediated by cytotoxic granules produced by cytotoxic T-cells. However, the pathogenesis of SJS and TEN is notfully understood. The most severe skin damage from acute graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation is clinically and histopathologically similar to TEN. Therefore, animal models of acute GvHD can reveal details about T-cell-induced SCARs. In this review, the pathogenesis of SJS and TEN is discussed in reference to animal models of keratinocyte-specific skin diseases that are similar to acute GvHD. These models demonstrated that CD8+ cytotoxic T-cells are the essential effector cells of both SJS and TEN, and the loss of suppression by thymus-derived, regulatory T-cells is important for the pathogenesis of TEN. Recently, animal models of SJS and TEN using human samples and drugs were established, providing different aspects of the pathological mechanisms of these diseases.

Cutaneous adverse drug reactions are unpredictable and represent a plethora of skin diseases of varying degrees of severity. Those of most concern are usually referred to as severe cutaneous adverse reactions (SCARs), and include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome or hypersensitivity syndrome (DIHS/HSS), Stevens-Johnson’s syndrome (SJS), and toxic epidermal necrolysis (TEN). All are delayed type IV hypersensitivity reactions in which a T cell-mediated drug-specific immune response is responsible for triggering the disease. Nonetheless, specific T cell subpopulations develop in response to certain environments and produce cytokines that orchestrate the various phenotypes. Tc1, Th1, Th2, Th17, and Treg, among other T cell subpopulations, participate in several SCARs. Immune cells belonging to the classically known as the innate immune system, comprising natural killer cells, monocytes, macrophages and dendritic cells, can also participate in shaping specific immune responses in various clinical entities. Additionally, tissue resident cells including keratinocytes can contribute to epidermal damage by secreting chemokines that attract proinflammatory immunocytes. The final phenotypes in each clinical entity result from the interactions between the cell types and their products. Although the pathophysiology of these reactions is not fully understood, intensive research during the last decade has led to major progress in our understanding of the contribution of certain cell types to the variability of SCAR phenotypes.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug induced eosinophilia and systemic syndrome, also known as drug-induced hypersensitivity syndrome (DRESS/DIHS) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly caused by a myriad of drugs. Although the pathological mechanisms underlying such reactions are not entirely understood, recent studies suggested that many cases of SCARs are specific immune reactions where interactions between human leukocyte antigen (HLA) molecules and certain drugs play a key role in the activation of immune cells (predominantly T lymphocytes) in defined populations. Upon the activation, multiple immunological and cytotoxic signals are triggered to mediate the damages in skin lesions and the subsequent exacerbation of the disease. These danger signals, including inflammatory cytokines, chemokines/chemokine receptors, and cytotoxic proteins, will be summarized and their pathogenic role in SCARs will be discussed in this review. The knowledge gained from these researches will be beneficial for prompt diagnosis and better treatment for this condition.

Regulatory T cells (Tregs) are essential for limiting immunopathology and maintaining immune homeostasis. They represent a major barrier to aberrant and excessive immune responses to pathogens and allergens in infectious and allergic diseases, respectively. In this review, we describe our current understanding of the immunopathogenic mechanism behind protection against the development and exacerbation of severe drug eruptions, with special emphasis on regulatory T cells (Tregs). In this regard, our previous study demonstrated that the timing of the dysfunction of Tregs could determine the pathological phenotype and sequelae of severe drug eruptions. We also discuss the factors that abrogate Treg function and demonstrate that Mycoplasma pneumoniae is the only pathogen shown to cause a persistent loss of Treg function long after clinical resolution. A loss of Treg function observed at the different stages of severe drug eruptions would be a driving force in the subsequent development of autoimmune disease as long-term sequelae of severe drug eruptions.

Severe cutaneous adverse reactions (SCAR) include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Although rare, SCAR has significant public health impact because of the unpredictability, high mortality and morbidity. The common culprit drugs for SCAR include aromatic antiepileptics (e.g., carbamazepine, phenytoin, lamotrigine, phenobarbital), antibiotics (e.g., sulfamethoxazole, sulfonamides, abacavir, nevirapine, dapsone), NSAIDs, and allopurinol, etc. Increasing studies revealed the strong genetic association between HLA alleles and SCAR. To explain how the interactions of a small chemical compound (drug/metabolite), HLA, TCR, and peptides induce the destructive T cell response in SCAR, three theories are proposed: the “hapten/prohapten” theory, the “pharmacological interaction with immune receptors” (p-i) concept, and the “altered peptide repertoire” model. In this article, we summarize important studies on the immunogenetic association between HLA and SCAR, review the molecular interaction of HLA/TCR/drug/peptide antigens, and discuss the potential pathological mechanistic models of HLA and TCR recognition of medications in SCAR. The accumulated knowledge will help to develop safer drugs, and thus facilitate preclinical immunotoxicity screening. Upon gaining insights into the molecular interaction in the immune synapse composing of the HLA/drug/peptide/TCR, we will advance our understandings to the pathogenesis of the SCAR, and a better strategy may be offered to avoid the occurrence, or improve the treatment of SCAR.