Drug hypersensitivity and eosinophilia: The decisive role of p-i stimulation.

Eosinophilia is a common finding in drug hypersensitivity reactions (DHR). Its cause is unclear, as neither antigen/allergen-driven inflammation nor clonal expansion is involved. Most delayed-DHRs are due to p-i (pharmacologic interaction of drugs with immune receptors).

Intradermal Testing With COVID-19 mRNA Vaccines Predicts Tolerance.

Background: The newly developed mRNA-based COVID-19 vaccines can provoke anaphylaxis, possibly induced by polyethylene glycol (PEG) contained in the vaccine. The management of persons with a history of PEG allergy or with a suspected allergic reaction after the first dose remains to be defined.

Methods: In this real-life study, we defined two cohorts of individuals: one pre-vaccination including 187 individuals with high-risk profiles for developing anaphylaxis and a second post-vaccination including 87 individuals with suspected allergic reactions after the COVID-19 mRNA vaccine.

Risk Assessment in Drug Hypersensitivity: Detecting Small Molecules Which Outsmart the Immune System.

Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimulations are not antigen-driven, but due to non-covalent drug-protein binding. The drugs may bind to immune receptors like HLA or TCR which elicits a strong T cell reaction (p-i concept), the binding may enhance the affinity of antibodies (enhanced affinity model), or drug binding may occur on soluble proteins which imitate a true antigen (fake antigen model). These novel models of DH could have a major impact on how to perform risk assessments in drug development.

The Activation Pattern of Drug-Reacting T Cells Has an Impact on the Clinical Picture of Hypersensitivity Reactions.

Rationale: β-lactam antibiotics cause drug hypersensitivity reactions (DHR) with various clinical pictures from minor affections like maculopapular exanthema (MPE) and urticaria to severe cutaneous adverse reactions and anaphylaxis. Currently, two different reactivity patterns have been shown to initiate an immune reaction by activating T cells-the hapten concept and the pharmacological interaction with immune receptor (p-i) concept.

Objectives: In this study, the relationship between the reactivity pattern of drug-reacting T cells of drug allergic patients and their clinical picture has been investigated.

Highly specific and reliable in vitro diagnostic analysis of memory T and B lymphocytes in a Swiss cohort of COVID-19 patients.

The SARS-CoV-2 pandemic has claimed many lives and disrupted the quality of life of most individuals. Diagnostic tests not only serve to confirm past exposure but can provide information crucial for guiding healthcare options for patients. Current diagnostic tests for the presence of the SARS-CoV-2 virus or anti-spike protein antibodies do not address the question whether longer lasting cellular immunity is mounted in most individuals.

Massive clonal expansion of polycytotoxic skin and blood CD8 T cells in patients with toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8 T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase.

Drug-related relapses in drug reaction with eosinophilia and systemic symptoms (DRESS).

Background: A drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T cell mediated hypersensitivity reaction. Relapses of symptoms in the recovery phase are frequent and linked to the reduction of the corticosteroid treatment, to viral reactivations or to the exposure to new drugs. Here, we analyzed, how often the exposure to new drugs leads to new sensitization or drug-related relapses without detectable sensitization.

The role of drug, dose, and the tolerance/intolerance of new drugs in multiple drug hypersensitivity syndrome.

Background: Multiple drug hypersensitivity syndrome (MDH) is used to describe persons with a drug hypersensitivity reaction (DHR) to at least two chemically unrelated drugs, confirmed by skin test or in vitro assay.

Methods: Medical records of 25 patients with MDH, tested and confirmed at our allergy division, were retrospectively evaluated in terms of clinical course, involved drugs, daily drug dose, latency periods, test results of skin test and cellular assays, and tolerated drugs in subsequent pharmacological treatments.

Results: Multiple drug hypersensitivity syndrome almost exclusively appeared as a delayed, often severe DHR and started in 14/25 with a drug reaction with eosinophilia and systemic symptoms (DRESS).

Risk of relapse after discontinuation of tocilizumab therapy in giant cell arteritis.

Objective: It is currently unknown how long GCA should be treated with tocilizumab. In the first randomized controlled trial, the biologic agent was stopped after 52 weeks. We therefore studied what proportion of patients relapsed, when relapses occurred and whether factors might predict relapse after tocilizumab treatment discontinuation.

Human "T9" cells are a subpopulation of PPAR-γ T2 cells.

Although T1, T2, and T17 cells are well-defined T cell lineages in humans, it remains debated whether IL-9-producing T cells represent a bona fide "T9" lineage. Our understanding of the cellular characteristics and functions of IL-9-producing T cells in humans is still nascent. Here, we report that human IL-9-producing T cells express the chemokine receptors CCR4 and CCR8, produce high levels of IL-5 and IL-13, and express T2 lineage-associated transcription factors.

Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis.

Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis.

Immuno-monitoring reveals an extended subclinical disease activity in tocilizumab-treated giant cell arteritis.

Objective: Tocilizumab is effective in inducing and maintaining remission of GCA. Despite clinical and serological control of disease, magnetic resonance angiography may show persistence of inflammatory signals of unknown significance in arterial walls. Thus, there is an unmet need for tools to detect subclinical disease activity.

Mechanisms leading to T-cell activation in drug hypersensitivity.

Purpose Of Review: Delayed-type or nonimmediate drug hypersensitivity reactions often involve the activation of drug-specific T cells. As such, the molecular initiating event is an interaction between HLA proteins, HLA-binding peptides and the drug. For many years, the formation of covalently modified drug protein adducts was assumed to be a prerequisite for T-cell activation.

Severe Cutaneous Adverse Drug Reactions: Presentation, Risk Factors, and Management.

Purpose Of Study: Immune-mediated adverse drug reactions occur commonly in clinical practice and include mild, self-limited cutaneous eruptions, IgE-mediated hypersensitivity, and severe cutaneous adverse drug reactions (SCAR). SCARs represent an uncommon but potentially life-threatening form of delayed T cell-mediated reaction. The spectrum of illness ranges from acute generalized exanthematous pustulosis (AGEP) to drug reaction with eosinophilia with systemic symptoms (DRESS), to the most severe form of illness, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Elevated levels of the antimicrobial peptide LL-37 in hidradenitis suppurativa are associated with a Th1/Th17 immune response.

Hidradenitis suppurativa (HS) is an inflammatory skin disease with poorly understood immunopathogenic mechanisms. LL-37 is an antimicrobial peptide, which is transcribed from the CAMP (cathelicidin antimicrobial peptide) gene. Previous reports showed upregulated levels of CAMP and LL-37 in HS lesions, and therefore, the aim of this study was to compare levels of LL-37 in HS to other inflammatory skin diseases and to establish immunomodulatory functions of LL-37 in HS.

A novel recycling mechanism of native IgE-antigen complexes in human B cells facilitates transfer of antigen to dendritic cells for antigen presentation.

Background: IgE-immune complexes (IgE-ICs) have been shown to enhance antibody and T-cell responses in mice by targeting CD23 (FcεRII), the low-affinity receptor for IgE on B cells. In humans, the mechanism by which CD23-expressing cells take up IgE-ICs and process them is not well understood.

Objective: To investigate this question, we compared the fate of IgE-ICs in human B cells and in CD23-expressing monocyte-derived dendritic cells (moDCs) that represent classical antigen-presenting cells and we aimed at studying IgE-dependent antigen presentation in both cell types.

Structural Elements Recognized by Abacavir-Induced T Cells.

Adverse drug reactions are one of the leading causes of morbidity and mortality in health care worldwide. Human leukocyte antigen (HLA) alleles have been strongly associated with drug hypersensitivities, and the causative drugs have been shown to stimulate specific T cells at the sites of autoimmune destruction. The structural elements recognized by drug-specific T cell receptors (TCRs) in vivo are poorly defined.

Interleukin-32 is highly expressed in lesions of hidradenitis suppurativa.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Its immunopathogenic mechanisms are still poorly understood. Previous studies demonstrated that the proinflammatory cytokine interleukin (IL)-32 is implicated in the pathogenesis of other inflammatory diseases.

Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis.

Background: During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells.

Methods: The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls.